2025

循环肿瘤DNA指导的局部晚期结肠癌辅助治疗 (11/8/2025)

Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: Phase II/III DYNAMIC-III trial

方法: 在这项多中心, 随机, II/III期试验中，III期结肠癌患者在术后5-6周接受ctDNA检测，并按1:1的比例随机分配至ctDNA指导治疗组或标准治疗组。在ctDNA指导治疗组中，ctDNA阴性患者接受降阶梯治疗，而ctDNA阳性患者接受升级治疗。标准治疗方案由临床医生预先设定。主要终点为ctDNA阴性患者的3年无复发生存期和ctDNA阳性患者的2年无复发生存期。次要终点包括治疗相关住院和ctDNA清除情况。

结果: 在968例可评估患者中，702例（72.5%）ctDNA检测结果为阴性。中位随访时间为47个月，ctDNA阴性患者的复发率显著低于ctDNA阳性患者（3年无复发生存率分别为87%和49%；P < 0.001）。在ctDNA阴性患者中，降阶梯治疗降低了奥沙利铂的使用率（34.8% vs 88.6%）和住院率（8.5% vs 13.2%），但无复发生存率略低于标准治疗（85.3% vs 88.1%），未达到非劣效性界值。在ctDNA阳性患者中，ctDNA负荷越高，复发风险越大（3年无复发生存率在各四分位数间分别为77%和23%；P < 0.001）。升级治疗并未改善疗效（2年无复发生存率分别为51%和61%）。未出现意外毒性。治疗后持续存在的ctDNA预示着预后显著更差（3年无复发生存率分别为14%和79%）。

结论：: ctDNA是一种有力的预后分类指标。ctDNA指导的降阶治疗降低了奥沙利铂的暴露量和不良事件发生率，疗效接近标准治疗水平；而探索性强化化疗并未带来无复发生存获益，提示ctDNA阳性疾病需要新的治疗策略。

Methods: In this multicenter, randomized, phase II/III trial, patients with stage III colon cancer underwent ctDNA testing 5–6 weeks post-surgery and were randomly assigned 1:1 to either the ctDNA-guided therapy group or the standard treatment group. In the ctDNA-guided therapy group, ctDNA-negative patients received de-escalation therapy, while ctDNA-positive patients received escalation therapy. The standard treatment regimen was pre-defined by the clinician. The primary endpoint was 3-year recurrence-free survival in ctDNA-negative patients and 2-year recurrence-free survival in ctDNA-positive patients. Secondary endpoints included treatment-related hospitalizations and ctDNA clearance.

Results: Of the 968 evaluable patients, 702 (72.5%) had negative ctDNA test results. The median follow-up was 47 months. The relapse rate was significantly lower in patients with negative ctDNA than in those with positive ctDNA (3-year relapse-free survival rates were 87% and 49%, respectively; P < 0.001). In patients with negative ctDNA, de-escalation therapy reduced oxaliplatin usage (34.8% vs 88.6%) and hospitalization rates (8.5% vs 13.2%), but the relapse-free survival rate was slightly lower than with standard treatment (85.3% vs 88.1%), not meeting the non-inferiority margin. In patients with positive ctDNA, higher ctDNA burden was associated with a greater risk of relapse (3-year relapse-free survival rates were 77% and 23% across the quartiles, respectively; P < 0.001). Escalaton treatment did not improve efficacy (2-year relapse-free survival rates were 51% and 61%, respectively). No unexpected toxicities were observed. Persistent ctDNA after treatment predicted a significantly worse prognosis (3-year relapse-free survival rates were 14% and 79%, respectively).

Conclusion: ctDNA is a powerful prognostic classifier. ctDNA-guided de-escalation reduced oxaliplatin exposure and the incidence of adverse events, with efficacy approaching standard treatment levels; whereas exploratory intensive chemotherapy did not provide relapse-free survival benefit, suggesting that ctDNA-positive diseases require new treatment strategies.

参考文献 Reference

Jie J et al. Nature Med 2025 ; Oct 20

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糖皮质激素治疗免疫检查点抑制剂引起的炎症性关节炎与癌症预后 (11/2/2025)

Glucocorticoids for inflammatory arthritis due to ICI use and cancer outcomes

根据在2025年美国风湿病学会年会上公布的数据，风湿病专家处方的糖皮质激素剂量用于治疗免疫检查点抑制剂引起的炎症性关节炎，可能不会显著影响癌症预后。

为了探究口服糖皮质激素的使用及其对免疫检查点抑制剂 (ICI) 相关性关节炎（ICI-IA）患者无进展生存期的影响，研究者分析了来自RADIOS（风湿病免疫治疗不良事件观察研究）注册库的数据。RADIOS是一个大型, 前瞻性, 多中心, 全国性的风湿病免疫相关不良事件队列研究。 该分析纳入了206名患者，平均年龄65岁，自2023年2月起入组，接受免疫检查点抑制剂治疗癌症后出现ICI-IA，并随后接受糖皮质激素治疗。研究人员将ICI-IA定义为炎症性关节炎、关节痛或风湿性多肌痛。大多数参与者患有黑色素瘤（32.5%）、肾细胞癌（18.4%）或非小细胞肺癌（11.7%），且处于III期（26.7%）或IV期（58.3%）。 既往患有自身免疫性疾病或因其他免疫相关不良事件使用糖皮质激素的患者被排除在外。研究人员收集了患者的人口统计学信息, 癌症诊断, 癌症治疗, 糖皮质激素使用情况和疾病修饰抗风湿药使用情况。

从ICI-IA诊断到首次服用糖皮质激素的中位时间为24.5天（IQR 3, 63）。 研究人员指出，22.3%的患者出现癌症进展，从开始服用糖皮质激素到疾病进展的中位时间为82.5天（IQR -70, 283）。在本研究中记录的糖皮质激素剂量均低于50毫克，ICI-IA治疗第一个月内泼尼松的中位剂量为15毫克。研究发现，在Kaplan-Meier生存曲线分析中，第一个月的糖皮质激素中位剂量与无进展生存期无关（P = 0.99）。高于和低于中位数的剂量，以及按四分位数划分的剂量，均未发现与无进展生存期恶化有关。在Kaplan-Meier生存曲线分析中，不同剂量的糖皮质激素与无进展生存期之间没有显著差异（P = 0.31），并且所有调整后的Cox回归模型均未显示糖皮质激素剂量与无进展生存期之间存在显著关联。

According to data presented at the 2025 American College of Rheumatology Annual Meeting, the doses of corticosteroids prescribed by rheumatologists to treat inflammatory arthritis caused by immune checkpoint inhibitors may not significantly impact cancer prognosis.

To investigate the use of oral corticosteroids and their impact on progression-free survival in patients with immune checkpoint inhibitor (ICI)-associated arthritis (ICI-IA), researchers analyzed data from the RADIOS (Rheumatology Adverse Events Observation Study) registry. RADIOS is a large, prospective, multicenter, nationwide cohort study of rheumatology-related adverse events. The analysis included 206 patients, with an average age of 65 years, enrolled since February 2023, who developed ICI-IA after receiving immune checkpoint inhibitor therapy for cancer and subsequently received corticosteroid treatment. Researchers defined ICI-IA as inflammatory arthritis, arthralgia, or polymyalgia rheumatica. Most participants had melanoma (32.5%), renal cell carcinoma (18.4%), or non-small cell lung cancer (11.7%), and were in stage III (26.7%) or stage IV (58.3%). Patients with a history of autoimmune disease or corticosteroid use for other immune-related adverse events were excluded. Researchers collected patient demographic information, cancer diagnosis, cancer treatment, corticosteroid use, and disease-modifying antirheumatic drug use.

The median time from ICI-IA diagnosis to the first dose of corticosteroids was 24.5 days (IQR 3, 63). Researchers noted that 22.3% of patients experienced cancer progression, with a median time from the start of corticosteroid treatment to disease progression of 82.5 days (IQR -70, 283). The corticosteroid doses recorded in this study were all less than 50 mg, with a median dose of 15 mg of prednisone in the first month of ICI-IA treatment. The study found that the median corticosteroid dose in the first month was not associated with progression-free survival in Kaplan-Meier survival curve analysis (P = 0.99). Neither doses above nor below the median, nor doses categorized by quartiles, were found to be associated with worsened progression-free survival. In Kaplan-Meier survival curve analysis, there was no significant difference in progression-free survival between different doses of glucocorticoids (P = 0.31), and all adjusted Cox regression models did not show a significant association between glucocorticoid dose and progression-free survival.  

参考文献 Reference

Jannat-Khah D. AM College Rheumat Convergence 2025; Abstr 1730

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长期服用质子泵抑制剂与50岁以下人群的早发性结直肠癌风险增加相关 (11/1/2025)

Long-term PPI use associated with higher risk for early-onset colorectal cancer before age 50

根据在2025年10月美国胃肠病学会年会上公布的研究结果，长期服用质子泵抑制剂（PPI）与50岁以下人群罹患早发性结直肠癌的风险增加独立相关。 研究人员回顾了2016年至2020年美国国家住院样本（NIS）的数据。研究对象年龄在18至49岁之间，主要诊断为结直肠癌。PPI的使用情况通过长期治疗或药物不良反应来确定。 研究人员通过诊断代码识别 PPI 暴露情况，这些代码指示长期使用 (Z79.891) 或不良反应 (T45.4X5A/D)。在控制年龄, 性别, 种族, 肥胖, 糖尿病, 炎症性肠病, 吸烟和医院层面变量后，采用多变量逻辑回归分析评估了 PPI 使用与早发性结直肠癌相关的调整风险。对无结直肠癌风险因素的患者进行了亚组分析。

在 7,140 例 50 岁以下早发性结直肠癌住院患者中，1056 例 (14.8%) 报告有长期 PPI 治疗史。经多变量调整后，PPI 使用者发生早发性结直肠癌的风险比未使用者高 41%（调整后比值比 [aOR] 为 1.41；95% 置信区间 [CI] 为 1.33-1.49；P < 0.001）。在亚组分析中，这种关联仍然显著，尤其是在非炎症性肠病（IBD）患者中（aOR，1.56；95% CI，1.43-1.70）。长期住院期间使用质子泵抑制剂PPI会增加结直肠癌的风险（P趋势<0.01）。

这些结果强调了谨慎使用PPI的必要性，尤其是在年轻人群中。

According to research presented at the 2025 American College of Gastroenterology Annual Meeting in October, long-term use of proton pump inhibitors (PPIs) is independently associated with an increased risk of early-onset colorectal cancer in individuals under 50 years of age. Researchers reviewed data from the 2016-2020 National Inpatient Sample (NIS) in the United States. The study included patients aged 18 to 49 years with a primary diagnosis of colorectal cancer. PPI use was determined through documentation of long-term treatment or adverse drug reactions. PPI exposure was identified through diagnostic codes indicating long-term use (Z79.891) or adverse reactions (T45.4X5A/D). After controlling for age, sex, race, obesity, diabetes, inflammatory bowel disease, smoking, and hospital-level variables, multivariate logistic regression analysis was used to assess the adjusted risk of early-onset colorectal cancer associated with PPI use. A subgroup analysis was performed on patients without colorectal cancer risk factors.

Of the 7,140 hospitalized patients under 50 years of age with early-onset colorectal cancer, 1,056 (14.8%) reported a history of long-term PPI treatment. After multivariate adjustment, PPI users had a 41% higher risk of early-onset colorectal cancer compared to non-users (adjusted odds ratio [aOR], 1.41; 95% confidence interval [CI], 1.33-1.49; P < 0.001). This association remained significant in subgroup analyses, particularly in patients without inflammatory bowel disease (IBD) (aOR, 1.56; 95% CI, 1.43-1.70). Long-term PPI use during hospitalization increased the risk of colorectal cancer (P trend < 0.01).

These results highlight the need for cautious use of PPIs, especially in younger populations.

参考文献 Reference

Sharma A et al. Am J gastroenterology 2025; 120: S129

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奥希替尼联合化疗延长EGFR突变晚期肺癌生存期 (10/25/25)

Osimertinib and chemotherapy prolongs overall survival in EGFR-mutated advanced NSCLC: FLAURA2 trial

方法: 这是一项全球性, 开放标签, 随机化III期研究，纳入了557例既往未接受治疗的局部晚期或转移性非小细胞肺癌 (NSCLC) 患者，携带常见的EGFR突变（外显子19缺失或L858R突变）。中枢神经系统转移但稳定的患者也获准入组。患者按1:1的比例随机分配接受奥希替尼 (80 mg，每日一次) 联合培美曲塞(pemetrexed, 研究者选择的方案为卡铂或顺铂)治疗，每3周1次，最多4个周期；随后接受奥希替尼联合培美曲塞维持治疗，或奥希替尼单药治疗(80 mg，每日一次)。治疗持续至疾病进展、出现不可接受的毒性反应或其他停药标准。最终总生存期分析在57%成熟度时进行。 两组的基线特征均衡。两组中约60%的患者存在EGFR外显子19缺失，约40%的患者在基线时出现脑转移。

结果: 联合治疗组的3年总生存率为63%，而单药治疗组为51%。中位总生存期为 47.5 个月，相对于奥希替尼单药治疗的 37.6 个月（风险比 [HR] = 0.77；P = .02）。联合治疗组的奥希替尼暴露中位持续时间显著延长，达到 30.5 个月，而单药治疗组为 21.2 个月，培美曲塞维持治疗的中位持续时间为 8.3 个月。在后续治疗方面，联合治疗组 69% 的患者在疾病进展后接受了二线治疗，其中最常见的是铂类化疗（44%）。在奥希替尼单药治疗组中，77% 的患者接受了后续治疗，72% 的患者接受了铂类化疗

奥希替尼联合化疗的安全性与既往报告的数据一致，未观察到新的安全性信号，联合治疗中也未发生新的治疗相关死亡。联合治疗组中导致奥希替尼停药的不良事件略高（12% vs 7%），但总体而言仍然较低。联合治疗组中 3 级或更高级别不良事件的发生率更高，主要发生在铂类化疗的诱导阶段。

结论：在 FLAURA2 试验中，对于 EGFR 突变的晚期 NSCLC 患者，奥希替尼联合化疗一线治疗与奥希替尼单药治疗相比，显著改善了总生存期。  

Methods: This global, open-label, randomized, phase III study enrolled 557 patients with previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring common EGFR mutations (exon 19 deletions or L858R mutations). Patients with stable central nervous system metastases were also eligible. Patients were randomly assigned in a 1:1 ratio to receive osimertinib (80 mg once daily) plus pemetrexed (investigator’s choice of carboplatin or cisplatin) every 3 weeks for up to 4 cycles, followed by maintenance osimertinib plus pemetrexed or osimertinib monotherapy (80 mg once daily). Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria. The final overall survival analysis was performed at 57% maturity. Baseline characteristics were well-balanced between the two groups. Approximately 60% of patients in both groups had EGFR exon 19 deletions, and approximately 40% had brain metastases at baseline.

Results: The 3-year overall survival rate was 63% in the combination group and 51% in the osimertinib monotherapy group. Median overall survival was 47.5 months, compared with 37.6 months in the osimertinib monotherapy group (hazard ratio [HR] = 0.77; P = .02). The median duration of osimertinib exposure was significantly prolonged in the combination group, reaching 30.5 months, compared with 21.2 months in the osimertinib monotherapy group, and the median duration of pemetrexed maintenance therapy was 8.3 months. Regarding subsequent treatment, 69% of patients in the combination group received second-line therapy after disease progression, most commonly platinum-based chemotherapy (44%). In the osimertinib monotherapy group, 77% of patients received subsequent therapy, with 72% receiving platinum-based chemotherapy. The safety profile of osimertinib combined with chemotherapy was consistent with previously reported data, with no new safety signals observed and no new treatment-related deaths occurring with the combination therapy. Adverse events leading to osimertinib discontinuation were slightly higher in the combination group (12% vs 7%) but remained low overall. Grade 3 or higher adverse events were more frequent in the combination group, primarily occurring during the induction phase of platinum-based chemotherapy.

Conclusion: In the FLAURA2 trial, first-line osimertinib plus chemotherapy significantly improved overall survival compared with osimertinib monotherapy in patients with advanced NSCLC harboring EGFR mutations.

参考文献 Reference

Planchard D, et al: 2025 World Conference on Lung Cancer. Abstr PL02.04

地塞米松减量方案治疗虚弱新诊断多发性骨髓瘤患者(10/18/2025)

Dexamethasone-sparing regimen in patients with frailty and newly diagnosed multiple myeloma: IFM2017-03 trial

本研究评估了达雷妥尤单抗(daratumumab)联合来那度胺治疗虚弱新诊断多发性骨髓瘤患者的地塞米松减量方案相比于来那度胺联合地塞米松治疗的疗效。

方法: 这项前瞻性, 随机, 开放标签试验(IFM2017-03, NCT03993912)在61个国家骨髓瘤跨组别研究中心开展，纳入了65岁及以上新诊断的多发性骨髓瘤患者。患者按2:1的比例随机分配至两组：一组接受达雷妥尤单抗（1800 mg，皮下注射）联合口服来那度胺（25 mg，每日一次，共21天，28天为一个周期）和地塞米松（20 mg，每周一次）治疗两个周期（地塞米松减量组）；另一组接受来那度胺（25 mg，每日一次）和口服地塞米松（20 mg，每周一次；对照组），主要终点是无进展生存期。在意向治疗人群中评估疗效，并在所有接受至少一剂随机干预的患者中评估安全性。

结果: 从2019年10月18日至2021年7月20日，共筛选了335例患者，其中295例患者被随机分配（200例接受来那度胺联合达雷妥尤单抗治疗，95例接受来那度胺联合地塞米松治疗）。患者中位年龄为81岁（四分位距：77-84岁），其中180例（61%）年龄超过80岁，151例（51%）为女性，144例（49%）为男性。

中位随访时间为46.3个月（四分位距：46.0​​-52.7个月）。地塞米松减量组的中位无进展生存期为53.4个月（95% CI 35.3–未达到），对照组为22.5个月（16.5–39.0）（风险比[HR] 0.51，95% CI 0.37–0.70，p<0.0001）。

最常见的3-5级不良反应为中性粒细胞减少症（地塞米松减量组200例患者中有110例[55%]，对照组95例患者中有23例[24%]）和感染（地塞米松减量组38例[19%]，对照组20例[21%]）。地塞米松减量组126例患者（63%）和对照组66例患者（69%）发生严重不良事件。地塞米松减量组有23例患者（12%）和对照组有12例患者（13%）发生了导致死亡的不良事件，其中分别有4例（2%）和2例（2%）5级治疗中出现的不良事件。

解读: 在IFM2017-03试验中，与来那度胺联合地塞米松治疗相比，来那度胺联合达雷妥尤单抗治疗（地塞米松仅在前2个治疗周期使用）降低了疾病进展或死亡风险，且没有额外的安全隐患。因此，来那度胺联合达雷妥尤单抗治疗可被视为体弱多发性骨髓瘤老年患者的一种治疗选择。

This study evaluated the efficacy of daratumumab combined with lenalidomide in a dexamethasone-sparing regimen compared with lenalidomide plus dexamethasone in patients with newly diagnosed multiple myeloma who were frail.

Methods: This prospective, randomized, open-label trial (IFM2017-03, NCT03993912) was conducted at 61 active Intergroup Francophone of Myeloma centers and enrolled patients 65 years of age and older with newly diagnosed multiple myeloma. Patients were randomly assigned in a 2:1 ratio to receive daratumumab (1800 mg subcutaneously) plus oral lenalidomide (25 mg once daily for 21 days in a 28-day cycle) and dexamethasone (20 mg once weekly) for two cycles (dexamethasone-sparing group); or to receive lenalidomide (25 mg once daily) and oral dexamethasone (20 mg once weekly; control group). The primary endpoint was progression-free survival. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of the randomized intervention.

Results: From October 18, 2019, to July 20, 2021, 335 patients were screened, of whom 295 were randomly assigned (200 to lenalidomide plus daratumumab and 95 to lenalidomide plus dexamethasone). The median age of the patients was 81 years (interquartile range, 77-84 years); 180 (61%) were older than 80 years; 151 (51%) were women, and 144 (49%) were men.

The median follow-up was 46.3 months (interquartile range, 46.0-52.7 months). The median progression-free survival was 53.4 months (95% CI 35.3–not reached) in the dexamthasone-sparing group and 22.5 months (16.5–39.0) in the control group (hazard ratio [HR] 0.51, 95% CI 0.37–0.70, p<0.0001). The most common grade 3–5 adverse reactions were neutropenia (110 [55%] of 200 patients in the dexamthasone-sparing group and 23 [24%] of 95 patients in the control group), and infections (38 [19%] of 200 patients in the dexamthasone-sparing group and 20 [21%] of 95 patients in the control group).

Serious adverse events occurred in 126 patients (63%) in the dexamthasone-sparing group and 66 patients (69%) in the control group. Adverse events leading to death occurred in 23 patients (12%) in the dexamethasone-sparing group and 12 patients (13%) in the control group, including grade 5 treatment-emergent adverse events in 4 (2%) and 2 (2%) patients, respectively.

Interpretation: In the IFM2017-03 trial, treatment with lenalidomide plus daratumumab (dexamethasone only for the first two cycles) reduced the risk of disease progression or death compared with lenalidomide plus dexamethasone, without any additional safety concerns. Therefore, lenalidomide plus daratumumab may be considered a treatment option for frail elderly patients with multiple myeloma.

参考文献 Reference

Manier S et al. Lanct Onc 2025 ; 26 :1323

贝伐单抗联合厄洛替尼治疗遗传性和散发性乳头状肾细胞癌 (10/12/2025)

Bevacizumab and erlotinib in hereditary and sporadic papillary kidney cancer

背景：遗传性平滑肌瘤病和肾细胞癌 (HLRCC) 是一种遗传性疾病，其特征是富马酸水合酶编码基因存在种系致病变异，且罹患乳头状肾细胞癌的风险增加。大多数患者死于疾病进展。

方法：在这项开放标签的 II 期研究中(NCT01130519)，研究者评估了贝伐单抗（每 2 周 10 mg/kg）和厄洛替尼（erlotinib, 每日 150 mg）对晚期 HLRCC 相关或散发性乳头状肾细胞癌患者的疗效。主要终点是总体响应率；次要终点包括无进展生存期和总生存期。

结果：共纳入43例HLRCC相关乳头状肾细胞癌患者和40例散发性乳头状肾细胞癌患者。31例HLRCC相关乳头状肾细胞癌患者（72%；95%置信区间[CI]，57-83）获得确认响应；中位无进展生存期为21.1个月（95% CI，15.6-26.6），中位总生存期为44.6个月（95% CI，32.7-无法估计）。 14例（35%；95% CI，22-51）散发性乳头状肾细胞癌患者确认响应，中位无进展生存期为8.9个月（95% CI，5.5-18.3个月），中位总生存期为18.2个月（95% CI，12.6-29.3个月）。

最常见的治疗相关不良事件为痤疮样皮疹（93%）、腹泻（89%）和蛋白尿（78%）。最常见的3级或以上治疗相关不良事件为高血压（34%）和蛋白尿（17%）。

结论：贝伐单抗联合厄洛替尼治疗HLRCC相关或散发性乳头状肾细胞癌患者表现出抗肿瘤活性。毒性作用已知与该联合治疗相关。

Background: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited disorder characterized by germline pathogenic variants in the gene encoding fumarate hydratase and an increased risk of developing papillary renal cell carcinoma. Most patients die from disease progression.

Methods: In this open-label, phase II study (NCT01130519), investigators evaluated the efficacy of bevacizumab (10 mg/kg every 2 weeks) and erlotinib (150 mg daily) in patients with advanced HLRCC-associated or sporadic papillary renal cell carcinoma. The primary endpoint was overall response rate; secondary endpoints included progression-free survival and overall survival.

Results: A total of 43 patients with HLRCC-associated papillary renal cell carcinoma and 40 patients with sporadic papillary renal cell carcinoma were enrolled. Thirty-one patients (72%; 95% confidence interval [CI], 57-83) with HLRCC-associated papillary renal cell carcinoma had a confirmed response; the median progression-free survival was 21.1 months (95% CI, 15.6-26.6), and the median overall survival was 44.6 months (95% CI, 32.7-not estimable). Fourteen patients (35%; 95% CI, 22-51) with sporadic papillary renal cell carcinoma had a confirmed response, with a median progression-free survival of 8.9 months (95% CI, 5.5-18.3 months) and a median overall survival of 18.2 months (95% CI, 12.6-29.3 months).

The most common treatment-related adverse events were acneiform rash (93%), diarrhea (89%), and proteinuria (78%). The most common grade 3 or higher treatment-related adverse events were hypertension (34%) and proteinuria (17%).

Conclusions: Bevacizumab combined with erlotinib showed antitumor activity in patients with HLRCC-associated or sporadic papillary renal cell carcinoma. Toxicity was known to be associated with this combination therapy.

参考文献 Reference

Srinivasan W et al. N Engl J Med 2025;392:2346

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ADCE-D01 用于治疗软组织肉瘤的临床试验: FDA 授予快速通道资格 (10/11/2025)

Clinical trial using ADCE-D01 for soft tissue sarcoma: Granted fast track designation by FDA

这项研究（ADCElerate1），旨在评估 ADCE-D01 在转移性/不可切除软组织肉瘤中的疗效。它是首创靶向尿激酶型纤溶酶原激活剂受体相关蛋白 (uPARAP) 的抗体-药物偶联物 ，用于治疗软组织肉瘤患者。ADCE-D01 也含有拓扑异构酶 I 抑制剂，已在多种间叶性肿瘤模型（包括与 uPARAP 过表达相关的软组织肉瘤）中显示出临床前抗肿瘤活性。该药物在非人灵长类动物毒理学研究中也表现出临床前耐受性，且未发现 uPARAP 特异性毒性的证据。 目前，它正在 I/II 期 ADCElerate1 临床试验（NCT06797999）中评估其在软组织肉瘤患者中的疗效。

这项首次人体试验是一项多中心, 开放标签, 剂量递增和扩展的 ADCElerate1 试验，正在招募年龄至少 18 岁, 经组织学确诊为转移性和/或不可切除的软组织肉瘤且无法接受根治性治疗的患者，这些患者在转移性/不可切除的情况下接受过 1 至 2 线全身治疗。其他关键纳入标准包括：根据 RECIST 1.1 标准，可测量病灶, ECOG 体能状态评分为 0 或 1 分，以及预期寿命至少 3 个月。研究者排除以下患者：在首次研究给药后 4 周内或 5 个半衰期内接受过全身抗癌治疗；患有原发性脑恶性肿瘤或已知未经治疗的中枢神经系统或软脑膜转移，或症状提示中枢神经系统受累；患有临床显著心血管疾病的患者；急性 HIV 1 或 2 感染者；目前因乙肝导致活动性肝病的患者；以及有特发性肺纤维化, 机化性肺炎, 药物性肺炎, 特发性肺炎病史或有活动性肺炎证据的患者。

所有入组患者均接受 ADCE-D01 单药治疗。该研究的主要终点是确定最大耐受剂量/最大给药剂量和推荐的 II 期剂量；以及安全性和耐受性。关于安全性和耐受性，研究人员正在评估治疗中出现的不良反应的发生率和严重程度，以及不良反应与治疗中断, 剂量减少和治疗终止的相关性。次要终点包括药代动力学, 客观缓解率, 缓解持续时间, 无进展生存期, 临床获益率和缓解时间。 ADCElerate1 试验于 2025 年 6 月开始招募患者，目标剂量递增和剂量扩展阶段招募约 270 名患者。

This study (ADCElerate1) is designed to evaluate ADCE-D01 in metastatic/unresectable soft tissue sarcomas. It is a first-in-class antibody-drug conjugate targeting urokinase-type plasminogen activator receptor-associated protein (uPARAP) for the treatment of patients with soft tissue sarcomas. ADCE-D01, which also contains a topoisomerase I inhibitor, has demonstrated preclinical antitumor activity in various mesenchymal tumor models, including soft tissue sarcomas associated with uPARAP overexpression. The drug also demonstrated preclinical tolerability in nonhuman primate toxicology studies, with no evidence of uPARAP-specific toxicity. It is currently being evaluated in patients with soft tissue sarcomas in the phase I/II ADCElerate1 clinical trial (NCT06797999). This first-in-human trial, a multicenter, open-label, dose-escalation and expansion ADCElerate1 trial, is enrolling patients aged at least 18 years with histologically confirmed metastatic and/or unresectable soft tissue sarcoma who are ineligible for curative therapy and have received one to two prior lines of systemic therapy in the metastatic/unresectable setting. Other key inclusion criteria include measurable disease according to RECIST 1.1, an ECOG performance status of 0 or 1, and a life expectancy of at least three months. Investigators excluded patients who had received systemic anticancer therapy within 4 weeks or 5 half-lives of the first study dose; had a primary brain malignancy or known untreated central nervous system or leptomeningeal metastasis, or symptoms suggestive of central nervous system involvement; had clinically significant cardiovascular disease; had acute HIV-1 or HIV-2 infection; had active liver disease due to hepatitis B; and had a history of or evidence of active pneumonia in idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonia. All enrolled patients received ADCE-D01 monotherapy. The primary endpoints of the study were to determine the maximum tolerated dose/maximum administered dose and the recommended phase II dose, as well as safety and tolerability. Regarding safety and tolerability, researchers are evaluating the incidence and severity of treatment-emergent adverse reactions, as well as their association with treatment interruptions, dose reductions, and discontinuations. Secondary endpoints include pharmacokinetics, objective response rate, duration of response, progression-free survival, clinical benefit rate, and duration of response. The ADCElerate1 trial began recruiting patients in June 2025, with the goal of enrolling approximately 270 patients in the dose-escalation and dose-expansion phases.

参考文献 Reference

https://adcendo.com/adcendo-aps-announces-fda-fast-track-designation-granted-to-adce-d01-for-the-treatment-of-soft-tissue-sarcoma. October 9, 2025.

https://clinicaltrials.gov/study/NCT06797999

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立体定向放射后加用肿瘤治疗场延长脑转移性非小细胞肺癌患者的颅内响应时间 (10/5/2025)

TTFields following SRS prolongs intracranial response in brain metastatic NSCLC

在接受免疫检查点抑制治疗的脑转移性非小细胞肺癌 (NSCLC) 患者中，TTFields 的疗效更佳。

本研究(METIS, NCT02831959) 纳入了NSCLC 脑转移瘤患者，并按 1:1 的比例随机分配，分别接受立体定向放射外科 (SRS)  治疗后联合 150kHz 肿瘤治疗场(TTFields) 治疗或单纯 SRS 治疗。每8周进行一次随访，首次颅内进展后，继续接受颅内电场治疗，或开​​始挽救性治疗。第二次颅内进展后，患者接受挽救性治疗，但可选择在单纯SRS治疗组中交叉至颅内电场治疗组。 研究入组时间为2016年10月至2023年3月，涉及13个国家/地区的78个研究中心。中位随访时间为8.6个月（范围：0.07-85.2个月）。 颅内电场治疗组和对照组患者的中位年龄分别为63.0岁和64.0岁，且大多数患者为男性（59.1% vs 65.8%）。大多数患者有 1 至 4 个脑转移灶（78.5% vs 77.8%）。NSCLC 最常见的病理诊断是腺癌（75.2% vs 78.5%）。 该试验的主要终点是颅内进展时间。次要终点包括神经认知功能衰竭时间、总生存期和放射学响应。探索性终点包括健康相关生活质量和基于独立放射学审查委员会的颅内远处进展时间。

根据研究结果，在SRS 后加用TTFields 可延长脑转移性NSCLC 患者的颅内进展时间。 数据显示，接受联合治疗的患者（n = 149）与接受单纯SRS 治疗的患者（n = 149）相比，分别有 44.3% 和 63.8% 的患者出现颅内进展事件。此外，两组患者 12 个月和 24 个月的颅内进展率分别为 46.9%（95% CI，37.6%-55.6%）和 59.4%（95% CI，50.7%-67.0%），以及 53.6%（95% CI，44.0%-62.3%）和 65.2%（95% CI，56.5%-72.6%）（HR，0.72；95% CI，0.53-0.98；P = 0.039）。这与电场治疗组 28% 的相对风险降低相对应。

进一步的数据显示，两组之间的总生存期和神经认知衰竭时间差异不显著。在 TTFields 组和对照组中，中位总生存期分别为 11.3 个月 (95% CI, 8.6-13.8) vs 10.6 个月 (95% CI, 6.8-14.1; HR, 1.04; 95% CI, 0.76-1.43; P = .763)。此外，两组的神经认知衰竭中位时间分别为 2.0 个月 (95% CI, 1.9-2.1) 和 2.0 个月 (95% CI, 1.9-2.2) (HR, 1.12; 95% CI, 0.72-1.74; P = .607)。另外，两组的放射学响应率没有显著差异；发生率分别为 49.0% (95% CI, 38.6%-59.4%) vs 46.0% (95% CI, 37.0%-55.2%) (P = 0.659)。

联合免疫检查点抑制治疗后，TTFields 在首次颅内进展时间（HR，0.63；95% CI，0.39-1.00；P = 0.049）和远处颅内进展时间（HR，0.41；95% CI，0.21-0.81；P = 0.009）方面的作用更加显著。其他研究结果表明，TTFields 与 SRS 联合治疗不会对健康相关生活质量产生负面影响。 SRS 联合 TTFields 治疗与单独 SRS 治疗的不良反应发生率相似；1/2 级不良反应发生率分别为 28.7% 和 16.5%，3 级或以上不良反应 发生率分别为 32.6% 和 29.1%。此外，TTFields 组 50.4% 的患者发生了与设备相关的不良事件，其中 1.6% 的患者出现 3 级或以上不良事件。1.6% 的患者发生了严重的与设备相关的不良事件，5.4% 的患者出现导致设备停用的不良事件。有1例死亡报告。

The tumor treating fields (TTFields) have shown improved efficacy in patients with brain metastases from non-small cell lung cancer (NSCLC) who were receiving immune checkpoint inhibitors.

Methods: This study (METIS, NCT02831959) enrolled patients with NSCLC patients with brain metastases and randomly assigned them in a 1:1 ratio to receive stereotactic radiosurgery (SRS) followed by  150kHz TTFields or SRS alone. Patients were followed up every 8 weeks. After the first intracranial progression, they continued to receive TTFields or initiated salvage therapy. After the second intracranial progression, patients received salvage therapy but had the option to cross over from the SRS-only group to the TTFields group. The study was enrolled from October 2016 to March 2023 at 78 centers in 13 countries. Median follow-up was 8.6 months (range: 0.07-85.2 months). The median age of patients in the TTFields group and the control group was 63.0 and 64.0 years, respectively, and the majority were male (59.1% vs 65.8%). Most patients had one to four brain metastases (78.5% vs 77.8%). The most common pathological diagnosis of NSCLC was adenocarcinoma (75.2% vs 78.5%). The primary endpoint of the trial was time to intracranial progression. Secondary endpoints included time to neurocognitive failure, overall survival, and radiographic response. Exploratory endpoints included health-related quality of life and time to distant intracranial progression as assessed by independent radiological review.

Results: The addition of TTFields after SRS prolonged time to intracranial progression in patients with brain metastatic NSCLC. Data showed that intracranial progression occurred in 44.3% of patients receiving the combined therapy (n = 149) and 63.8% of patients receiving SRS alone (n = 149), respectively. Furthermore, the 12-month and 24-month rates of intracranial progression were 46.9% (95% CI, 37.6%-55.6%) and 59.4% (95% CI, 50.7%-67.0%) in the two groups, and 53.6% (95% CI, 44.0%-62.3%) and 65.2% (95% CI, 56.5%-72.6%), respectively (HR, 0.72; 95% CI, 0.53-0.98; P = 0.039). This corresponded to a 28% relative risk reduction in the electric field treatment group.

Further data showed no significant differences in overall survival or time to neurocognitive decline between the two groups. Median overall survival was 11.3 months (95% CI, 8.6-13.8) in the TTFields group and 10.6 months (95% CI, 6.8-14.1; HR, 1.04; 95% CI, 0.76-1.43; P = .763) in the control group. Furthermore, the median time to neurocognitive decline was 2.0 months (95% CI, 1.9-2.1) in the TTFields group and 2.0 months (95% CI, 1.9-2.2) in the control group (HR, 1.12; 95% CI, 0.72-1.74; P = .607), respectively. Additionally, there was no significant difference in radiographic response rates between the two groups; the rates were 49.0% (95% CI, 38.6%-59.4%) and 46.0% (95% CI, 37.0%-55.2%), respectively (P = 0.659). When combined with immune checkpoint inhibition, TTFields significantly improved time to first intracranial progression (HR, 0.63; 95% CI, 0.39-1.00; P = 0.049) and time to distant intracranial progression (HR, 0.41; 95% CI, 0.21-0.81; P = 0.009).

Additional findings suggest that combining TTFields with SRS did not negatively impact health-related quality of life. Adverse event rates were similar between SRS combined with TTFields and SRS alone. Grade 1/2 adverse events occurred in 28.7% and 16.5%, respectively, and grade 3 or higher adverse events occurred in 32.6% and 29.1%, respectively. Furthermore, device-related adverse events occurred in 50.4% of patients in the TTFields group, including 1.6% with grade 3 or higher adverse events. Serious device-related adverse events occurred in 1.6% of patients, and 5.4% led to device discontinuation. One death was reported.

参考文献 Reference

V. Gondi el al. 2025 American Society for Radiation Oncology (ASTRO) Annual Meeting; September 27-October 1, 2025; Abstr LBA03

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两年固定疗程与持续性免疫检查点抑制剂治疗晚期非小细胞肺癌的疗效和安全性 (10/4/2025)

Efficacy and safety of two-year fixed versus continuous immune checkpoint inhibitor therapy in advanced NSCLC

方法: 本研究对截至 2024 年 8 月 24 日接受免疫检查点抑制剂 (ICI)  治疗的晚期/转移性非小细胞肺癌成年患者进行了随机对照试验和真实世界证据研究的系统综述。患者被分为两组：一组为 2 年固定疗程组，即 ICI 治疗 2 年后停止；另一组为持续性治疗组，即 ICI 治疗持续超过 2 年。

结果: 共纳入 20 项研究，5,027 名患者。各项研究中，两年固定治疗组的5年总生存率范围为 69% 至 83%，与持续治疗组相当。四项真实世界证据研究比较了两年固定治疗组和持续治疗组的生存结果，发现差异无统计学意义。在随机对照试验中，完成两年治疗的患者发生免疫抑制剂不良反应的机率往往高于基线随机对照试验人群。三项真实世界证据研究报告称，持续治疗组的免疫抑制剂不良反应发生率高于两年固定治疗组。在两个组中，许多在两年后出现疾病进展的患者在数据截止时仍然存活。与社区中心相比，大型/学术中心更倾向于两年固定治疗。

结论:在晚期/转移性非小细胞肺癌中，ICI 停药 2 年后的生存结果与持续治疗相当。免疫抑制剂不良反应往往会随着时间的推移而累积。

Methods: This study conducted a systematic review of randomized controlled trials and real-world evidence studies of adult patients with advanced/metastatic non-small cell lung cancer who were treated with immune checkpoint inhibitors (ICIs) as of August 24, 2024. Patients were divided into two groups: a 2-year fixed-course group (i.e., ICI treatment was discontinued after 2 years) and a continuous-therapy group (i.e., ICI treatment continued for more than 2 years).

Results: Twenty studies with 5,027 patients were included. Across studies, 5-year overall survival rates in the 2-year fixed-course group ranged from 69% to 83%, comparable to those in the continuous-therapy group. Four real-world evidence studies compared survival outcomes between the two groups and found no statistically significant differences.

In randomized controlled trials, patients who completed 2 years of treatment tended to have higher rates of adverse effects of immunosuppressants than those in the baseline randomized controlled trial population. Three real-world evidence studies reported higher rates of adverse effects of immunosuppressants in the continuous-therapy group compared with the 2-year fixed-course group. In both groups, many patients who experienced disease progression after 2 years were still alive at the time of data cutoff. Large/academic centers were more likely to adopt a two-year fixed-dose treatment schedule compared with community centers.

Conclusion: In advanced/metastatic non-small cell lung cancer, survival outcomes after 2 years of ICI discontinuation are comparable to those achieved with continued therapy. Adverse effects of immunosuppressants tend to accumulate over time.

参考文献 Reference

T Pandey et al. Cancer Immunol Immunother. 2025;74:317

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ASCO 对治疗无驱动基因改变的非小细胞肺癌指南更新，包括首次比较免疫疗法 (9/28/2025)

Update to ASCO guideline for NSCLC without driver alterations includes first comparison of immunotherapy options

该更新基于近期发表的三项 3 期临床试验的结果：NIPPON、HARMONi-2 和 DUBLIN-3。1) NIPPON 是一项在日本进行的随机, 开放标签, III 期临床试验。该试验共纳入 295 例不适合根治性治疗的 III 期或 IV 期非小细胞肺癌 (NSCLC) 患者，随机分配接受铂类双药化疗联合帕博利珠单抗或纳武利尤单抗联合伊匹单抗治疗。由于纳武利尤单抗/伊匹单抗组治疗相关死亡人数较高（148 例患者中有 11 例 [7%]，而帕博利珠单抗组 144 例患者中有 3 例 [2%]），该试验提前终止。 中位随访时间为15.3个月，帕博利珠单抗组的中位总生存期 (OS) 为20.5个月，纳武利尤单抗/伊匹单抗组的中位总生存期 (OS) 为23.7个月，差异无统计学意义 (P = 0.46)。两组的中位无进展生存期分别为7.4个月和6.0个月，客观响应率分别为65%和55%。

2) 专家组还审查了 HARMONi-2 试验的结果。该试验是一项在中国开展的随机, 双盲, III 期临床试验。该试验在 398 例 PD-L1 阳性（> 1%）, EGFR 或 ALK 阴性的转移性或晚期 NSCLC 患者中比较了抗 PD-1 和 VEGF 双特异性抗体  ivonescimab 与帕博利珠单抗的疗效。 该研究达到了主要终点，ivonescimab 组的中位无进展生存期为 11.1 个月，而 pembrolizumab 组为 5.8 个月（HR 0.51，95% CI [0.38, 0.69]；P < .0001）。尽管结果令人鼓舞，但根据现有证据，尚不推荐使用 ivonescimab。 需要了解无进展生存期的改善是否也转化为总生存期，以帮助确定哪些患者可能从该策略中获益。在HARMONi-2研究中，ivonescimab组患者的3级或更高级别治疗相关不良事件发生率也更高（29% vs 帕博利珠单抗组为16%）。

3) DUBLIN-3 和普那布林 (plinabulin) 。 DUBLIN-3 是一项单盲, 随机, III 期临床试验，比较了多西他赛联合微管蛋白结合剂普那布林与多西他赛联合安慰剂的疗效。该试验共纳入 559 例接受含铂双药化疗后疾病进展的 EGFR 野生型 NSCLC 患者。 普那布林组的中位总生存期为 10.5 个月，而安慰剂组为 9.4 个月（HR 0.82，95% CI [0.68, 0.99]）。值得注意的是，只有 20% 的研究对象接受过既往免疫治疗（目前已成为标准治疗）；在这些接受过免疫治疗的患者中，普那布林组的总体生存期未见统计学显著改善。

This update is based on the results of three recently published phase III clinical trials: NIPPON, HARMONi-2, and DUBLIN-3.

1) NIPPON was a randomized, open-label, phase III clinical trial conducted in Japan. The trial enrolled 295 patients with stage III or IV non-small cell lung cancer (NSCLC) who were not candidates for curative therapy and randomly assigned to receive either platinum-doublet chemotherapy plus pembrolizumab or nivolumab plus ipilimumab. The trial was terminated early due to a higher number of treatment-related deaths in the nivolumab/ipilimumab group (11 of 148 patients [7%] compared with 3 of 144 patients [2%] in the pembrolizumab group). With a median follow-up of 15.3 months, the median overall survival was 20.5 months in the pembrolizumab group and 23.7 months in the nivolumab/ipilimumab group, a difference that was not statistically significant (P = 0.46). The median progression-free survival was 7.4 months and 6.0 months, respectively, with objective response rates of 65% and 55%, respectively.

2) The panel also reviewed the results of the HARMONi-2 trial, a randomized, double-blind, phase III clinical trial conducted in China. The trial compared the anti-PD-1 and VEGF bispecific antibody ivonescimab with pembrolizumab in 398 patients with PD-L1-positive (>1%), EGFR- or ALK-negative metastatic or advanced NSCLC. The study met its primary endpoint, with a median progression-free survival of 11.1 months in the ivonescimab group compared with 5.8 months in the pembrolizumab group (HR 0.51, 95% CI [0.38, 0.69]; P < .0001). Despite these encouraging results, the use of ivonescimab cannot be recommended based on the current evidence. Whether the improvement in progression-free survival also translates to overall survival is crucial to determine which patients may benefit from this strategy. In the HARMONi-2 study, patients in the ivonescimab group also experienced a higher rate of grade 3 or higher treatment-related adverse events (29% vs 16% in the pembrolizumab group).

3) DUBLIN-3 and plinabulin. DUBLIN-3 was a single-blind, randomized, phase III clinical trial comparing docetaxel plus the tubulin-binding agent plinabulin with docetaxel plus placebo. The trial enrolled 559 patients with EGFR wild-type NSCLC whose disease had progressed after platinum-doublet chemotherapy. The median overall survival was 10.5 months in the plinabulin group compared with 9.4 months in the placebo group (HR 0.82, 95% CI [0.68, 0.99]). Notably, only 20% of the study participants had received prior immunotherapy, which is now the standard of care; among these patients, the plinabulin group did not demonstrate a statistically significant improvement in overall survival.

参考文献 Reference

Owen DH et al.  J Clin Onc 2025 ; on line July 17

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纳武单抗或纳武单抗联合伊匹单抗治疗可切除弥漫性胸膜间皮瘤 (9/27/2025)

Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase II trial 

这项II期临床试验(NCT03918252)探讨了纳武单抗和纳武单抗/伊匹单抗联合治疗在可切除弥漫性胸膜间皮瘤中的新辅助疗效，以及基于肿瘤信息的液体活检残留病灶评估。

可切除的上皮样/双相弥漫性胸膜间皮瘤患者入组顺序为每 2 周接受 240 mg 纳武单抗治疗三个周期（A 组，n = 16）或 3 mg/kg nivolumab 每 2 周治疗三个周期加第 1 周期的 1 mg/kg ipilimumab（B 组，n = 14），随后进行手术, 可选化疗和/或放疗，以及 480 mg 每 4 周 nivolumab 治疗 1 年。共同主要终点包括安全性和可行性；关键探索性终点包括无进展生存期, 总生存期和 ctDNA 分析。

该试验达到了其主要终点，在 A 组和 B 组中，分别有 81.3% 和 85.7% 的患者接受了手术。治疗是安全的，每组均发生一例剂量限制性毒性。A 组中，中位无进展生存期和总生存期分别为 9.6 个月（95% 置信区间 (CI)：2.5–27.7）和 19.3 个月（95% CI：14.9–34.7）。B 组中，中位无进展生存期和总生存期分别为 19.8 个月（7.1 – 未达到）和 28.6 个月（20.4 – 未达到）。

在因疾病进展而未接受完全手术切除的患者中，在新辅助治疗期间检测到持续性 ctDNA（Fisher 精确检验，P = 0.00013）。在第 3 个周期和术前可检测到 ctDNA 的患者的无进展生存期较短（对数秩检验，分别为 P = 0.027 和 P = 0.0059）；当考虑定量ctDNA变化时，这种关联更为明显（对数秩检验，P = 1.8×10−6）。

这项研究结果支持新辅助免疫检查点阻断的可行性，以及ctDNA分析在可切除弥漫性胸膜间皮瘤中捕获残留病变的临床应用。

This phase II clinical trial (NCT03918252) investigated the neoadjuvant efficacy of nivolumab and the nivolumab/ipilimumab combination in resectable diffuse pleural mesothelioma, along with tumor-informed liquid biopsy residual disease assessment.

Patients with resectable epithelioid/biphasic diffuse pleural mesothelioma were enrolled to receive either 240 mg of nivolumab every 2 weeks for three cycles (Arm A, n = 16) or 3 mg/kg of nivolumab every 2 weeks for three cycles plus 1 mg/kg of ipilimumab in the first cycle (Arm B, n = 14), followed by surgery, optional chemotherapy and/or radiotherapy, and 480 mg of nivolumab every 4 weeks for one year. Co-primary endpoints included safety and feasibility; key exploratory endpoints included progression-free survival, overall survival, and ctDNA analysis.

The trial met its primary endpoint, with 81.3% of patients in Arm A and 85.7% in Arm B undergoing surgery. Treatment was safe, with one dose-limiting toxicity occurring in each arm. In Arm A, median progression-free survival and overall survival were 9.6 months (95% confidence interval (CI): 2.5–27.7) and 19.3 months (95% CI: 14.9–34.7), respectively. In Arm B, median progression-free survival and overall survival were 19.8 months (7.1–not reached) and 28.6 months (20.4–not reached), respectively.

In patients who did not undergo complete surgical resection due to disease progression, persistent ctDNA was detected during neoadjuvant therapy (Fisher’s exact test, P = 0.00013). Patients with detectable ctDNA at cycle 3 and preoperatively had shorter progression-free survival (log-rank test, P = 0.027 and P = 0.0059, respectively); this association was even more pronounced when quantitative ctDNA changes were considered (log-rank test, P = 1.8 × 10−6).

These findings support the feasibility of neoadjuvant immune checkpoint blockade and the clinical utility of ctDNA analysis for capturing residual disease in resectable diffuse pleural mesothelioma.

参考文献 Reference

Reuss JE et al. Nature Med 2025 ; Sept 8.

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三种 CDK4/6 抑制剂一线治疗晚期雌激素受体 (HR) 阳性/HER2 阴性乳腺癌真实世界疗效比较 (9/21/2025)

Real-world efficacy comparison of three CDK4/6 inhibitors as first-line therapy for advanced estrogen receptor-Positive/HER2-Negative Breast Cancer: PALMARES-2

PALMARES-2 是一项多中心观察性研究，比较了三种 CDK4/6 抑制剂联合内分泌治疗在 HR 阳性/HER2 阴性晚期乳腺癌患者中的 真实世界无进展生存期率。

方法: 这是一项多中心, 观察性的研究，比较了第一线帕博西尼, 瑞博西尼和abemaciclib联合内分泌治疗的疗效，这些患者于2016年1月至2023年9月期间在意大利18家癌症中心开始接受治疗的HR阳性/HER2阴性乳腺癌患者。该分析的主要终点是真实世界无进展生存期（rwPFS）。使用多变量Cox回归模型调整了单个CDK4/6i与rwPFS之间的关联，以评估临床相关变量。

结果: 在PALMARES-2研究中，1,982名患者分别接受了帕博西尼, 瑞博西尼和阿贝西尼治疗。中位rwPFS为34.1个月。在整个研究队列中，与哌柏西利相比，abemaciclib和瑞博西尼的rwPFS均更长 [校正风险比(aHR) 0.76，95%置信区间(CI) 0.63-0.92，P = 0.004和aHR 0.83，95% CI 0.73-0.95，P = 0.007]。在内分泌敏感性疾病患者中，仅abemaciclib的rwPFS优于哌柏西利。相反，对于绝经前、内分泌耐药或管腔B样乳腺癌患者，abemaciclib 和瑞博西尼的疗效优于帕博西尼；而对于新发转移性乳腺癌患者，abemaciclib 的疗效优于瑞博西尼和帕博西尼；对于体能状态较差的患者，abemaciclib 的疗效优于帕博西尼。对于仅骨转移的乳腺癌患者，三种 CDK4/6i 的疗效相似。

结论: 在 HR 阳性/HER2 阴性的乳腺癌患者中，帕博西尼, 瑞博西尼和 abemaciclib 的现实世界疗效不同。这项研究结果可以帮助临床医生根据具体的临床情况选择最合适的 CDK4/6抑制剂。

PALMARES-2 is a multicenter, observational study comparing real-world progression-free survival (rwPFS) in patients with HR-positive, HER2-negative advanced breast cancer treated with three CDK4/6 inhibitors in combination with endocrine therapy.

Methods: This multicenter, observational study compared the efficacy of first-line palbociclib, ribociclib, and abemaciclib in combination with endocrine therapy in patients with HR-positive, HER2-negative breast cancer who initiated treatment at 18 cancer centers in Italy between January 2016 and September 2023. The primary endpoint of this analysis was real-world progression-free survival (rwPFS). Multivariable Cox regression models were used to assess the association between individual CDK4/6 inhibitors and rwPFS, adjusting for clinically relevant variables. Results: In the PALMARES-2 study, 1,982 patients received palbociclib, ribociclib, and abemaciclib. The median rwPFS was 34.1 months. Abemaciclib and ribociclib both resulted in longer rwPFS compared with palbociclib across the entire study cohort [adjusted hazard ratio (aHR) 0.76, 95% confidence interval (CI) 0.63-0.92, P = 0.004 and aHR 0.83, 95% CI 0.73-0.95, P = 0.007, respectively]. Among patients with endocrine-sensitive disease, only abemaciclib demonstrated superior rwPFS compared with palbociclib. Conversely, abemaciclib and ribociclib were superior to palbociclib in patients with premenopausal, endocrine-resistant, or luminal B-like breast cancer; abemaciclib was superior to ribociclib and palbociclib in patients with de novo metastatic breast cancer; and abemaciclib was superior to palbociclib in patients with a poor performance status. The three CDK4/6 inhibitors demonstrated similar efficacy in patients with bone-only metastases.

Conclusions: The real-world efficacy of palbociclib, ribociclib, and abemaciclib differed in patients with HR-positive/HER2-negative breast cancer. These findings may help clinicians select the most appropriate CDK4/6 inhibitor based on specific clinical circumstances.

参考文献 Reference

Provenzano L et al. Ann Onc 2025; 36: 762

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免疫疗法有效治疗表皮T细胞淋巴瘤（9/20/2025）

Durvalumab plus lenalidomide versus durvalumab in refractory/advanced cutaneous T cell lymphoma: a randomized phase II trial

蕈样肉芽肿(mycosis fungoides, MF)和白血病变异型Sézary综合征 (SS)，为皮肤T细胞淋巴瘤(CTCL)，是无法治愈的恶性肿瘤。本文介绍了I/II期临床试验 (NCT03011814) 的随机II期部分，旨在比较Durvalumab单药治疗与Durvalumab联合来那度胺治疗复发性/晚期CTCL。主要终点是客观响应率，采用基于皮肤, 血液, 淋巴结和内脏的综合响应率，并根据共识指南进行计算。次要终点包括响应持续时间, 无进展生存期和毒性。探索性终点是基因表达谱、肿瘤微环境和抗肿瘤活性之间的关系。

方法：纳入经组织学确诊为 MF/SS 且≥2 种全身疗法失败的成年患者，按 1:1 的比例随机分配接受单药度伐利尤单抗（1500 mg（28 天周期的第 1 天）或度伐利尤单抗（相同剂量）联合来那度胺（第 1 周期 10 mg，第 2 周期 15 mg，随后每个周期每天服用 20 mg，持续 21 天，每个 28 天为一个周期）。对治疗前和治疗中皮肤和血液样本的基因表达谱, 肿瘤微环境和抗肿瘤活性进行分析。

结果：共计 25 名患者被随机分配（意向治疗人群：12 名单独接受度伐利尤单抗 vs. 13 名接受度伐利尤单抗 + 来那度胺治疗），入组时患者具有以下特征：中位年龄 56 岁（26-79 岁）vs 65 岁（32-88 岁）； IB 期，2 (17%) vs 4 (31%)；IIB 期，5 (42%) vs 3 (23%)；III/IV 期，5 (42%) vs 6 (46%)；大细胞转化 3 (25%) vs 5 (38%)。单药组和联合组既往全身治疗次数的中位数均为 3。

Durvaluma 单药治疗的全球最佳客观响应率为 42% (5/12)，联合组的全球最佳客观响应率 为 75% (9/12，1 名患者无法评估反应)。中位随访时间为 14.5 个月（范围：0.5-29.7 个月）。Durvaluma 组的中位无进展生存期为 6.2 个月，联合组尚未达到（2.8-NA）。Durvaluma组的 12 个月无进展生存期为 36%（95% CI：11%-63%），联合组为73% (95% CI: 38%-91%)。

在2025年SOHO的最新报告中，更新数据显示，接受度伐利尤单抗联合来那度胺治疗的12例患者中，有8例获得全身客观缓解，其中4例获得完全缓解（CR），其余4例病情稳定。单独接受度伐利尤单抗治疗的13例患者中，有6例获得全身缓解（1例获得CR），7例病情稳定。

未观察到严重不良事件。最常见的治疗中出现的不良事件在联合组中发生率高于 Durvaluma 组，包括疲劳（n=10）、腹泻（n=6）、贫血（n=5）、血小板减少（n=5）、白细胞减少和中性粒细胞减少（n=4）、便秘（n=4）和腿部水肿（n=4）。两个治疗组的大多数不良事件严重程度均为轻度至中度（I/II 级，92%；III 级，8%）。联合组观察到一例 IV 级中性粒细胞减少症。单药组和联合组的中位治疗周期分别为 4.5（范围：2-26+）和 8（范围：1-29+）。每组分别在 2.2 个月（Durvaluma）和 6.6 个月（联合组）时发生一例死亡。停用研究药物后。每组仍有2名患者继续接受治疗。

使用CIBERSORT和单细胞分析进行的分子分析显示，与基线相比，每个治疗组的适应性和先天性免疫细胞特征以及肿瘤微环境中的细胞信号传导相互作用均发生了明显变化。多重细胞因子分析强调，联合组促进了Th1细胞因子微环境。

结论：这项随机II期临床试验表明，Durvalumab/来那度胺联合治疗难治性/晚期CTCL患者的临床疗效优于Durvalumab单药治疗。疗效持久且持续，且耐受性良好。

Mycosis fungoides (MF) and the leukemic variant of Sézary syndrome (SS) are cutaneous T-cell lymphomas (CTCL) that are incurable malignancies. This article describes the randomized phase II portion of a phase I/II clinical trial (NCT03011814) comparing durvalumab monotherapy with durvalumab plus lenalidomide in patients with relapsed/advanced CTCL. The primary endpoint was objective response rate, calculated according to consensus guidelines using a composite response rate based on skin, blood, lymph node, and visceral findings. Secondary endpoints included duration of response, progression-free survival, and toxicity. An exploratory endpoint investigated the relationship between gene expression profiling, the tumor microenvironment, and antitumor activity.

Methods: Adult patients with histologically confirmed MF/SS who had failed ≥2 prior systemic therapies were randomized in a 1:1 ratio to receive either durvalumab (1500 mg on day 1 of a 28-day cycle) alone or durvalumab (same dose) plus lenalidomide (10 mg in cycle 1, 15 mg in cycle 2, followed by 20 mg daily for 21 days per 28-day cycle). Pre-treatment and on-treatment skin and blood samples were analyzed for gene expression profiles, tumor microenvironment, and antitumor activity.

Results: A total of 25 patients were randomly assigned (intention-to-treat population: 12 to durvalumab alone vs. 13 to durvalumab plus lenalidomide). Patient characteristics at enrollment were as follows: median age 56 years (range, 26-79) vs. 65 years (range, 32-88); stage IB, 2 (17%) vs 4 (31%); stage IIB, 5 (42%) vs 3 (23%); stage III/IV, 5 (42%) vs 6 (46%); large cell transformation, 3 (25%) vs 5 (38%). The median number of prior systemic therapies was 3 for both the monotherapy and combination arms.

The global best objective response rate was 42% (5/12) with Durvaluma monotherapy and 75% (9/12, 1 patient was not evaluable for response) with the combination arm. The median follow-up was 14.5 months (range: 0.5-29.7 months). The median progression-free survival was 6.2 months with Durvaluma and not reached (2.8-NA) with the combination arm. The 12-month progression-free survival was 36% (95% CI: 11%-63%) with Durvaluma and 73% (95% CI: 38%-91%) for the combination group.

In the latest SOHO report in 2025, updated data showed that among the 12 patients treated with durvalumab plus lenalidomide, 8 achieved an objective systemic response, including 4 complete responses (CR), and the remaining 4 had stable disease. Among the 13 patients treated with durvalumab alone, 6 achieved a systemic response (1 CR) and 7 had stable disease.

No serious adverse events were observed. The most common treatment-emergent adverse events, which occurred more frequently in the combination group than in the durvalumab group, included fatigue (n=10), diarrhea (n=6), anemia (n=5), thrombocytopenia (n=5), leukopenia and neutropenia (n=4), constipation (n=4), and leg edema (n=4). Most adverse events in both treatment groups were mild to moderate in severity (grade I/II, 92%; grade III, 8%). One case of grade IV neutropenia was observed in the combination group. The median treatment duration for the monotherapy and combination groups was 4.5 (range: 2-26+) and 8 (range: 1-29+) months respectively. One death occurred in each group at 2.2 months (Durvalumab) and 6.6 months (combination group), respectively. After discontinuation of study drug, two patients in each group remained on treatment.

Molecular analysis using CIBERSORT and single-cell analysis revealed significant changes in adaptive and innate immune cell signatures, as well as cell signaling interactions within the tumor microenvironment, in each treatment group compared with baseline. Multiplex cytokine analysis highlighted a Th1 cytokine-enhanced microenvironment in the combination group.

Conclusion: This randomized phase II clinical trial demonstrated that the durvalumab/lenalidomide combination demonstrated superior clinical efficacy compared with durvalumab monotherapy in patients with refractory/advanced CTCL. The efficacy was durable and sustained, and the combination was well tolerated.

参考文献 Reference

Querfeld C et al. Blood 2024 ; 144 [ suppl 1, p468]

Querfield C et al. SOHO 2025 abstr TCL-1020

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GLP-1受体激动剂与肥胖成人癌症风险  (9/14/2025)

GLP-1 receptor agonists and cancer risk in adults with obesity

目的：比较服用 GLP-1RA 的肥胖成人和非服用者中 14 种癌症的发病率。

这项回顾性队列研究采用目标试验模拟设计，使用了 OneFlorida+（一个整合了来自不同医疗机构的真实世界临床数据的多中心健康研究网络）2014 年至 2024 年的电子健康记录数据。研究对象为 18 岁及以上、符合抗肥胖药物使用条件且无既往癌症病史的成年人。参与者被分为 GLP-1RA 服用者和非服用者，并使用倾向评分进行 1:1 匹配。 主要结果为14种癌症的发病率，包括13种肥胖相关癌症（肝癌. 甲状腺癌, 胰腺癌, 膀胱癌, 结直肠癌, 肾癌, 乳腺癌, 子宫内膜癌, 脑膜瘤, 上消化道癌, 卵巢癌, 多发性骨髓瘤和前列腺癌）和肺癌。

结果：共纳入86,632名匹配的成年人（平均[SD]年龄52.4[14.5]岁；68.2%为女性），其中43,317名GLP-1RA使用者和43,315名符合其他条件的非使用者。这14种癌症的发病率分别为每1000人年13.6例和16.4例，表明服用GLP-1RAs的个体总体癌症风险显著低于未使用者（风险比[HR]，0.83[95%CI，0.76-0.91]；P =.002）。具体而言，服用GLP-1RAs与降低子宫内膜癌（HR，0.75[95%CI，0.57-0.99]；P =.05）、卵巢癌（HR，0.53[95%CI，0.29-0.96]；P =.04）和脑膜瘤（HR，0.69[95%CI，0.48-0.97]；P,=.05）的风险相关。然而，GLP-1RAs 与肾癌风险略微增加相关，但差异不显著（HR，1.38 [95% CI，0.99-1.93]；P  = 0.04）。

结论与意义: 这项回顾性队列研究发现，服用 GLP-1RAs 与肥胖或超重患者的总体癌症风险降低相关，包括降低子宫内膜癌, 卵巢癌和脑膜瘤风险。然而，服用 GLP-1RAs 可能与肾癌风险增加相关，这凸显了需要进行更长期的随访，以阐明这些发现的潜在机制和临床意义。

Objective: To compare the incidence of 14 cancers in obese adults taking GLP-1RAs and non-users. This retrospective cohort study employed a targeted trial simulation design and utilized electronic health record data from OneFlorida+ (a multicenter health research network integrating real-world clinical data from diverse healthcare settings) from 2014 to 2024. The study included adults aged 18 years and older who were eligible for anti-obesity medication use and had no prior history of cancer. Participants were categorized as GLP-1RA users or non-users and matched 1:1 using a propensity score. The primary outcome was the incidence of 14 cancers, including 13 obesity-related cancers (liver, thyroid, pancreatic, bladder, colorectal, renal, breast, endometrial, meningioma, upper gastrointestinal, ovarian, multiple myeloma, and prostate) and lung cancer.

Results: A total of 86,632 matched adults (mean [SD] age, 52.4 [14.5] years; 68.2% women) were included, including 43,317 GLP-1RA users and 43,315 otherwise eligible nonusers. The incidence rates for the 14 cancers were 13.6 and 16.4 cases per 1000 person-years, respectively, indicating a significantly lower overall cancer risk among GLP-1RA users compared with nonusers (hazard ratio [HR], 0.83 [95% CI, 0.76-0.91]; P = .002). Specifically, use of GLP-1RAs was associated with a reduced risk of endometrial cancer (HR, 0.75 [95% CI, 0.57-0.99]; P = .05), ovarian cancer (HR, 0.53 [95% CI, 0.29-0.96]; P = .04), and meningioma (HR, 0.69 [95% CI, 0.48-0.97]; P = .05). However, GLP-1RA use was associated with a slightly increased risk of renal cancer, but the difference was not significant (HR, 1.38 [95% CI, 0.99-1.93]; P = .04).

Conclusions and Relevance: This retrospective cohort study found that use of GLP-1RAs was associated with a reduced overall cancer risk in obese or overweight patients, including a reduced risk of endometrial, ovarian, and meningioma cancers. However, the possible association between GLP-1RA use and an increased risk of renal cancer highlights the need for longer-term follow-up to elucidate the underlying mechanisms and clinical significance of these findings.

参考文献 Reference

Dai H et al. JAMA Onc 2025 ; doi: 10.1001/jamaoncol.2025.2681

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Dato-DXd 对脑转移的非小细胞肺癌患者的颅内效果 (9/13/2025)

Intracranial response of Dato-DXd in patients with non-small cell lung cancer with brain metastases: TROPION-Lung01 trial

根据在国际肺癌研究协会 (IASLC) 2025 年世界肺癌大会上提交的 3 期 TROPION-Lung01 研究 (NCT04656652) 的事后分析数据，Datopotamab deruxtecan-dlnk (Dato-DXd) 对患有脑转移的非小细胞肺癌 (NSCLC) 患者表现出颅内活性。

TROPION-Lung01 是一项开放标签研究，纳入了 IIIB, IIIC 或 IV 期NSCLC 患者。 基线时，Dato-DXd 组和多西他赛组患者的中位年龄分别为 65.5 岁（范围：35-81 岁）和 57.5 岁（范围：34-77 岁）。组织学类型为非鳞状细胞癌（82% vs 83%），且未发现可操作的基因组变异（68% vs 60%）。从确诊到随机分配的中位时间分别为 14.4 个月（范围：3.0-87.0 个月）和 20.6 个月（范围：3.4-73.1 个月）。

研究结果表明，接受 Dato-DXd 治疗的患者 (n = 38) 的中位中枢神经系统无进展生存期为 5.0 个月 (95% CI, 3.5-无法估计 [NE])，而接受多西他赛治疗的患者 (n = 30；未分层) 的中位中枢神经系统无进展生存期为 3.0 个月 (95% CI, 1.3-6.6) HR，0.48；95% CI，0.23-0.98）。3个月中枢神经系统无进展生存率分别为77%和48%，6个月中枢神经系统无进展生存率分别为41%和29%。

事后分析的其他结果显示，接受 Dato-DXd 治疗的未经治疗脑转移瘤患者或放疗后病情进展且中枢神经系统可测量病灶的患者（n = 16）的中枢神经系统确认的客观响应率为 38%（95% CI，15%-65%），疾病控制率为 88%（95% CI，62%-98%）。中枢神经系统确认的完全响应 , 部分响应和疾病稳定率分别为 6%、31% 和 50%。 多西他赛组（n = 11）的中枢神经系统确认的客观响应率为 0%（95% CI，0%-29%），疾病控制率为 36%（95% CI，11%-69%）。无患者达到中枢神经系统完全响应或部分响应，36% 的患者中枢神经系统疾病稳定。 在非鳞状细胞癌患者（n = 56；HR，0.37；95% CI，0.16-0.83）, EGFR未突变患者（n = 46；HR，0.51；95% CI，0.21-1.27）和EGFR突变患者（n = 22；HR，0.33；95% CI，0.09-1.20）中，Dato-DXd组在中枢神经系统无进展生存期方面均获益。鳞状细胞癌患者（n = 12）未从Dato-DXd治疗中获得中枢神经系统无进展生存期获益（HR，1.81；95% CI，0.30-11.02）。

2025 年 6 月，Dato-DXd 获得 FDA 加速批准，用于治疗已接受过 EGFR 靶向治疗和铂类化疗的局部晚期 EGFR 突变 NSCLC 成年患者。

Datopotamab deruxtecan-dlnk 是一种抗体–药物偶联物 (ADC)，其作用机制是选择性地将拓扑异构酶 I 抑制剂有效载荷递送至表达 Trop-2 的癌细胞。单克隆抗体与肿瘤细胞上的 Trop-2 结合，导致活性药物 (deruxtecan) 被内化并释放到细胞内。Deruxtecan 会破坏癌细胞的 DNA，抑制其生长并导致其死亡。

Datopotamab deruxtecan-dlnk (Dato-DXd) demonstrated intracranial activity in patients with non-small cell lung cancer (NSCLC) with brain metastases, according to post-hoc analysis data from the phase 3 TROPION-Lung01 study (NCT04656652) presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Lung Cancer Conference.

TROPION-Lung01 was an open-label study that enrolled patients with stage IIIB, IIIC, or IV NSCLC. At baseline, the median age of patients in the Dato-DXd and docetaxel groups was 65.5 years (range: 35-81) and 57.5 years (range: 34-77), respectively. Histology was non-squamous cell carcinoma (82% vs 83%), and no actionable genomic alterations were identified (68% vs 60%). The median time from diagnosis to randomization was 14.4 months (range: 3.0-87.0 months) and 20.6 months (range: 3.4-73.1 months), respectively. The results showed that patients treated with Dato-DXd (n = 38) had a median CNS progression-free survival of 5.0 months (95% CI, 3.5-not estimable [NE]), compared with 3.0 months (95% CI, 1.3-6.6) for patients treated with docetaxel (n = 30; unstratified). The 3-month CNS progression-free survival rates were 77% and 48%, respectively, and the 6-month CNS progression-free survival rates were 41% and 29%, respectively.

Additional results from a post-hoc analysis showed that among patients with untreated measurable CNS metastases or progression after radiation therapy, who received Dato-DXd (n = 16), the CNS-confirmed objective response rate was 38% (95% CI, 15%-65%), and the disease control rate was 88% (95% CI, 62%-98%). CNS-confirmed complete response, partial response, and stable disease rates were 6%, 31%, and 50%, respectively. In the docetaxel group (n = 11), the CNS-confirmed objective response rate was 0% (95% CI, 0%-29%), and the disease control rate was 36% (95% CI, 11%-69%). No patient achieved a complete or partial CNS response, and 36% experienced stable CNS disease. Dato-DXd demonstrated a CNS progression-free survival benefit in patients with non-squamous cell carcinoma (n = 56; HR, 0.37; 95% CI, 0.16-0.83), those without EGFR mutations (n ​​= 46; HR, 0.51; 95% CI, 0.21-1.27), and those with EGFR mutations (n ​​= 22; HR, 0.33; 95% CI, 0.09-1.20). Patients with squamous cell carcinoma (n = 12) did not benefit from Dato-DXd treatment in terms of CNS progression-free survival (HR, 1.81; 95% CI, 0.30-11.02).

In June 2025, Dato-DXd received accelerated approval from the FDA for the treatment of adult patients with locally advanced EGFR-mutated NSCLC who have received prior EGFR-targeted therapy and platinum-based chemotherapy.

Datopotamab deruxtecan-dlnk is an antibody-drug conjugate (ADC) that works by selectively delivering a topoisomerase I inhibitor payload to cancer cells expressing Trop-2. A monoclonal antibody binds to Trop-2 on tumor cells, leading to internalization and release of the active drug (deruxtecan) inside the cell. Deruxtecan damages the cancer cell’s DNA, arresting its growth and causing it to die.

参考文献 Reference

Pons-Tostivint E. et al. Int Assoc for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer Abstr OA10.01.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer

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III 期试验评估术后纳武单抗联合放化疗治疗高风险头颈部鳞状细胞癌 (9/7/2025)

Adjuvant nivolumab plus radio-chemotherapy in resected, high-risk head and neck squamous cell carcinoma: A phase III  NIVOPOSTOP trial

过去二十年，对于复发风险高的局部晚期头颈部鳞状细胞癌患者，其标准治疗是辅助顺铂联合放疗。本研究评估了术后辅助顺铂联合放疗联合纳武单抗与单纯辅助放疗的疗效。

方法：NIVOPOSTOP (NCT03576417) 是一项国际随机, 开放标签的III期临床试验。主要纳入标准为年龄 < 75 岁的患者，切除了口腔、口咽, 下咽或喉部的局部晚期头颈部鳞状细胞癌患者。复发风险高的定义为存在淋巴结包膜外扩散和/或阳性肿瘤边缘, ≥4 个淋巴结受累, 多发性神经周围侵犯。主要终点是无病生存期；关键次要终点包括总生存期和安全性。患者在手术后按 1:1 随机分配接受 A 组66 Gy 放疗和顺铂（每 3 周 100 mg/m2，共 3 个周期）或 B 组纳武单抗 240 mg，随后接受标准治疗辅助顺铂联合放疗，3 个周期的纳武单抗, 每 3 周 360 mg，随后接受 6 个周期的纳武单抗每 4周480 mg。通过 p16 状态进行治疗分配。为了在双侧 α 误差 0.05 和功效 90% 时检测到 HR 0.65 的事件，需要 230 个事件。当达到此所需事件数时进行分析（截止日期为 2024 年 4 月 30 日）。

结果：共计 680 名患者被随机分配。无病生存期分析基于截止日期前随机分配的 666 名患者（A 组 334 例 vs B 组 332 例；意向治疗分析）和中位随访期 30.3 个月（IQR 16.0；44.9）的 252 个事件。两组的基线特征平衡。与单纯顺铂联合放疗相比，无论PD-L1表达如何的患者接受辅助纳武单抗 + 顺铂联合放疗的无病生存期均显着改善（HR 0.76（95% CI，0.60-0.98）；分层对数秩检验顺铂联合放疗组的 3 年无病生存期为 52.5%（95% CI，46.2-58.4%），纳武单抗 + 顺铂联合放疗组为 63.1%（57-68.7%）。当达到所需的死亡人数（目前为 158 例，要求为 283 例死亡）时，将进行总生存期分析。

顺铂联合放疗后长达 9 个月的安全性分析基于接受过至少一次治疗的患者。与纳武单抗 + 顺铂联合放疗组相比，顺铂联合放疗组患者发生 4 级不良事件的几率较低（顺铂联合放疗后 100 天内分别为 5.6% 相比于 13.1%，之后长达 9 个月内分别为 0% 相比于1.2%），治疗相关死亡发生率分别为 0.7% 相比于0.6%。

结论：无论PD-L1表达如何的局部晚期头颈部鳞状细胞癌患者，术后辅助纳武单抗联合顺铂联合放疗疗法可带来统计学和临床​​意义上的无病生存期改善。这是20多年来首次在高复发风险的局部晚期头颈部鳞状细胞癌术后患者中，一种疗法被证明优于标准治疗辅助顺铂联合放疗。

编者注：此前有一篇关于局部晚期头颈癌患者新辅助治疗的报道，FDA已于2025年6月22日批准帕博利珠单抗用于治疗PD-L1阳性患者。本文报道了纳武单抗在无论PD-L1表达如何的局部晚期头颈癌患者中的阳性疗效。

For the past two decades, adjuvant cisplatin combined with radiation has been the standard of care for patients with locally advanced head and neck squamous cell carcinoma with high risk of recurrence. This study evaluated the efficacy of postoperative adjuvant cisplatin combined with radiotherapy plus nivolumab compared with adjuvant radiotherapy alone.

Methods: NIVOPOSTOP is an international, randomized, open-label, phase III clinical trial (NCT03576417). Inclusion criteria were patients aged <75 years with resected locally advanced head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. High risk of recurrence was defined as the presence of extracapsular lymph node extension and/or positive tumor margins, involvement of ≥4 lymph nodes, and multiple perineural invasion. The primary endpoint was disease-free survival; key secondary endpoints included overall survival and safety. After surgery, patients were randomly assigned in a 1:1 ratio to 1) arm A,  receiving in arm A, 66 Gy of radiation and cisplatin (100 mg/m² every 3 weeks for 3 cycles) or 2) arm B, receiving nivolumab 240 mg, followed by standard treatment of adjuvant cisplatin plus radiotherapy with nivolumab 360 mg every 3 weeks for 3 cycles, followed by nivolumab 480 mg every 4 weeks for 6 cycles. Treatment assignment was determined by p16 status. To detect an event with a hazard ratio (HR) of 0.65 at a two-sided alpha error of 0.05 and 90% power, 230 events were required. Analysis was performed when this required number of events was reached (cutoff date: April 30, 2024).

Results: A total of 680 patients were randomized. The analysis of disease-free survival was based on 666 patients who were randomly assigned by the cutoff date (334 patients in group A vs 332 patients in group B; intention-to-treat analysis) and 252 events over a median follow-up of 30.3 months (IQR 16.0; 44.9). Baseline characteristics were balanced between the two groups. Adjuvant nivolumab plus cisplatin plus RT had significantly improved disease-free survival across PD-L1 allcomers compared with cisplatin plus RT alone (HR 0.76 (95% CI, 0.60-0.98); stratified log-rank test. Three-year disease-free survival was 52.5% (95% CI, 46.2-58.4%) in the cisplatin plus RT group and 63.1% (57-68.7%) in the nivolumab plus cisplatin and radiation group). An overall survival analysis will be performed when the required number of deaths has been reached (currently 158, with a target of 283 deaths).

Safety analyses up to nine months after cisplatin plus radiotherapy were based on patients who had received at least one prior line of therapy. Compared with the nivolumab plus cisplatin and radiotherapy group, the cisplatin plus radiotherapy group had fewer grade 4 adverse events (5.6% vs. 13.1% within 100 days and 0% vs. 1.2% up to nine months after cisplatin plus radiotherapy, respectively) and treatment-related deaths (0.7% vs. 0.6%, respectively).

Conclusion: Postoperative adjuvant nivolumab plus cisplatin and radiation resulted in a statistically and clinically significant improvement in disease-free survival in patients with locally advanced head and neck squamous cell carcinoma in POL1 allcomers. This is the first time in over 20 years that a single therapy has been shown to be superior to standard treatment with adjuvant cisplatin plus radiotherapy in patients with locally advanced head and neck squamous cell carcinoma with high risk of recurrence.

Editor note: in a previous report about neoadjuvant pembrolizumab in locally advanced head and neck cancer patients, FDA approved pembrolizumab in PD-L1 posotive patients (6/22/2025). This article reported positive outcome in PD-L1 allcomers with nivolumab.

参考文献 Reference

Bourhis J et al. J Clin Onc 2025 ; 43 [17, suppl Abstr LBA2]

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Tarlatamab 对比化疗作为小细胞肺癌二线治疗 (9/5/2025)

Tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer: DeLLphi-304 trial

Tarlatamab 是一种双特异性 T 细胞衔接器 (靶向 δ 样配体 3 [DLL3]) 免疫疗法，在 I/II 期临床试验中，对既往接受过治疗的小细胞肺癌显示出良好的疗效。这项报告是随机对照 III 期 DeLLphi-304 (NCT05740566)研究的初步分析结果，该研究评估了 Tarlatamab 对比化疗在铂类化疗期间或之后病情进展的小细胞肺癌患者中的疗效。  

方法： 患者按 1:1 的比例随机分配接受Tarlatamab或化疗（拓扑替康、鲁比奈替丁或氨柔比星）治疗，并根据既往 PD-(L)1 抑制剂治疗史, 无化疗间隔期, 脑转移情况和拟接受化疗的情况进行分层。主要终点是总生存期。关键次要终点是无进展生存期和患者的报告。其他次要终点包括客观响应率. 响应持续时间, 疾病控制率和安全性。

结果：509 名患者随机分组（254 名接受Tarlatamab治疗；255 名接受化疗）。 Tarlatamab 组的中位随访时间为 11.2 个月，化疗组为 11.7 个月。Tarlatamab 组患者的总生存期（中位 总生存期：13.6 个月 vs 8.3 个月；风险比 [HR]，0.60 [95% CI：0.47, 0.77]；P < 0.001）和无进展生存期（中位无进展生存期：4.2 个月 vs 3.2 个月；HR，0.72 [95% CI：0.59, 0.88]；P < 0.001）均显著优于化疗组。与化疗相比，Tarlatamab 改善了癌症相关症状，如呼吸困难和咳嗽。Tarlatamab组≥3级治疗相关不良事件发生率低于化疗组（27% vs 62%）； Tarlatamab 组因治疗相关不良事件导致的停药率较低（3% vs 6%）。Tarlatamab 组最常见的 ≥3 级治疗相关不良事件为中性粒细胞减少症 (4%) 和淋巴细胞减少症 (4%)，而化疗组则为贫血 (28%) 和中性粒细胞减少症 (22%)。Tarlatamab 组的细胞因子释放综合征主要为低级别（42% 为 1 级；13% 为 2 级；1% 为 3 级），且可控。   

结论： DeLLphi-304 试验表明，对于在初始铂类化疗治疗期间或之后出现进展的小细胞肺癌患者，Tarlatamab 显著改善了总生存期,  无进展生存期和患者的报告，且安全性和耐受性优于化疗，这为这些患者确立了新的治疗标准。

Tarlatamab, a bispecific T cell engager (targeting delta-like ligand 3 [DLL3]) immunotherapy, has shown promising activity in previously treated small cell lung cancer (SCLC) in a phase I/II clinical trial. This report presents the primary analysis of the randomized, controlled, phase III DeLLphi-304 (NCT05740566) study, which evaluated tarlatamab versus chemotherapy in patients with SCLC whose disease progressed during or after platinum-based chemotherapy.

Methods: Patients were randomly assigned in a 1:1 ratio to receive tarlatamab or chemotherapy (topotecan, lurbinectedin or amrubicin) and stratified by prior PD-(L)1 inhibitor therapy, chemotherapy-free interval, brain metastasis status, and intended chemotherapy. The primary endpoint was overall survival. Key secondary endpoints were progression-free survival and patient-reported outcomes. Other secondary endpoints included objective response rate, duration of response, disease control rate, and safety.

Results: 509 patients were randomized (254 to tarlatamab; 255 to chemotherapy). Median follow-up was 11.2 months in the tarlatamab group and 11.7 months in the chemotherapy group. Patients in the tarlatamab group had significantly better overall survival (median overall survival: 13.6 months vs 8.3 months; hazard ratio [HR], 0.60 [95% CI: 0.47, 0.77]; P < .001) and progression-free survival (median progression-free survival: 4.2 months vs 3.2 months; HR, 0.72 [95% CI: 0.59, 0.88]; P < .001) than those in the chemotherapy group. Tarlatamab improved cancer-related symptoms, such as dyspnea and cough, compared with chemotherapy. The incidence of grade ≥3 treatment-related adverse events was lower in the tarlatamab group than in the chemotherapy group (27% vs 62%); discontinuation due to treatment-related adverse events was lower in the tarlatamab group (3% vs 6%). The most common grade ≥3 treatment-related adverse events in the tarlatamab group were neutropenia (4%) and lymphopenia (4%), compared with anemia (28%) and neutropenia (22%) in the chemotherapy group. Cytokine release syndrome in the tarlatamab group was primarily low-grade (42% grade 1; 13% grade 2; 1% grade 3) and manageable. Conclusion: The DeLLphi-304 trial demonstrated that tarlatamab significantly improved overall survival, progression-free survival, and patient-reported outcomes in patients with small cell lung cancer who had progressed during or after initial platinum-based chemotherapy, with a superior safety and tolerability profile compared to chemotherapy. This establishes a new standard of care for these patients.

参考文献 Reference

Rudin, C et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA8008)

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加巴喷丁类药物可使胶质母细胞瘤患者有生存获益 (8/31/2025)

Gabapentinoids confer survival benefit in human glioblastoma

这项回顾性, 多机构队列研究纳入了1,072例患者，其中包括693例发现队列患者 (Brigham and Women’s Hospital/Dana–Farber Cancer Institute or the Massachusetts General Hospital)，以及来自独立机构 (University of California, San Francisco) 的379例用于外部验证的患者。此外，研究结果表明，加巴喷丁给药与血清TSP-1水平降低相关，提示其有望成为未来的生物标志物。

发现队列 693 名新诊断的胶质母细胞瘤患者于 2010 年至 2022 年期间接受手术治疗。术后，103 名患者接受加巴喷丁治疗，中位剂量为 495 mg，中位疗程为 180天；590 名患者未接受加巴喷丁治疗。加巴喷丁组和非加巴喷丁组的诊断年龄中位数分别为 63 岁和 65 岁。加巴喷丁组和非加巴喷丁组的女性比例分别为 53.4% 和 44.6%。加巴喷丁组 O-6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 甲基化患者比例为 45.6%，非加巴喷丁组为 39.7%。术后接受加巴喷丁治疗的患者中，57.3% 的患者实现了肿瘤大体全切除术，而未接受加巴喷丁治疗的患者中，该比例为 44.7%。加巴喷丁组和未接受加巴喷丁治疗的患者中，36.9% 的患者实现了次全切除术，而未接受加巴喷丁治疗的患者中分别有 5.8% 和 5.9% 的患者接受了肿瘤活检。加巴喷丁组和未接受加巴喷丁治疗的患者中，分别有 81.6% 和 79.1% 的患者接受了放化疗联合治疗。

整个发现队列的中位总生存期为 13.0 个月（95% 置信区间 [CI] = 12.1-13.9 个月）。术后接受加巴喷丁治疗的患者的中位总生存期为16.0个月（95% CI = 13.2-18.8个月），而未接受加巴喷丁治疗的患者中位总生存期为12.0个月（95% CI = 11.1-12.9个月）（对数秩检验，p = 0.001）。多变量调整的Cox回归分析显示，生存时间的差异仍然显著（风险比[HR] = 0.65；95% CI = 0.51-0.84）。调整放疗和化疗后，使用加巴喷丁后仍观察到生存获益（HR = 0.72；95% CI = 0.56-0.92）。同样，调整左额叶肿瘤位置（即作为功能皮质的替代）后，加巴喷丁治疗后的生存获益几乎保持不变（HR = 0.66；95% CI = 0.51-0.84）。

加州大学旧金山分校验证队列纳入了379例新诊断的胶质母细胞瘤患者。接受加巴喷丁治疗的患者诊断时的中位年龄为58.1岁，未接受加巴喷丁治疗的患者诊断时的中位年龄为61.4岁。加巴喷丁组和非加巴喷丁组的女性比例分别为50.0%和37.3%。加巴喷丁组中16名已知MGMT甲基化状态的患者中，62.5%患有甲基化肿瘤。非加巴喷丁组中155名已知MGMT甲基化状态的患者中，46.5%患有甲基化肿瘤。加巴喷丁组80.6%的患者接受了放化疗联合治疗，非加巴喷丁组该比例为82.5%。加巴喷丁日总剂量中位数为600毫克。加巴喷丁组的中位总生存期为20.8（IQR = 11.7–32.1）个月，非加巴喷丁组为14.7（IQR = 8.9–23.5）个月。多变量 Cox 比例风险分析显示，术后加巴喷丁治疗具有生存优势 (HR = 0.65, 95% CI = 0.44-0.97)。

与对照组相比，给予已知的TSP-1抑制剂加巴喷丁与循环血清TSP-1水平降低相关。这一初步发现进一步证明，加巴喷丁介导的TSP-1抑制（相当于外周TSP-1水平降低）可抑制胶质母细胞瘤的增殖。

This retrospective, multi-institutional cohort study enrolled 1,072 patients, including 693 from the discovery cohort (Brigham and Women’s Hospital/Dana–Farber Cancer Institute or the Massachusetts General Hospital) and 379 from an independent institution (University of California, San Francisco) for external validation. Furthermore, the study results showed that gabapentin administration was associated with decreased serum TSP-1 levels, suggesting its potential as a future biomarker.

The discovery cohort included 693 newly diagnosed glioblastoma patients who underwent surgery between 2010 and 2022. Postoperatively, 103 patients received gabapentin at a median dose of 495 mg for a median duration of 180 days; 590 patients did not receive gabapentin. The median age at diagnosis was 63 years in the gabapentin group and 65 years in the non-gabapentin group. The proportion of women in the gabapentin group and the non-gabapentin group was 53.4% ​​and 44.6%, respectively. O-6-methylguanine-DNA methyltransferase (MGMT) methylation was observed in 45.6% of patients in the gabapentin group and 39.7% of patients in the non-gabapentin group. Postoperatively, 57.3% of patients who received gabapentin achieved gross complete resection of the tumor, compared with 44.7% of those who did not receive gabapentin. Subtotal resection was achieved in 36.9% of patients in the gabapentin group and 5.9% of those who did not receive gabapentin, respectively. Tumor biopsy was performed in 5.8% and 5.9% of those who did not receive gabapentin, respectively. Combined chemoradiotherapy was administered in 81.6% of patients in the gabapentin group and 79.1% of those who did not receive gabapentin, respectively.

The median overall survival for the entire discovery cohort was 13.0 months (95% confidence interval [CI] = 12.1-13.9 months). Patients who received gabapentin after surgery had a median overall survival of 16.0 months (95% CI = 13.2-18.8 months), compared with 12.0 months (95% CI = 11.1-12.9 months) for those who did not (log-rank test, p = 0.001). Multivariable-adjusted Cox regression analysis showed that the difference in survival remained significant (hazard ratio [HR] = 0.65; 95% CI = 0.51-0.84). After adjusting for radiotherapy and chemotherapy, the survival benefit observed with gabapentin was maintained (HR = 0.72; 95% CI = 0.56-0.92). Similarly, after adjusting for left frontal lobe tumor location (as a surrogate for functional cortex), the survival benefit with gabapentin treatment remained virtually unchanged (HR = 0.66; 95% CI = 0.51-0.84).

The UCSF validation cohort included 379 patients with newly diagnosed glioblastoma. The median age at diagnosis was 58.1 years for patients who received gabapentin, compared with 61.4 years for those who did not. The proportion of women in the gabapentin and non-gabapentin groups was 50.0% and 37.3%, respectively. Of the 16 patients in the gabapentin group with known MGMT methylation status, 62.5% had methylated tumors. Of the 155 patients in the non-gabapentin group with known MGMT methylation status, 46.5% had methylated tumors. 80.6% of patients in the gabapentin group received combined chemoradiotherapy, compared with 82.5% of patients in the non-gabapentin group. The median total daily gabapentin dose was 600 mg.

The median overall survival was 20.8 (IQR = 11.7–32.1) months in the gabapentin group and 14.7 (IQR = 8.9–23.5) months in the non-gabapentin group. Multivariable Cox proportional hazards analysis demonstrated a survival advantage with postoperative gabapentin treatment (HR = 0.65, 95% CI = 0.44-0.97).

Administration of gabapentin, a known TSP-1 inhibitor, was associated with reduced circulating serum TSP-1 levels compared with the control group. This preliminary finding further supports the idea that gabapentin-mediated TSP-1 inhibition (equivalent to reduced peripheral TSP-1 levels) can inhibit glioblastoma proliferation.

参考文献 Reference

Bernsock JD et al. Nature communication 2025 ;16 :4483

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单独化疗或联合阿特珠单抗术后治疗DNA错配修复缺陷 III期结肠癌: 一项III随机试验

Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for stage III deficient DNA mismatch repair (dMMR) colon cancer: ATOMIC trial

方法： 这是一项由 NCI 资助的多中心随机 III 期试验 (Alliance A021502, ATOMIC, NCT02912559)，纳入了已手术切除的 III 期DNA错配修复缺陷 (dMMR) 结肠腺癌患者（任何 T, N1, 2, M0）。患者按 1:1 的比例随机分配接受 mFOLFOX6 加阿特唑（atezolizumab, 840 毫克，每 2 周静脉注射）12 个周期（6 个月），随后接受阿特唑单药治疗 13 个周期（共 12 个月）或单独接受 mFOLFOX6 治疗 12 个周期。主要终点是无病生存期；次要终点是总生存期和不良事件概况（CTCAE、PRO-CTCAE）。在意向治疗人群中进行了主要疗效分析；按组比较无病生存期（分层对数秩检验）。使用分层 Cox 模型计算风险比和 95% 置信区间；通过 Kaplan-Meier 方法确定 3 年无病生存期。在700例患者中，165例无病生存事件（事件发生率分别为50%和75%）通过两次中期分析，以90%的检验功效检测出HR 0.6（3年无病生存期分别为75%和84.2%），假设生存期呈指数增长且α值单侧为0.025。

结果： 从2017年9月至2023年1月，712例患者（1例为儿科患者）随机分配接受阿替佐米联合mFOLFOX6治疗（阿替佐米组，n= 355）或mFOLFOX6治疗（n= 357）。患者中位年龄为64岁。55.1%为女性。肿瘤类型中，83.8%为近端肿瘤，46.1%为临床低危（T1-3N1），53.9%为高危（T4和/或N2）。在第二次中期分析中，患者随访中位数为37.2个月（四分位距，24.2-55.5），观察到124例无病生存事件。阿替佐组3年无病生存率为86.4%（95% CI，81.8-89.9），mFOLFOX6组为76.6%（95% CI，71.3-81.0）（HR，0.50；95% CI，0.35-0.72）。分层对数秩检验p值<0.0001，超过预设的疗效界限0.009。阿替佐组的疗效在各亚组间一致，包括70岁以上患者以及低危和高危组。阿特珠单抗组患者发生治疗相关3级以上不良事件的比例为71.7%，而mFOLFOX6组患者发生的比例为62.1%。

结论： 在mFOLFOX6方案中添加阿特珠单抗显著改善了无病生存期，应被视为dMMR III期结肠癌患者的新型辅助治疗标准。

Methods: This was a multicenter, randomized, phase III trial funded by the National Cancer Institute (NCI) (Alliance A021502, ATOMIC, NCT02912559) that enrolled patients with surgically resected stage III DNA mismatch repair-deficient (dMMR) colorectal adenocarcinoma (any T, N1, 2, M0). Patients were randomly assigned in a 1:1 ratio to receive mFOLFOX6 plus atezolizumab (840 mg intravenously every 2 weeks) for 12 cycles (6 months), followed by atezolizumab monotherapy for 13 cycles (12 months) or mFOLFOX6 alone for 12 cycles. The primary endpoint was disease-free survival; secondary endpoints were overall survival and adverse event profile (CTCAE, PRO-CTCAE). The primary efficacy analysis was performed in the intention-to-treat population; disease-free survival was compared by group (stratified log-rank test). Hazard ratios and 95% confidence intervals were calculated using a stratified Cox model; 3-year disease-free survival was determined by the Kaplan-Meier method. Among 700 patients, 165 disease-free survival events occurred (event rates of 50% and 75%, respectively). Two interim analyses provided 90% power to detect a hazard ratio (HR) of 0.6 (3-year disease-free survival rates of 75% and 84.2%, respectively), assuming exponential survival and a one-sided alpha value of 0.025.

Results: From September 2017 to January 2023, 712 patients (1 pediatric patient) were randomly assigned to receive atezolizumab plus mFOLFOX6 (atezolizumab group, n = 355) or mFOLFOX6 (n = 357). The median age of the patients was 64 years. 55.1% were female. Among tumor types, 83.8% were proximal, 46.1% were clinically low-risk (T1-3N1), and 53.9% were high-risk (T4 and/or N2). At the second interim analysis, with a median follow-up of 37.2 months (interquartile range, 24.2-55.5), 124 disease-free events were observed. The 3-year disease-free survival rate was 86.4% (95% CI, 81.8-89.9) in the atezolizumab group and 76.6% (95% CI, 71.3-81.0) in the mFOLFOX6 group (hazard ratio, 0.50; 95% CI, 0.35-0.72). The stratified log-rank test p-value was <0.0001, exceeding the prespecified efficacy limit of 0.009. The efficacy of the atezolizumab group was consistent across subgroups, including patients older than 70 years and those in both low- and high-risk groups. Treatment-related adverse events of grade 3 or higher occurred in 71.7% of patients in the atezolizumab group and 62.1% of patients in the mFOLFOX6 group.

Conclusion: The addition of atezolizumab to the mFOLFOX6 regimen significantly improved disease-free survival and should be considered a standard of care for patients with dMMR stage III colon cancer.

参考文献 Reference

Sinicrope FA et al. J Clin Onc 2025 ; 43 [17 suppl]

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Glofitamab 联合Pola-R-CHP或R-CHOP作为高危大B细胞淋巴瘤年轻患者的一线治疗 (8/24/2025)

Glofitamab combined with Pola-R-CHP or R-CHOP as First Therapy in younger patients with high-risk large B-cell lymphoma: the COALITION Study

目的 对于高危大B细胞淋巴瘤患者, 一线R-CHOP方案治愈率低于50%。由于筛选要求，高肿瘤负荷或快速进展的患者通常会被排除在一线临床试验之外。这项报告关于由研究者发起的II期COALITION试验，旨在研究CD20xCD3双特异性抗体Glofitamab联合R-CHOP或Pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone)方案，用于治疗具有高危特征的年轻患者，尽可能最大限度地缩短诊断和治疗之间的时间。

方法: 年龄≤65岁，患有大B细胞淋巴瘤且至少存在一项高危特征（国际预后指数[IPI]≥3、美国国家综合癌症网络-IPI≥4，或MYC和BCL2和/或BCL6基因重排）的患者接受1个周期的R-CHOP方案治疗，并被随机分配接受5个周期的Glofit-Pola-R-CHP方案（n = 40）或Glofit-R-CHOP方案（n = 40），以及2个周期的Glofitamab巩固治疗。患者入组时间为R-CHOP方案治疗之前或之后。主要研究目标是安全性和治疗可及性。次要终点包括响应率和生存期。

结果: 纳入了80名可评估患者，中位年龄为58岁，总代谢性肿瘤体积为842 cm³，从确诊到开始治疗的中位时间为14天。超过95%的患者完成了所有治疗，中位相对剂量强度 >94%。 21% 的患者出现细胞因子释放综合征，所有患者均≤2 级且可控。总响应率和完全响应率分别为 100% 和 98%。中位随访时间为 20.7 个月，预计 2 年无进展生存率和总生存率分别为 86% 和 92%。

结论: Glofitamab联合 R-CHOP 或 Pola-R-CHP 方案治疗效果显著，且在高肿瘤负荷, 高危大B细胞淋巴瘤年轻患者中可获得较高的持久响应率，支持其作为一线治疗方案的持续探索。

Purpose: For patients with high-risk large B-cell lymphoma, first-line R-CHOP has a cure rate of less than 50%. Patients with high tumor burden or rapidly progressive disease are often excluded from first-line clinical trials due to screening requirements. This report describes the investigator-initiated phase II COALITION trial, which was investigating the CD20xCD3 bispecific antibody Glofitamab in combination with R-CHOP or Pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone) in young patients with high-risk features, minimizing the time between diagnosis and treatment.

Methods: Patients aged ≤65 years with large B-cell lymphoma and at least one high-risk feature (International Prognostic Index [IPI] ≥3, National Comprehensive Cancer Network-IPI ≥4, or MYC and BCL2 and/or BCL6 gene rearrangements) received one cycle of R-CHOP and were randomly assigned to receive five cycles of Glofit-Pola-R-CHP (n = 40) or Glofit-R-CHOP (n = 40), followed by two cycles of glofitamab consolidation. Patients were enrolled before or after R-CHOP. The primary study objectives were safety and treatment accessibility. Secondary endpoints included response rate and survival.

Results: Eighty evaluable patients were enrolled, with a median age of 58 years and a total metabolic tumor volume of 842 cm³. The median time from diagnosis to treatment initiation was 14 days. More than 95% of patients completed all treatments, and the median relative dose intensity was >94%. Twenty-one percent of patients developed cytokine release syndrome, which was grade ≤2 and manageable in all patients. The overall response rate and complete response rate were 100% and 98%, respectively. With a median follow-up of 20.7 months, the estimated 2-year progression-free survival and overall survival rates were 86% and 92%, respectively.

Conclusion: Glofitamab combined with R-CHOP or Pola-R-CHP demonstrated significant efficacy and achieved high durable response rates in young patients with high-risk large B-cell lymphoma and a high tumor burden, supporting its continued exploration as a first-line treatment option.

参考文献 Reference

Minson A et al. J Clin Onc 2025 ; 43 : 2595

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新辅助化疗联合纳武利尤单抗治疗肺癌改善了总生存期 (8/23/2025)

Overall survival improved with neoadjuvant nivolumab plus chemotherapy in lung cancer

方法: 在这项开放标签的III期临床试验中(CheckMate 816, NCT02998528 )，IB期至IIIA期可切除非小细胞肺癌患者被随机分配接受纳武利尤单抗联合化疗或单纯化疗，治疗三个周期后接受手术。主要终点是无事件生存率和病理完全响应率。本文报告了计划内总生存率的分析结果。

结果: 共358例患者被同时分配接受纳武利尤单抗联合化疗（179例）或单纯化疗（179例）。最终的总生存率分析显示，新辅助治疗 nivolumab 联合化疗明显优于化疗（死亡风险比 0.72；95% 置信区间 [CI]，0.523 至 0.998；P=0.048）。中位随访时间为 68.4 个月，nivolumab 联合化疗组的 5 年总生存率为 65.4%，单纯化疗组为 55.0%，大多数亚组结果一致。探索性分析显示，在 nivolumab 联合化疗组中，病理完全响应患者的 5 年总生存率为 95.3%（95% CI，82.7 至 98.8），而未达到病理完全响应患者的 5 年总生存率为 55.7%（95% CI，46.9 至 63.7）；在术前循环肿瘤DNA 已清除的患者中，生存率为75.0%，而在未清除的患者中，生存率为52.6%。未观察到新的安全性信号。   

结论: 与单纯化疗相比，三周期纳武单抗联合化疗的新辅助治疗显著改善了可切除非小细胞肺癌患者的总生存期。 

Methods: In this open-label, phase III clinical trial (CheckMate 816, NCT02998528), patients with stage IB to IIIA resectable non-small cell lung cancer were randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone for three cycles followed by surgery. The primary endpoints were event-free survival and pathological complete response. The results of a planned analysis of overall survival were reported.  

Results: A total of 358 patients were concurrently assigned to receive nivolumab plus chemotherapy (n=179) or chemotherapy alone (n=179). The final overall survival analysis showed a significant benefit for neoadjuvant nivolumab plus chemotherapy compared with chemotherapy (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.523 to 0.998; P=0.048). With a median follow-up of 68.4 months, the 5-year overall survival rate was 65.4% in the nivolumab plus chemotherapy group and 55.0% in the chemotherapy alone group, with consistent results across most subgroups. Exploratory analyses showed that in the nivolumab plus chemotherapy group, the 5-year overall survival rate was 95.3% (95% CI, 82.7 to 98.8) for patients with a pathological complete response, compared with 55.7% (95% CI, 46.9 to 63.7) for those without a pathological complete response. Among patients with preoperative circulating tumor DNA clearance, the survival rate was 75.0%, compared with 52.6% for those without clearance. No new safety signals were observed.

Conclusion: Neoadjuvant treatment with three cycles of nivolumab plus chemotherapy significantly improved overall survival in patients with resectable non-small cell lung cancer compared with chemotherapy alone.

参考文献 Reference

Forde PM et al. N Engl J Med 2025 ; 393 :741

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拓扑异构酶 I 抑制剂的树枝状聚合物-纳米颗粒：在晚期实体瘤中的安全性及初步疗效 (8/17/2025)

Dendrimer-nanoparticle delivery of topoisomerase I inhibitor, SN38: Safety and preliminary efficacy study in advanced solid tumors

这项早期研究评估了树枝状聚合物-纳米颗粒递送平台(DEP)-SN38（一种基于聚赖氨酸的伊立替康活性代谢物SN38纳米颗粒偶联物）的安全性/耐受性, 药代动力学和初步疗效。

方法: 晚期实体瘤患者接受DEP-SN38静脉注射，每3周一次或每2周一单药治疗，或每2周一次联合氟尿嘧啶/亚叶酸钙治疗，以确定每种方案的推荐剂量。主要终点是安全性/耐受性。次要终点包括疗效和药代动力学。

结果: 接受过大量治疗的患者（N = 114；中位数为4种既往疗法）接受了DEP-SN38（8-15 mg/m² SN38），所有方案均推荐剂量为12.5 mg/m²。大多数与DEP-SN38相关的治疗相关不良事件为轻度/中度（89.7%），其中中性粒细胞减少症是主要的剂量限制性毒性反应，也是最常见的3/4级治疗相关不良事件（占3/4级事件的48%）。严重胃肠道治疗相关不良事件罕见（3级腹泻和呕吐[各占0.9%的患者]；恶心[1.8%]）。未观察到胆碱能症状。

在多种肿瘤类型中均观察到疗效信号，尤其是在每2周一次方案以及铂类耐药卵巢癌和结直肠癌患者中。在可评估患者中，每3周一次或每2周一次单药治疗以及每2周一次DEP-SN38/FU/LV治疗的客观响应率分别为1.8%、21.4%（铂类耐药卵巢癌 42.9%）和12.5%（结直肠14.3%）；疾病控制率分别为56.4%、71.4%和81.3%。每3周一次或每2周一次和每2周一次DEP-SN38/FU/LV治疗的中位无进展生存期分别为2.1个月、6.0个月和4.2个月。达到至少 6 个月无进展生存期的患者包括 7 例原发性结肠癌患者（每两周一次单药治疗，n = 5；> 12 个月，n = 3），12 例结直肠癌 患者（DEP-SN38/FU/LV，n = 6，其中 4 例患者治疗时间 > 12 个月），1 例胰腺癌患者（10.2 个月），1 例非小细胞肺癌患者（8.4 个月）以及 2 例乳腺癌患者（16.6 个月，6 个月）。  

结论: DEP-SN38 临床耐受性良好，严重胃肠道不良事件发生率极低。在接受过大量治疗的癌症患者中，初步的抗肿瘤活性证明了 DEP-SN38 单药治疗和联合方案的潜在临床应用。

This early-stage study evaluated the safety/tolerability, pharmacokinetics, and preliminary efficacy of the dendrimer-nanoparticle delivery platform (DEP)-SN38, a polylysine-based nanoparticle conjugate of the active metabolite of irinotecan, SN38.

Methods: Patients with advanced solid tumors received DEP-SN38 intravenously every 3 weeks or every 2 weeks as monotherapy or in combination with fluorouracil/leucovorin every 2 weeks to determine the recommended dose for each regimen. The primary endpoint was safety/tolerability. Secondary endpoints included efficacy and pharmacokinetics.

Results: Heavily pre-treated patients (N = 114; median 4 prior lines of therapy) received DEP-SN38 (8-15 mg/m² SN38), with the recommended dose of 12.5 mg/m² being used for all regimens. Most DEP-SN38-related treatment-related adverse events were mild/moderate (89.7%), with neutropenia being the major dose-limiting toxicity and the most common grade 3/4 treatment-related adverse event (accounting for 48% of grade 3/4 events). Severe gastrointestinal treatment-related adverse events were rare (grade 3 diarrhea and vomiting [each in 0.9% of patients]; nausea [1.8%]). No cholinergic symptoms were observed.

Efficacy signals were observed across multiple tumor types, particularly with the every-two-week regimen and in patients with platinum-resistant ovarian and colorectal cancers. Among evaluable patients, objective response rates were 1.8% with every-three-week or every-two-week monotherapy and 21.4% with every-two-week DEP-SN38/FU/LV (42.9% for platinum-resistant ovarian cancer), and 12.5% with every-two-week treatment (14.3% for colorectal cancer). Disease control rates were 56.4%, 71.4%, and 81.3%, respectively. Median progression-free survival (PFS) was 2.1 months, 6.0 months, and 4.2 months for patients treated with every 3 weeks, every 2 weeks, and every 2 weeks DEP-SN38/FU/LV, respectively. Patients achieving at least 6 months of PFS included 7 patients with primary colon cancer (n = 5 with biweekly monotherapy and n = 3 with treatment duration > 12 months), 12 patients with colorectal cancer (n = 6 with DEP-SN38/FU/LV, 4 of whom received treatment duration > 12 months), 1 patient with pancreatic cancer (10.2 months), 1 patient with non-small cell lung cancer (8.4 months), and 2 patients with breast cancer (16.6 months, 6 months).

Conclusion: DEP-SN38 was well tolerated clinically, with minimal incidence of serious gastrointestinal adverse events. Preliminary antitumor activity in heavily pretreated cancer patients demonstrates the potential clinical utility of DEP-SN38 as monotherapy and in combination regimens.

参考文献 Reference

Liu J et al. J Clin Onc 2025 ; Aug 1. https://doi.org/10.1200/JCO-25-00236

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TAR-200 治疗对卡介苗治疗无响应的高危非肌层浸润性膀胱癌 (8/16/2025)

TAR-200 for BCG–unresponsive high-risk non–muscle-invasive bladder cancer: SunRISe-1 trial

TAR-200 是一种首创的膀胱内药物释放系统，旨在持续向膀胱输送吉西他滨。

方法: 在这项 IIb 期平行队列研究中（SunRISe-1, NCT04640623。），BCG 无响应的原位癌伴/不伴乳头状病变患者接受 TAR-200 单药治疗（队列 2, C2）, TAR-200 联合cetrelimab (C1) 或cetrelimab单药治疗 (C3)。BCG 无响应的高危乳头状病变非肌层浸润性膀胱癌患者接受 TAR-200 单药治疗 (C4)。TAR-200 给药至第 24 个月；cetrelimab给药至第 18 个月。主要终点为总体完全响应率 (C1-3) 或无病生存率 (C4)。 

结果: 截至数据截止（2025 年 3 月 31 日），C1-4 组分别有 53, 85, 28 和 52 例患者接受治疗。TAR-200 单药治疗组的完全响应率和中位响应持续时间分别为 82.4%（95% CI，72.6-89.8）和 25.8 个月（95% CI，8.3-无法估计）。C4 组的 6,  9 和 12 个月无病生存率率分别为 85.3%（95% CI，71.6-92.7）, 81.1%（95% CI，66.7-89.7）和 70.2%（95% CI，51.6-82.8）。 TAR-200 单药治疗组和cetrelimab单药治疗组患者的完全响应率分别为 67.9%（95% CI，53.7-80.1%）和 46.4%（95% CI，27.5-66.1%）。C2,, C4、C1 和 C3 组≥3 级治疗相关不良事件发生率分别为 12.9%、13.5%、37.7% 和 7.1%，严重治疗相关不良事件发生率分别为 5.9%、5.8%、15.1% 和 3.6%。未发生治疗相关死亡病例。  

结论:  TAR-200 单药治疗对 BCG 无响应的高危非肌层浸润性膀胱癌患者耐受性良好，完全响应率高，疗效持久，无病生存期延长。对于 BCG 无响应的 CIS，TAR-200 单一疗法比 TAR-200 加 cetrelimab 或单独使用 cetrelimab 具有更有利的风险收益特征。

Methods: In this phase IIb, parallel-cohort study (SunRISe-1, NCT04640623), patients with BCG-unresponsive carcinoma in situ with or without papillary lesions received TAR-200 monotherapy (cohort 2, C2, experimental arm), TAR-200 combined with cetrelimab (C1), or cetrelimab monotherapy (C3). Patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary lesions received TAR-200 monotherapy (C4). TAR-200 was administered until month 24; cetrelimab was administered until month 18. The primary endpoint was overall complete response rate (C1-3) or disease-free survival (C4).

Results: As of data cutoff (March 31, 2025), 53, 85, 28, and 52 patients had been treated in arms C1-4, respectively. The complete response rate and median duration of response in the TAR-200 monotherapy group were 82.4% (95% CI, 72.6-89.8) and 25.8 months (95% CI, 8.3-not estimable), respectively. Disease-free survival rates at 6, 9, and 12 months in the C4 group were 85.3% (95% CI, 71.6-92.7), 81.1% (95% CI, 66.7-89.7), and 70.2% (95% CI, 51.6-82.8), respectively. The complete response rate in the TAR-200 monotherapy group and cetrelimab monotherapy group was 67.9% (95% CI, 53.7-80.1%) and 46.4% (95% CI, 27.5-66.1%), respectively. The incidence of grade ≥3 treatment-related adverse events was 12.9%, 13.5%, 37.7%, and 7.1% in the C2, C4, C1, and C3 groups, respectively. The incidence of serious treatment-related adverse events was 5.9%, 5.8%, 15.1%, and 3.6%, respectively. No treatment-related deaths occurred.

Conclusion: TAR-200 monotherapy was well tolerated in patients with high-risk non-muscle-invasive bladder cancer who were unresponsive to BCG, resulting in a high complete response rate, durable efficacy, and prolonged disease-free survival. For patients with BCG-unresponsive CIS, TAR-200 monotherapy has a more favorable risk-benefit profile than TAR-200 plus cetrelimab or cetrelimab alone.

参考文献 Reference

Daneshmand S et al. 2025; July 30.  https://doi.org/10.1200/JCO-25-01651

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个人护理产品中的甲醛和释放甲醛的防腐剂 (8/10/2025)

Formaldehyde and formaldehyde releasing preservatives in personal care products

甲醛和释放甲醛的防腐剂用于个人护理产品，以防止微生物生长并延长保质期。由于致癌性和其他健康问题，一些国家和美国各州已禁止或限制使用这些化学物质。这项报告调查了“盘点研究”( Taking Stock Study, TSS) 中列出的个人护理产品成分中甲醛和释放甲醛的防腐剂的普遍性。TSS 是一项社区参与研究，调查了南洛杉矶的 70 名女性使用智能手机应用程序记录了她们的个人护理产品使用情况。研究者利用美国环保署的化学品和产品数据库 (CPDat)（一个公共成分数据库）对研究结果进行了背景分析。超过一半的TSS参与者（53%）报告称她们使用至少一种含有甲醛或释放甲醛的防腐剂的个人护理产品，尽管只有4%的TSS 个人护理产品和8%的CPDat 个人护理产品将甲醛和/或释放甲醛的防腐剂列为成分。调查发现，在乳液和清洁剂等常用产品中也列出了甲醛和释放甲醛的防腐剂。最常见的释放甲醛的防腐剂是1,3-二羟甲基-5,5-二甲基乙内酰脲。这些结果可以为制定必要的法规提供参考，以保护美国民众免受个人护理产品使用过程中甲醛暴露带来的不良健康风险。 

编者注： 根据美国癌症协会的数据

人们接触甲醛的方式如下： 吸入（主要接触途径）, 通过皮肤吸收或食用或饮用含甲醛的食物或液体

甲醛在产品标签上可能有许多其他名称，例如： 福尔马林, 甲醛, 甲缩醛, 甲二醇, 环氧甲烷

一些用作防腐剂的化学物质会释放甲醛，例如： 苄基半缩甲醛,  2-溴-2-硝基丙烷-1,3-二醇,  5-溴-5-硝基-1,3-二氧六环,  二唑烷基脲, 1,3-二羟甲基-5,5-二甲基乙内酰脲（或DMDM乙内酰脲）,  咪唑烷基脲, 羟甲基甘氨酸钠, 季铵盐-15

Formaldehyde and formaldehyde-releasing preservatives are used in personal care products to prevent microbial growth and extend shelf life. Due to carcinogenicity and other health concerns, several countries and US states have banned or restricted the use of these chemicals.

This report examined the prevalence of formaldehyde and formaldehyde-releasing preservatives in personal care product ingredients listed in the Taking Stock Study (TSS). The TSS was a community-based study that surveyed 70 women in South Los Angeles who used a smartphone app to logged in their personal care product use. The researchers contextualized the study results using the US Environmental Protection Agency’s Chemicals and Products Database (CPDat), a public ingredient database. More than half of TSS participants (53%) reported using at least one personal care product containing formaldehyde or a formaldehyde-releasing preservative, although only 4% of TSS personal care products and 8% of CPDat personal care products listed formaldehyde and/or formaldehyde-releasing preservatives as ingredients.

The survey found that formaldehyde and formaldehyde-releasing preservatives were also listed in common products such as lotions and cleansers. The most common formaldehyde-releasing preservative is 1,3-dihydroxymethyl-5,5-dimethylhydantoin. These results could inform the types of regulation needed to protect the U.S. population from adverse health risks associated with formaldehyde exposure during the use of personal care products.

Editor’s note:as per American Cancer Society

People can be exposed to formaldehyde by: Inhaling it (the main way people are exposed), absorbing it through the skin, pr eating foods or drinking liquids containing formaldehyde

Formaldehyde can be listed on a product label by many other names, such as:

    Formalin

    Formic aldehyde

    Methanal

    Methyl aldehyde

    Methylene glycol

    Methylene oxide

Some chemicals that are used as preservatives can release formaldehyde, such as:

    Benzylhemiformal

    2-bromo-2-nitropropane-1,3-diol

    5-bromo-5-nitro-1,3-dioxane

    Diazolidinyl urea

    1,3-dimethylol-5,5-dimethylhydantoin (or DMDM hydantoin)

    Imidazolidinyl urea

    Sodium hydroxymethylglycinate

    Quaternium-15

参考文献 Reference

Dodson RE et al. Environ Sci Technol letter 2025 ; May 7.

https://www.cancer.org/cancer/risk-prevention/chemicals/formaldehyde.html (last revised Sept. 10, 2024)

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Polatuzumab vedotin, 利妥昔单抗, 吉西他滨和奥沙利铂治疗复发/难治性弥漫大B细胞淋巴瘤 (8/9/2025)

Pola-R-GemOx in patients with relapsed/refractory DLBCL : POLARGO trial

这是一项随机III期临床试验（POLARGO , NCT04182204），该试验评估了Polatuzumab vedotin,   利妥昔单抗, 吉西他滨和奥沙利铂(Pola-R-GemOx) 与 R-GemOx 在接受过≥1线治疗复发/难治性弥漫大B细胞淋巴瘤 ( DLBCL) 患者中的疗效。

方法： 在 Pola-R-GemOx 安全性试运行（n=15）后，不适合自体干细胞移植的复发/难治性DLBCL患者按 1:1 的比例随机分配接受 polatuzumab vedotin（1.8mg/kg）联合 R-GemOx（R，375mg/m²；Gem，1000mg/m²；Ox，100mg/m²）或单用 R-GemOx，每 21 天给药一次，最多 8 个周期。 主要终点是总生存期。次要终点包括研究者评估的无进展生存期，以及客观响应率和完全响应率。安全性终点包括不良事件的发生率, 性质和严重程度。

结果： 共入组270例DLBCL患者（中位年龄66岁[范围：20-89岁]），其中176例（65.2%）患者接受过1种既往治疗。246例非特发性弥漫性大B细胞淋巴瘤（DLBCL NOS）患者中，143例（58.1%）患有原发性难治性疾病。 截至2024年11月29日，在随机队列（n =255；中位总生存期随访：24.6个月）中，Pola-R-GemOx（n=129）组与R-GemOx（n=126；风险比[HR] 0.60，95%置信区间[CI]：0.43-0.83；p=0.0017）相比，观察到统计学上显著的总生存期优势。Pola-R-GemOx组的中位总生存期为19.5个月（95% CI：13.3-无法评估），而R-GemOx组的中位总生存期为12.5个月（95% CI：8.9-15.8）。 总生存期获益在大多数亚组中一致，包括基因表达谱分析的 ABC 和 GCB 亚型（分别为 HR 0.53 [95% CI: 0.3-0.9] 和 HR 0.54 [95% CI: 0.3-0.9]）。

在安全性可评估的患者中（Pola-R-GemOx，n=128；R-GemOx，n=125），Pola-R-GemOx 组的中位治疗周期数高于 R-GemOx 组（7.5 vs 4.0）。 Pola-R-GemOx 组 3-4 级不良事件发生率与 R-GemOx 组相似（57.0% vs 58.4%），但 Pola-R-GemOx 组的血小板减少症 (34.4% vs 26.4%) 和感染 (14.1% vs 8.0%) 发生率更高。Pola-R-GemOx 组周围神经病变发生率高于 R-GemOx 组（57.0% vs 28.8%），主要为 1 级 (37.5% vs 23.2%)。Pola-R-GemOx 组有 5 名患者出现 3 级周围神经病变。Pola-R-GemOx 组因不良事件导致的治疗中断率 (23.4%) 高于 R-GemOx 组 (8.0%)。 Pola-R-GemOx 组 5 级不良事件高于 R-GemOx 组 (11.7% vs 4.0%)，主要由包括 COVID-19 在内的感染引起。

结论： 本研究达到了主要终点和所有关键次要终点。Pola-R-GemOx 在总生存期和无进展生存期方面表现出统计学上显著且具有临床意义的获益。对于不适合移植的复发/难治性 DLBCL 患者，Pola-R-GemOx 是一种替代治疗方案。

This randomized phase III clinical trial (POLARGO, NCT04182204) evaluated polatuzumab vedotin, rituximab, gemcitabine, and oxaliplatin (Pola-R-GemOx) versus R-GemOx in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who had received ≥1 line of therapy.

Methods: Following a Pola-R-GemOx safety run-in (n=15), patients with relapsed/refractory DLBCL who were ineligible for autologous stem cell transplantation were randomly assigned in a 1:1 ratio to receive polatuzumab vedotin (1.8 mg/kg) plus R-GemOx (R, 375 mg/m²; Gem, 1000 mg/m²; Ox, 100 mg/m²) or R-GemOx alone, administered every 21 days for up to 8 cycles. The primary endpoint was overall survival. Secondary endpoints included investigator-assessed progression-free survival, as well as objective response rate and complete response rate. Safety endpoints included the incidence, nature, and severity of adverse events.

Results: A total of 270 patients with DLBCL (median age, 66 years [range, 20-89 years]) were enrolled, of whom 176 (65.2%) had received at least one prior therapy. Of the 246 patients with not-otherwise-specified diffuse large B-cell lymphoma (DLBCL NOS), 143 (58.1%) had primary refractory disease. As of November 29, 2024, in the randomized cohort (n = 255; median overall survival follow-up: 24.6 months), a statistically significant overall survival advantage was observed in the Pola-R-GemOx group (n = 129) compared with the R-GemOx group (n = 126; hazard ratio [HR] 0.60, 95% confidence interval [CI]: 0.43-0.83; p = 0.0017). The median overall survival was 19.5 months (95% CI: 13.3-not evaluable) in the Pola-R-GemOx group and 12.5 months (95% CI: 8.9-15.8) in the R-GemOx group. The overall survival benefit was consistent across most subgroups, including the ABC and GCB subtypes analyzed by gene expression profiling (HR 0.53 [95% CI: 0.3-0.9] and HR 0.54 [95% CI: 0.3-0.9], respectively). Among patients evaluable for safety (Pola-R-GemOx, n=128; R-GemOx, n=125), the median number of treatment cycles was higher in the Pola-R-GemOx group than in the R-GemOx group (7.5 vs 4.0).

The incidence of grade 3-4 adverse events was similar in the Pola-R-GemOx and R-GemOx groups (57.0% vs 58.4%), but the Pola-R-GemOx group had higher rates of thrombocytopenia (34.4% vs 26.4%) and infections (14.1% vs 8.0%). The incidence of peripheral neuropathy was higher in the Pola-R-GemOx group than in the R-GemOx group (57.0% vs 28.8%), primarily grade 1 (37.5% vs 23.2%). Five patients in the Pola-R-GemOx group experienced grade 3 peripheral neuropathy. The rate of treatment discontinuation due to adverse events was higher in the Pola-R-GemOx group (23.4%) than in the R-GemOx group (8.0%). Grade 5 adverse events were more common in the Pola-R-GemOx group than in the R-GemOx group (11.7% vs 4.0%), primarily due to infections including COVID-19.

Conclusion: This study met its primary endpoint and all key secondary endpoints. Pola-R-GemOx demonstrated statistically significant and clinically meaningful benefits in overall survival and progression-free survival. Pola-R-GemOx is an alternative treatment option for patients with relapsed/refractory DLBCL who are not transplant candidates.   

参考文献 Reference

Matasar M, et al: EHA 2025 Congress. Abstract S101

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Savolitinib与奥希替尼对MET+ 的 EGFR 突变型非小细胞肺癌的增强作用 (8/3/2025)

Additional effect of savolitinib and osimertinib in MET+ EGFR-mutant non-small cell lung cancer

Savolitinib是一个选择性 MET 抑制剂。

方法: SAVANNAH试验 (NCT03778229) 是一项随机双盲II期临床研究，在这项试验中，如果患者的肿瘤在奥希替尼治疗后出现进展并出现MET驱动的耐药迹象，则符合入选条 件。两种关键生物标志物用于识别MET激活：MET过表达（定义为90%或更多肿瘤细胞的IHC 3+染色强度）和MET扩增（通过FISH检测确定至少10个MET基因拷贝数）。  参与者按2:1的比例随机分配接受Savolitinib（每日两次，每次300毫克）联合奥希替尼（每日一次，每次80毫克）或Savolitinib联合安慰剂治疗。该试验纳入了脑转移患者，前提是这些转移灶稳定或既往接受过治疗。根据脑转移的存在进行分层随机分组。 该研究的主要目标是评估该组合疗法的客观响应率, 响应持续时间以及无进展生存期。此外，该试验还评估中枢神经系统特异性无进展生存期和追踪任何新的中枢神经系统病变的发生发展。

结果: 在 SAVANNAH 试验中，Savolitinib联合奥希替尼组 (联合治疗组)的中位年龄为 67 岁，Savolitinib联合安慰剂组(安慰剂组)的中位年龄为 65 岁。 联合治疗组患者中女性（73% vs 64%）和白种人（73% vs 52%）的比例更高。 联合治疗组在所有测量结果中均显示出显著优于安慰剂组的临床活性。联合治疗组的客观响应率为 58%，安慰剂组为 16%。联合治疗组的患者的中位响应持续时间为 11.8 个月，安慰剂组为 4.5 个月。联合治疗组的中位无进展生存期为8.3个月，安慰剂组为3.6个月。

在基线脑转移患者中，联合治疗的患者中有36%（14 例中有 5 例）发生了中枢神经系统无进展生存事件，而安慰剂组为 50%（4 例中有 2 例）。 在基线无脑转移的患者中，接受联合治疗的 13 例患者在疾病进展时均未出现新的中枢神经系统病变。相比之下，安慰剂组 11 例患者中，6 例（55%）在疾病进展时出现了新的中枢神经系统转移。 这些结果表明联合疗法具有良好的中枢神经系统保护作用。

结论: 这些结果显示了EGFR和MET双抑制剂的附加价值，尤其是在肿瘤存在MET驱动耐药机制的患者中。Savolitini联合奥希替尼不仅提高了响应率，还延长了响应持续时间和疾病控制率。

Savolitinib is a selective MET inhibitor.

Methods: The SAVANNAH trial (NCT03778229) was a randomized, double-blind, phase II clinical study in which patients’ tumors had progressed after osimertinib treatment and demonstrated signs of MET-driven resistance. Two key biomarkers were used to identify MET activation: MET overexpression (defined as IHC 3+ staining intensity in 90% or more tumor cells) and MET amplification (at least 10 MET gene copies as determined by FISH). Participants were randomly assigned in a 2:1 ratio to receive savolitinib (300 mg twice daily) plus osimertinib (80 mg once daily) or savolitinib plus placebo. The trial enrolled patients with stable or previously treated brain metastases. Randomization was stratified according to the presence of brain metastases. The primary objectives of the study were to assess the objective response rate, duration of response, and progression-free survival of this combination therapy. In addition, the trial assessed CNS-specific progression-free survival and tracked the development of any new CNS lesions.

Results: The median age was 67 years in the savolitinib plus osimertinib group (combination group) and 65 years in the savolitinib plus placebo group (placebo group). A higher proportion of patients in the combination group were female (73% vs 64%) and white (73% vs 52%). The combination group demonstrated significantly superior clinical activity compared with the placebo group across all outcome measures. The objective response rate was 58% in the combination group and 16% in the placebo group. The median duration of response was 11.8 months in the combination group and 4.5 months in the placebo group. The median progression-free survival was 8.3 months in the combination group and 3.6 months in the placebo group.

Among patients with baseline brain metastases, 36% (5 of 14) of those receiving the combination therapy had CNS progression-free survival events, compared with 50% (2 of 4) of those receiving placebo. Among patients without baseline brain metastases, none of the 13 patients receiving the combination therapy developed new CNS lesions at the time of disease progression. In contrast, 6 of 11 patients (55%) in the placebo group developed new CNS metastases at the time of disease progression. These results suggest that the combination therapy has a strong CNS protective effect. Conclusion: These results demonstrate the added value of dual EGFR and MET inhibitors, particularly in patients whose tumors harbor MET-driven resistance mechanisms.

参考文献 Reference

Levy BP et al. 2025 ASCO, June 2.

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肿瘤电场治疗联合吉西他滨/白蛋白结合型紫杉醇治疗局部晚期胰腺癌(8/2/2025)

Tumor treating fields with gemcitabine and nab-paclitaxel for locally advanced pancreatic adenocarcinoma: Phase III PANOVA-3 study

肿瘤电场治疗 (TTFields) 使用交变电场来抑制癌细胞增殖。PANOVA-3 旨在验证肿瘤电场治疗对无法切除的局部晚期胰腺癌患者的安全性和有效性。

方法: 在这项全球开放标签, 随机, III 期临床试验中，571 名新诊断为局部晚期胰腺癌的患者被随机分配接受吉西他滨 1,000 mg/m² 和白蛋白结合型紫杉醇 125 mg/m² 静脉输注，第 1、8 和 15 天给药，28 天为一个周期，联合或不联合肿瘤电场治疗治疗。主要终点是总生存期。次要终点包括无进展生存期, 局部无进展生存期, 无痛生存期和总缓解率。对远处无进展生存期进行了事后分析。

结果: 与吉西他滨/白蛋白结合型紫杉醇方案相比，肿瘤电场联合化疗治疗方案的总生存期显著延长（中位总生存期为 16.2 个月 [95% CI, 15.0 – 18.0] vs 14.2 个月 [95% CI, 12.8 – 15.4]；风险比 [HR] 为 0.82 [95% CI, 0.68 – 0.99]；P = 0.039）。无进展生存期, 局部无进展生存期和响应均未改善。肿瘤电场治疗联合吉西他滨 / 白蛋白结合型紫杉醇治疗组的无痛生存期显著延长 （中位数，15.2 个月 [95% CI, 10.3 至 22.8] v 9.1 个月 [95% CI, 7.4 至 12.7]；HR，0.74 [95% CI, 0.56 至 0.97]；P = 0.027），远处无进展生存期也显著延长（中位数，13.9 个月 [95% CI, 12.2 至 16.8] v 11.5 个月 [95% CI, 10.4 至 12.9]；HR，0.74 [95% CI, 0.57 至 0.96]；P = 0.022）。

76.3% 的患者经历了与器械相关的皮肤不良事件。大多数与器械相关的皮肤不良事件为轻度至中度，7.7% 的患者报告为 3 级不良事件。

结论 本研究表明，对于无法切除的局部晚期胰腺癌患者，肿瘤电场治疗联合吉西他滨/白蛋白结合型紫杉醇相比吉西他滨/白蛋白结合型紫杉醇具有显著的总生存期, 无痛生存期和远处无进展生存期优势，且未增加全身毒性。

Tumor Treating Fields (TTFields) uses alternating electric fields to inhibit cancer cell proliferation. PANOVA-3 was designed to evaluate the safety and efficacy of TTFields in patients with unresectable, locally advanced pancreatic cancer.

Methods: In this global, open-label, randomized, phase III clinical trial, 571 patients with newly diagnosed locally advanced pancreatic cancer were randomly assigned to receive gemcitabine 1,000 mg/m² and nab-paclitaxel 125 mg/m² intravenously on days 1, 8, and 15 of a 28-day cycle, with or without TTFields. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, local progression-free survival, pain-free survival, and overall response rate. A post hoc analysis of distant progression-free survival was performed.  

Results: Overall survival was significantly prolonged with tumor TTFields plus chemotherapy compared with chemotherapy alone (median overall survival, 16.2 months [95% CI, 15.0 – 18.0] vs 14.2 months [95% CI, 12.8 – 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 – 0.99]; P = .039). Progression-free survival, local progression-free survival, and response were not improved. The combination of TTFields and gemcitabine/nab-paclitaxel resulted in significantly longer pain-free survival (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as well as longer distant progression-free survival (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022).

Device-related skin adverse events occurred in 76.3% of patients. Most device-related cutaneous adverse events were mild to moderate, with grade 3 adverse events reported in 7.7% of patients. Conclusion: This study showed that for patients with unresectable locally advanced pancreatic cancer,  TTFields combined with gemcitabine/nab-paclitaxel demonstrated significant advantages in overall survival, pain-free survival, and distant progression-free survival compared with gemcitabine/nab-paclitaxel alone, without increasing systemic toxicity.

参考文献 Reference

Babiker HM et al. J Clin Onc 2025 ; 43 : https://doi.org/10.1200/JCO-25-007

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Patritumab deruxtecan 治疗实体瘤软脑膜转移 (7/27/2025)

Patritumab deruxtecan in metastatic leptomeningeal disease: phase 2 TUXEDO-3 trial

抗体-药物偶联物 patritumab deruxtecan (HER3-DXd) 已证实对乳腺癌和肺癌有效，HER3 参与中枢神经系统转移。这项研究评估了 HER3-DXd 在 TUXEDO-3 II 期试验 (NCT05865990)第 3 组软脑膜转移患者中的疗效和安全性。关键入选标准包括年龄≥18 岁、未接受过治疗的软脑膜转移或任何实体瘤放疗后软脑膜转移进展。 2024 年 1 月至 7 月期间，共收集到 20 名可评估患者（9 名 I 型软脑膜转移患者和 11 名 II 型软脑膜转移患者），每 3 周静脉注射 HER3-DXd 5.6 mg/kg。主要原发肿瘤类型包括乳腺癌（60%）和肺癌（30%）。

中位随访时间为 5.4 个月。65.0% 的患者在 3 个月后存活，达到了主要终点。Kaplan-Meier 估计的 3 个月和 6 个月总生存率分别为 69.6% 和 58.9%。颅内总有效率 11.1%，颅外总有效率 30.8%，整体病变总有效率 26.3%。颅内临床受益率为 50.0%，颅外临床受益率为 38.5%，整体病变临床受益率为 47.4%。

在研究治疗期间，神经系统症状和生活质量保持稳定或有所改善。未观察到新的神经系统不良事件。最常见的不良事件（各级别）包括贫血（9例（40.9%）患者，其中1例（4.5%）≥3级）、恶心（7例（31.8%）患者，无≥3级）、中性粒细胞减少症（6例（27.3%）患者，其中3例（13.6%）≥3级）、腹泻（6例（27.3%）患者，其中1例（4.5%）≥3级）、乏力（6例（27.3%）患者，无≥3级）以及血小板减少症和头痛（5例（22.7%）患者，各1例（4.5%）≥3级）。

TUXEDO-3 是首个评估 HER3-DXd 对软脑膜转移患者疗效和安全性的试验。HER3-DXd 表现出显著的中枢神经系统活性，可能成为癌症患者中枢神经系统疾病的一种潜在新型治疗方法。

The antibody-drug conjugate patritumab deruxtecan (HER3-DXd) has demonstrated efficacy in breast and lung cancer, and HER3 is involved in central nervous system metastases. This study evaluated the efficacy and safety of HER3-DXd in patients with leptomeningeal metastases in cohort 3 of the phase II TUXEDO-3 trial (NCT05865990). Key inclusion criteria included age ≥18 years, untreated leptomeningeal metastases, or leptomeningeal metastases that progressed after radiation therapy for any solid tumor. Between January and July 2024, a total of 20 evaluable patients (9 patients with type I leptomeningeal metastases and 11 patients with type II leptomeningeal metastases) were enrolled and received HER3-DXd 5.6 mg/kg intravenously every 3 weeks. The main primary tumor types included breast cancer (60%) and lung cancer (30%).

The median follow-up was 5.4 months. 65.0% of patients were alive after 3 months, reaching the primary endpoint. The Kaplan-Meier estimated 3-month and 6-month overall survival rates were 69.6% and 58.9%, respectively. The total intracranial response rate was 11.1%, the total extracranial response rate was 30.8%, and the total overall lesion response rate was 26.3%. The intracranial clinical benefit rate was 50.0%, the extracranial clinical benefit rate was 38.5%, and the overall lesion clinical benefit rate was 47.4%.

During the study treatment, neurological symptoms and quality of life remained stable or improved. No new neurological adverse events were observed. The most common adverse events (all grades) included anemia (9 (40.9%) patients, including 1 (4.5%) grade ≥3), nausea (7 (31.8%) patients, none grade ≥3), neutropenia (6 (27.3%) patients, including 3 (13.6%) grade ≥3), diarrhea (6 (27.3%) patients, including 1 (4.5%) grade ≥3), fatigue (6 (27.3%) patients, none grade ≥3), and thrombocytopenia and headache (5 (22.7%) patients, each 1 (4.5%) grade ≥3).

TUXEDO-3 is the first trial to evaluate the efficacy and safety of HER3-DXd in patients with leptomeningeal metastases. HER3-DXd has demonstrated significant CNS activity and may be a potential novel treatment for CNS disease in cancer patients.

参考文献 Reference

Preusser M et al. J Clin Onc 2025 ; https://doi.org/10.1200/JCO.2025.43.16_suppl.2005

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针对 TCR b 链靶向抗体 invikafusp alfa 用于治疗抗 PD(L)1 耐药的实体瘤 (7/26/2025)

Invikafusp alfa, a TCR b-chain targeting antibody, treating anti-PD(L)1-resistant solid tumors

Invikafusp alfa (STAR0602) 是一种靶向 Vβ6/Vβ10 T 细胞的选择性双 T 细胞激动剂。

方法： 这是一项针对抗 PD(L)1 耐药, 富含抗原的实体瘤（包括高肿瘤突变负担, MSI-H/dMMR 或病毒相关）患者的多中心 I/II期单药治疗临床试验。这报告包括了 1) 静脉注射 invikafusp 剂量递增的最新临床结果，每两周一次，按照 3+3 方案给药，并以最佳生物剂量水平进行补充给药； 2) 首次基于药代动力学, 药效学, 安全性和抗肿瘤活性确定推荐的II期剂量；3) 转化免疫学研究的新成果。

结果： 截至2025年1月7日，共入组41例患者（18例高肿瘤突变负担肿瘤患者），患者既往接受过18种不同类型富含抗原肿瘤的中位数为4线的治疗。更新的临床结果为：自先前报告以来未发现新的安全性信号，最常见的治疗相关的不良反应是细胞因子释放综合征（主要为1级和2级），这与invikafusp的作用机制一致。

在12例接受最佳生物剂量（0.08或0.12 mg/kg）单药治疗的高肿瘤突变负担患者中，9例在提交研究报告时进行了≥1次肿瘤评估。总体而言，这9例患者中有6例（66.6%）获得了疾病控制 [确认部分响应 + 病情稳定]。这 6 例患者中有 4 例 (44.4%) 可测量到肿瘤缩小：2 例 (22.2%) 微卫星稳定性结肠直肠癌患者出现部位分响应，其中一次响应持续约 12 个月；2 例 (22.2%)（1 例黑色素瘤患者和 1 例胰腺癌患者）肿瘤缩小，病情稳定。另外 6 例患者中有 2 例 (22.2%)（1 例食管癌患者和 1 例微卫星稳定性结肠直肠癌患者）病情稳定。

推荐的II期剂量：Invikafusp 血清峰浓度 (Cmax) 与剂量 ≥ 0.08 mg/kg 成比例增加，导致 Cmax 等于或高于药理学90%有效浓度 (EC90)。基因表达分析显示在所有患者中均观察到外周 Vβ6 和 Vβ10 T 细胞的剂量依赖性选择性扩增，最大峰值扩增在 0.08 和 0.12 mg/kg 剂量时达到。在推荐的II期剂量（0.08 mg/kg）剂量下，CD8+ Vβ6/ Vβ10 T细胞在第8天达到平均峰值扩增约600%。转化研究（n=7例患者）：与临床前研究一致，扩增的外周Vβ6/Vβ10 T细胞表现出非典型中央记忆表型，并表达细胞毒性效应分子。部分患者出现循环肿瘤DNA减少和抗原特异性Vβ6/Vβ10 T细胞扩增，其中1例循环肿瘤DNA减少的患者病情稳定，并接受了约15个月的试验。给药后数小时内观察到T细胞活化可溶性标志物（例如IFN-γ、sCD25）增加，促炎细胞因子（例如TNF-α和IL-6）释放减少。   

结论： Invikafusp 是一种选择性双 T 细胞激动剂，单药治疗在抗 PD(L)-1 耐药肿瘤中表现出具有临床意义的抗肿瘤活性。它能够促进以 CD8+ Vβ6/ Vβ10 为主的 T 细胞强效且选择性地扩增，并具有新的非典型中央记忆表型，同时导致循环肿瘤DNA 减少和抗原特异性 T 细胞扩增。基于这些初步临床结果，美国 FDA 授予 Invikafusp 用于治疗高肿瘤突变负担结直肠癌的快速通道资格认定，目前正在针对富含抗原（例如高肿瘤突变负担和 MSI-H/dMMR）的肿瘤开展 II 期临床试验。

Invikafusp alfa (STAR0602) is a selective dual T cell agonist targeting Vβ6/Vβ10 T cells. Methods: This is a multicenter phase I/II monotherapy clinical trial in patients with anti-PD(L)1-resistant, antigen-rich solid tumors (including high tumor mutation burden, MSI-H/dMMR or virally related). This report includes 1) updated clinical results of intravenous invikafusp dose escalation, once every two weeks, according to a 3+3 schedule, and supplemented with optimal biologic dose levels; 2) the first determination of the recommended phase II dose based on pharmacokinetics, pharmacodynamics, safety and antitumor activity; 3) new results from translational immunology research.

Results: As of January 7, 2025, a total of 41 patients (18 patients with high tumor mutation burden tumors) were enrolled, and patients had previously received a median of 4 lines of treatment for 18 different types of antigen-rich tumors. Updated clinical results: No new safety signals were found since the previous report, and the most common treatment-related adverse reaction was cytokine release syndrome (mainly grade 1 and 2), which is consistent with the mechanism of action of invikafusp.

Among the 12 patients with high tumor mutation burden who received the optimal biologic dose (0.08 or 0.12 mg/kg) monotherapy, 9 had ≥1 tumor assessment at the time of study submission. Overall, 6 of these 9 patients (66.6%) achieved disease control [confirmed partial response + stable disease]. Four of these 6 patients (44.4%) had measurable tumor shrinkage: 2 patients (22.2%) with microsatellite stable colorectal cancer had a partial response, one of which lasted approximately 12 months; 2 patients (22.2%) (1 melanoma patient and 1 pancreatic cancer patient) had tumor shrinkage and stable disease. Two of the six additional patients (22.2%) (one with esophageal cancer and one with microsatellite-stable colorectal cancer) had stable disease. Recommended Phase II Dose: Invikafusp peak serum concentrations (Cmax) increased proportionally with doses ≥ 0.08 mg/kg, resulting in Cmax equal to or above the pharmacological 90% effective concentration (EC90). Gene expression analysis showed dose-dependent selective expansion of peripheral Vβ6 and Vβ10 T cells was observed in all patients, with maximum peak expansion achieved at 0.08 and 0.12 mg/kg doses. At the recommended phase II dose (0.08 mg/kg), CD8+ Vβ6/ Vβ10 T cells achieved a mean peak expansion of approximately 600% on day 8. Translational Studies (n=7 patients): Consistent with preclinical studies, expanded peripheral Vβ6/Vβ10 T cells exhibited an atypical central memory phenotype and expressed cytotoxic effector molecules. Some patients experienced a decrease in circulating tumor DNA and expansion of antigen-specific Vβ6/Vβ10 T cells, and one patient with a decrease in circulating tumor DNA had stable disease and was on the trial for approximately 15 months. Increases in soluble markers of T cell activation (e.g., IFN-γ, sCD25) and decreased release of proinflammatory cytokines (e.g., TNF-α and IL-6) were observed within hours of administration. Conclusion: Invikafusp is a selective dual T cell agonist that exhibits clinically significant antitumor activity as a monotherapy in anti-PD(L)-1 resistant tumors. It promotes potent and selective expansion of CD8+ Vβ6/ Vβ10-dominant T cells with a novel atypical central memory phenotype, while leading to a decrease in circulating tumor DNA and expansion of antigen-specific T cells. Based on these preliminary clinical results, the FDA granted Invikafusp Fast Track designation for the treatment of colorectal cancer with a high tumor mutation burden, and a phase II clinical trial is currently underway for tumors that are antigen-rich (e.g., high tumor mutation burden and MSI-H/dMMR). 

参考文献 Reference

Sullivan RJ et al. Cancer Res 2025; 85[8, suppl_2]

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RP1 联合纳武单抗治疗抗PD-1治疗失败的晚期黑色素瘤 (7/20/225)

RP1 combined with nivolumab in advanced anti–PD-1–failed melanoma (IGNYTE)

免疫检查点阻断失败后，黑色素瘤的有效治疗方案有限。RP1（vusolimogene oderparepvec）是一种基于HSV-1的溶瘤免疫疗法，本文评估其与纳武单抗联合治疗抗PD-1治疗失败的黑色素瘤的效果。

方法: 患者为经抗PD-1治疗（≥8周）的晚期黑色素瘤患者。RP1瘤内注射（≤8剂，≤10 mL/剂；允许额外剂量），联合纳武单抗治疗（≤2年）。客观响应率由独立中央评审机构进行评估。

结果: 在这项临床试验 (IGNYTE, NCT03767348) 入选的140例患者中，48.6%为IV M1b/c/d期患者，65.7%为原发性抗PD-1耐药患者，56.4%为PD-L1阴性患者，46.4%接受过抗PD-1和抗CTLA-4治疗（43.6%为联合治疗，2.9%为序贯治疗）。确认的客观响应率为32.9%（25.2% -41.3%；完全响应率为15.0%）。对于注射和非注射（包括内脏）病变，响应频率, 深度, 持续时间和动力学相似。中位响应持续时间（95% CI）为33.7个月（14.1个月-未达到）。 1年和2年总生存率（95% CI）分别为75.3%（66.9%-81.9%）和63.3%（53.6%-71.5%）。生物标志物分析显示，与疗效相关的免疫激活广泛存在，包括CD8+ T细胞浸润增加和PD-L1表达增加。治疗相关不良事件发生率分别为1/2级77.1%、3级9.3%、4级3.6%，无5级事件。

结论: RP1联合纳武单抗可为抗PD-1疗法失败的黑色素瘤患者（包括预后不良的患者）带来深度且持久的全身响应。安全性良好，不良事件多为1/2级。

After failure of immune checkpoint blockade, effective treatment options for melanoma are limited. This article evaluates the effect of RP1 (vusolimogene oderparepvec), an HSV-1-based oncolytic immunotherapy, in combination with nivolumab in the treatment of melanoma that has failed anti-PD-1 therapy.

Methods: Patients in the trial had advanced melanoma who had been treated with anti-PD-1 (≥ 8 weeks). RP1 was injected intratumorally (≤ 8 doses, ≤10 mL/dose; additional doses were allowed) and combined with nivolumab treatment (≤ 2 years). Objective response rate was assessed by an independent central review organization.

Results: Among the 140 patients enrolled in this clinical trial (IGNYTE, NCT03767348), 48.6% were stage IV M1b/c/d, 65.7% were primary anti-PD-1 resistant, 56.4% were PD-L1 negative, and 46.4% had received anti-PD-1 and anti-CTLA-4 therapy (43.6% combination therapy, 2.9% sequential therapy). The confirmed objective response rate was 32.9% (25.2% -41.3%; complete response rate was 15.0%). The response frequency, depth, duration and kinetics were similar for injected and non-injected (including visceral) lesions. The median duration of response (95% CI) was 33.7 months (14.1 months-not reached). The 1-year and 2-year overall survival rates (95% CI) were 75.3% (66.9%-81.9%) and 63.3% (53.6%-71.5%), respectively. Biomarker analysis showed widespread immune activation associated with efficacy, including increased CD8+ T cell infiltration and increased PD-L1 expression. The incidence of treatment-related adverse events was 77.1% for grade 1/2, 9.3% for grade 3, and 3.6% for grade 4, with no grade 5 events. Conclusion: RP1 combined with nivolumab can bring deep and durable systemic responses to melanoma patients who have failed anti-PD-1 therapy, including those with poor prognosis. The safety profile is good, and most adverse events are grade 1/2.

参考文献 Reference

Wong MK et al. J Clin Onc 2025 ; https://doi.org/10.1200/JCO-25-01346

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Aprepitant 在化疗期间的使用与早期乳腺癌生存期的相关性 (7/19/2025)

Aprepitant use during chemotherapy and association with survival in early breast cancer

阿瑞匹坦（一种用于预防化疗引起的恶心和呕吐的止吐药）可减缓乳腺肿瘤的生长和进展。

方法: 挪威全国范围内的登记数据确定了2008年至2020年间被诊断患有早期乳腺癌并接受化疗和止吐治疗的13,811名女性。从确诊后一年起至2021年底，研究人员对女性患者的转移和死亡情况进行了随访。为了评估阿瑞匹坦的使用与远处无病生存期 (DDFS) 和乳腺癌特异性生存期 (BCSS) 之间的关联，研究人员使用了 Cox 回归模型，校正了肿瘤和患者特征, 化疗方案以及其他止吐药物的使用。

结果: 在化疗期间，7,047 名（51%）女性患者接受了阿瑞匹坦治疗。总体而言，阿瑞匹坦的使用与更好的远处无病生存期HRDDFS 0.89；95% CI 0.79-1.00）和乳腺癌特异性生存期（HRBCSS 0.83；95% CI 0.71-0.97）相关。生存优势仅体现在非腔内 (non-luminal) 乳腺癌患者身上（HRDDFS 0.69；95% CI 0.56-0.83；HRBCSS 0.64；95% CI 0.51-0.81），且在三阴性乳腺癌患者中最为显著（HRDDFS 0.66；95% CI 0.53-0.83；HRBCSS 0.61；95% CI 0.47-0.80）。对于非腔内乳腺癌患者，阿瑞匹坦使用时间越长，生存结局越好 (远处无病生存期：Ptrend=0.002；乳腺癌特异性生存期：Ptrend=0.016)。不同类别的其他止吐药的供应与生存率无关。

结论: 化疗期间使用阿瑞匹坦与非腔内早期乳腺癌患者（尤其是三阴性乳腺癌）的预后较好相关。需要长期临床试验来证实这些发现。

Aprepitant, an antiemetic used to prevent chemotherapy-induced nausea and vomiting, slows breast tumor growth and progression.

Methods: Nationwide Norwegian register data identified 13,811 women diagnosed with early breast cancer and treated with chemotherapy and antiemetics between 2008 and 2020. Women were followed for metastases and death from one year after diagnosis until the end of 2021. To assess the association between aprepitant use and distant disease-free survival and breast cancer-specific survival, Cox regression models were used, adjusting for tumor and patient characteristics, chemotherapy regimen, and use of other antiemetics.

Results: During chemotherapy, 7,047 (51%) women received aprepitant. Overall, aprepitant use was associated with better distant disease-free survival (HRDDFS 0.89; 95% CI 0.79-1.00) and breast cancer-specific survival (HRBCSS 0.83; 95% CI 0.71-0.97). The survival advantage was only seen in patients with non-luminal breast cancer (HRDDFS 0.69; 95% CI 0.56-0.83; HRBCSS 0.64; 95% CI 0.51-0.81) and was most significant in patients with triple-negative breast cancer (HRDDFS 0.66; 95% CI 0.53-0.83; HRBCSS 0.61; 95% CI 0.47-0.80). For patients with non-luminal breast cancer, longer duration of aprepitant use was associated with better survival outcomes (distant disease-free survival: Ptrend=0.002; breast cancer-specific survival: Ptrend=0.016). The availability of other antiemetics from different classes was not associated with survival.

Conclusions: The use of aprepitant during chemotherapy is associated with better outcomes in patients with non-luminal early breast cancer, especially triple-negative breast cancer. Long-term clinical trials are needed to confirm these findings.

参考文献 Reference

Botteri E et al. JNCI 2025 ; July 14 2025; https://doi.org/10.1093/jnci/djaf178

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Durvalumab 联合化疗治疗晚期胆道癌：III 期 TOPAZ-1  3 年总生存期更新 (7/13/2025)

Durvalumab plus chemotherapy in advanced biliary tract cancer: 3-year overall survival update from TOPAZ-1 study

在TOPAZ-1 (NCT03875235) 的初步分析中，Durvalumab联合吉西他滨和顺铂 (GemCis) 显著改善了晚期胆道癌患者的总生存期。最新的探索性分析，涵盖总生存期和安全性, 延长的长期生存期以及后续的抗癌治疗。

方法: 晚期胆道癌患者每 3 周接受一次Durvalumab联合 GemCis 或安慰剂联合 GemCis 治疗（≤8 个周期），之后每 4 周接受一次Durvalumab或安慰剂单药治疗，直至病情进展或满足其他停药标准。在完整分析和安全性分析中分别评估了总生存期和严重不良事件。评估了延长的长期生存期结果（随机分组后存活≥30 个月）。  

结果: 共 685 名患者被随机分配：Durvalumab联合 GemCis (n = 341)；安慰剂+吉西他滨 (n = 344)。所有参与者经中位随访41.3个月（95% CI 39.3–44.1）后，durvalumab+ GemCis与安慰剂+ GemCis的中总生存期（95% CI）分别为12.9个月（11.6–14.1个月）vs. 11.3个月（10.1–12.5个月）（风险比，0.74 [95% CI 0.63–0.87]）；36个月总生存率分别为14.6% vs. 6.9%。在达到疾病控制的参与者中（566/685；82.6%），durvalumab+ GemCis (17.0%) 的36个月总生存率高于安慰剂+ GemCis (7.6%)。总体而言，延长的长期生存期为 12.8%，其中 Durvalumab+ GemCis (17.0%) 组的延长的长期生存期高于安慰剂+ GemCis (8.7%) 组；延长的长期生存期涵盖所有临床相关亚组。无论后续是否接受抗癌治疗，Durvalumab+ GemCis均改善了总生存期。在延长的长期生存期中，各组严重不良事件的发生率相当，且低于完整安全性分析集。   

结论 在最后一名受试者随机分组后约 3 年，Durvalumab+ GemCis与安慰剂+ GemCis相比，仍具有生存获益和可控的安全性。所有临床相关亚组均在延长的长期生存期中得到体现，支持 Durvalumab+ GemCis在晚期胆道癌中的标准治疗地位。

Durvalumab significantly improved overall survival in patients with advanced biliary tract cancer with the combination of gemcitabine and cisplatin (GemCis) in the primary analysis of TOPAZ-1 (NCT03875235). Updated exploratory analysis covers overall survival and safety, prolonged long-term survival, and subsequent anticancer therapy.

Methods: Patients with advanced biliary tract cancer received either durvalumab plus GemCis or placebo plus GemCis every 3 weeks (≤8 cycles), followed by durvalumab or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Overall survival and serious adverse events were assessed in the full analysis cohort and safety analysis cohort, respectively. Prolonged long-term survival outcomes (survival ≥30 months after randomization) were assessed.

Results: A total of 685 patients were randomized: durvalumab plus GemCis (n = 341); placebo plus GemCis (n = 344). After a median follow-up of 41.3 months (95% CI 39.3–44.1) for all participants, median overall survival (95% CI) was 12.9 months (11.6–14.1 months) for durvalumab plus GemCis and 11.3 months (10.1–12.5 months) for placebo plus GemCis (hazard ratio, 0.74 [95% CI 0.63–0.87]); 36-month overall survival was 14.6% vs. 6.9%, respectively. Among participants who achieved disease control (566/685; 82.6%), 36-month overall survival was higher with durvalumab plus GemCis (17.0%) than with placebo plus GemCis (7.6%). Overall, the prolonged long-term survival was 12.8%, of which the prolonged long-term survival of the Durvalumab+ GemCis group (17.0%) was higher than that of the placebo+ GemCis group (8.7%); the prolonged long-term survival covered all clinically relevant subgroups. Durvalumab+ GemCis improved overall survival regardless of subsequent anticancer treatment. In the prolonged long-term survival, the incidence of serious adverse events in each group was comparable and lower than that in the full safety analysis set.

Conclusion Durvalumab+ GemCis still had a survival benefit and manageable safety compared with placebo+ GemCis approximately 3 years after the last subject was randomized. All clinically relevant subgroups were reflected in the prolonged long-term survival, supporting the standard treatment status of Durvalumab+ GemCis in advanced biliary tract cancer.

参考文献 Reference

Oh D-Y et al. J Hepat 2025; doi: 10.1016/j.jhep.2025.05.003.

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FDA 批准了Teal Wand™ 用于宫颈癌筛查的家用阴道样本自采设备 (7/12/2025)

FDA approves Teal Wand™, an at-home vaginal sample collection device for cervical cancer screening

2025年5月9日 FDA批准了美国首款也是唯一用于宫颈癌筛查的家用阴道样本自采设备。这项批准得益于 SELF-CERV 研究，该研究是美国同类研究中规模最大的比较研究。研究证实，使用 Teal Wand 自行采集样本的性能与临床医生采集的样本相同，经证实可检测到 96% 的宫颈癌前病变。研究参与者包括了种族, 民族和社会经济多样性。它使用拭子采集阴道样本。女性随后将样本邮寄到实验室进行HPV（人乳头瘤病毒）筛查，这种病毒是几乎所有宫颈癌的致病因素。86% 的参与者表示，如果可以在家中进行宫颈癌筛查，她们更有可能及时进行筛查；94% 的参与者表示，如果她们知道 Teal Wand 的准确性，她们更愿意在家中自行采集样本。

Teal Wand是一款处方设备，即将在getteal.com上面向25至65岁平均风险人群发售。这项家用筛查服务包含Teal Wand样本采集套装和端到端远程医疗服务，通过该服务，女性可以远程访问Teal医疗服务提供者，这些提供者会开具样本套装，查看实验室结果，并在整个家庭筛查过程中为女性提供支持。 Teal Health 表示，其自测设备将于下个月开始在加州上市，随后将扩大到其他地区。该设备将通过远程医疗服务凭处方为 25 至 65 岁“中等风险”的女性提供。该公司表示，正在与保险公司合作，为其提供保险。

May 9, 2025 The FDA has approved the first and only vaginal sample collection device for cervical cancer screening in the U.S. The approval was made possible by the SELF-CERV study, the largest comparative study of its kind in the U.S. The study confirmed that the performance of self-collected samples using the Teal Wand was equivalent to samples collected by clinicians and was proven to detect 96% of cervical precancer. The study participants reflected racial, ethnic and socioeconomic diversity. It uses a swab to collect vaginal samples. Women then mail the sample to a laboratory for screening for HPV (human papillomavirus), the virus that causes nearly all cervical cancers. 86% of participants said they would be more likely to get a cervical cancer screening if they could do it at home, and 94% said they would be more willing to collect their own samples at home if they knew the accuracy of the Teal Wand.

The Teal Wand is a prescription device that will be available for sale on getteal.com for average-risk people aged 25 to 65. The home screening service includes the Teal Wand sample collection kit and an end-to-end telehealth service, through which women can remotely access Teal healthcare providers who will prescribe the sample kit, review the lab results, and support women throughout the home screening process. As per Teal Health, its self-test device will be first available in California and will be expanded to other regions later. The device will be available for “medium-risk” women aged 25 to 65 years old with a prescription through telehealth services. The company was said to work with insurance companies in the future to provide coverage for it.

参考文献 Reference

https://www.getteal.com/news/fda-approves-teal-healths-teal-wand-tm—the-first-and-only-at-home-self-collection-device-for-cervical-cancer-screening-introducing-a-comfortable-alternative-to-in-person-screening

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Lurbinectedin 联合 Atezolizumab 维持治疗广泛期小细胞肺癌 (7/6/2025)

Lurbinectedin with atezolizumab maintenance therapy in extensive-stage small-cell lung cancer

方法：这是一项III期临床试验（IMforte），纳入了 660 名既往未接受治疗的广泛期小细胞肺癌患者，这些患者无脑或脊髓转移病史，且体能状态良好。所有患者均接受了 4 个周期的标准诱导治疗，包括阿替利珠单抗, 卡铂和依托泊苷。 如果患者在 4 个周期治疗后肿瘤仍保持缓解或病情稳定，则有资格继续参与研究。483 名患者继续接受维持治疗。他们被随机分配接受 Lurbinectedin 联合 Atezolizumab 治疗（242 名患者）或 Atezolizumab 单药治疗（241 名患者）。参与者来自 13 个不同国家的 91 个研究中心。参与者的中位年龄为 66 岁，约 63% 为男性。 Lurbinectedin是一种烷化剂，其作用机制是损伤癌细胞的 DNA。中位随访时间为 15 个月。

结果：Lurbinectedin 联合阿替利珠单抗组的中位无进展生存期为 5.4 个月，而单用阿替利珠单抗组为 2.1 个月。 接受 Lurbinectedin 联合阿替利珠单抗治疗的患者癌症进展风险比单用阿替利珠单抗治疗的患者低 46%。 接受 Lurbinectedin 联合阿替利珠单抗治疗的患者中位总生存期为 13.2 个月，而单用阿替利珠单抗治疗的患者中位总生存期为 10.6 个月。 与仅接受阿替利珠单抗治疗的患者相比，接受Lurbinectedin和阿替利珠单抗治疗的患者死亡风险降低了 27%。

两组之间的不良事件存在显著差异。Lurbinectedin 联合阿替利珠单抗组83.5%的患者发生了治疗相关不良事件，而阿替利珠单药组仅为40%。Lurbinectedin联合阿替利珠单抗组25.6%的患者经历了3级或4级不良事件，0.8%的患者经历了5级不良事件。阿替利珠单抗单药组5.8%的患者经历了3级或4级不良事件，0.4%的患者经历了5级不良事件。Lurbinectedin联合阿替利珠单抗组6.2%的患者因副作用停止治疗，而阿替利珠单抗单药组为3.3% 。IMforte 研究仍在进行中。

Methods: This is a phase III clinical trial (IMforte) that enrolled 660 patients with previously untreated extensive-stage small-cell lung cancer, with no history of brain or spinal cord metastases, and good performance status. All patients received 4 cycles of standard induction therapy, including atezolizumab, carboplatin, and etoposide. Patients were eligible to continue in the study if they had an ongoing response or stable disease after 4 cycles of treatment. 483 patients continued to receive maintenance therapy. They were randomly assigned to receive lurbinectedin plus atezolizumab (242 patients) or atezolizumab alone (241 patients). Participants were from 91 centers in 13 different countries. The median age of participants was 66 years, and about 63% were men. Lurbinectedin is an alkylating agent, which works by damaging the DNA of cancer cells. The median follow-up was 15 months.

Results: The median progression-free survival was 5.4 months in the lurbinectedin plus atezolizumab group, compared with 2.1 months in the atezolizumab alone group. The risk of cancer progression was 46% lower in patients treated with lurbinectedin plus atezolizumab than in patients treated with atezolizumab alone. The median overall survival was 13.2 months in patients treated with lurbinectedin plus atezolizumab, compared with 10.6 months in patients treated with atezolizumab alone. The risk of death was reduced by 27% in patients treated with lurbinectedin and atezolizumab compared with patients treated with atezolizumab alone.

There were significant differences in adverse events between the two groups. Treatment-related adverse events occurred in 83.5% of patients in the lurbinectedin plus atezolizumab group, compared with only 40% in the atezolizumab alone group. In the lurbinectedin plus atezolizumab group, 25.6% of patients experienced grade 3 or 4 adverse events, and 0.8% experienced grade 5 adverse events. In the atezolizumab group, 5.8% of patients experienced grade 3 or 4 adverse events, and 0.4% experienced grade 5 adverse events. 6.2% of patients in the lurbinectedin plus atezolizumab group discontinued treatment due to side effects, compared with 3.3% in the atezolizumab group. The IMforte study is ongoing.

参考文献 Reference

Choudhury NJ et a. Lancet 2025 ; 405 :2104

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曲妥珠单抗德鲁替康 + 帕妥珠单抗对比紫杉烷/曲妥珠单抗/帕妥珠单抗用于HER2+ 晚期乳腺癌一线治疗 (7/5/2025)

Trastuzumab deruxtecan + pertuzumab vs taxane + trastuzumab + pertuzumab as first-line treatment for HER2+ advanced breast cancer: Interim results from DESTINY-Breast09

背景：DESTINY-Breast09 (NCT04784715) 是一项全球随机 III 期研究，旨在评估 1,157 名 HER2+ 晚期/转移性乳腺癌一线曲妥珠单抗德鲁替康 (T-DXd) ± 帕妥珠单抗对比紫杉烷/曲妥珠单抗/帕妥珠单抗 (THP) 的疗效和安全性。

方法：符合条件的患者经中心确诊为 HER2+（IHC 3+ 或 ISH+），并且未接受过针对晚期/转移性乳腺癌的化疗或 HER2 靶向治疗（允许无病间隔 > 6 个月的[新]辅助 HER2 靶向治疗/化疗，且转移性疾病的内分泌治疗≤1 线）。患者按 1:1:1 的比例随机分配接受 T-DXd 5.4 mg/kg（+安慰剂）, T-DXd + 帕妥珠单抗或 THP 治疗，根据新发疾病与复发疾病以及激素受体 (HR) 和 PIK3CA 突变状态分层。在此计划的中期分析中，展示了 T-DXd + P 与 THP 的数据；T-DXd + 安慰剂组在最终 PFS 分析前保持盲法。主要终点是意向治疗人群的无进展生存期。其他终点包括总生存期, 客观响应率, 响应持续时间和安全性。

结果：随机分配接受 T-DXd + 帕妥珠单抗 (n =383) 和 THP (n =387) 的患者中，52% 患有新发疾病，54% 为 HR+ 状态。在此中期数据截止时（2025 年 2 月 26 日；中位随访 29 个月；38% 的无进展生存期成熟），T-DXd + 帕妥珠单抗显著改善了无进展生存期（风险比 0.56；95% CI 0.44, 0.71；P<0.00001）。所有亚组的无进展生存期获益一致。总生存期数据不成熟。T-DXd + 帕妥珠单抗的中位响应持续时间超过 3 年。 T-DXd + 帕妥珠单抗组和 THP 组患者中，≥3 级治疗中出现的不良事件发生率分别为 63.5% 和 62.3%，严重不良事件发生率分别为 27.0% 和 25.1%。经裁定，T-DXd + 帕妥珠单抗组 46 例（12.1%；主要为 1/2 型；n =2 [0.5%] 为 5 型）患者和 THP 组 4 例（1.0%；均为 1/2 型）患者发生了药物相关的间质性肺疾病/肺炎未发现新的安全信号  

结论：与 THP 组相比，T-DXd + 帕妥珠单抗组在无进展生存期 方面表现出统计学上显著且具有临床意义的改善，且在所有亚组中均有一致表现，可能代表 HER2+ 晚期/转移性乳腺癌的一线治疗新标准。

Background: DESTINY-Breast09 (NCT04784715) is a global, randomized, phase III study designed to evaluate the efficacy and safety of first-line trastuzumab derutilecan (T-DXd) ± pertuzumab versus taxane/trastuzumab/pertuzumab (THP) in 1,157 patients with HER2+ advanced/metastatic breast cancer.

Methods: Eligible patients were centrally confirmed to be HER2+ (IHC 3+ or ISH+) and had not received prior chemotherapy or HER2-targeted therapy for advanced/metastatic breast cancer (disease-free interval > 6 months with [neo]adjuvant HER2-targeted therapy/chemotherapy and ≤1 line of endocrine therapy for metastatic disease were allowed). Patients were randomized in a 1:1:1 ratio to receive T-DXd 5.4 mg/kg (+placebo), T-DXd + pertuzumab, or THP, stratified by new versus relapsed disease and hormone receptor (HR) and PIK3CA mutation status. Data for T-DXd + P versus THP were presented at this planned interim analysis; the T-DXd + placebo group remained blinded until the final PFS analysis. The primary endpoint was progression-free survival in the intention-to-treat population. Other endpoints included overall survival, objective response rate, duration of response, and safety.

Results: Of patients randomized to T-DXd + pertuzumab (n = 383) and THP (n = 387), 52% had new disease and 54% were HR+. At this interim data cutoff (February 26, 2025; median follow-up, 29 months; 38% PFS mature), T-DXd plus pertuzumab significantly improved PFS (hazard ratio, 0.56; 95% CI, 0.44, 0.71; P<0.00001). The PFS benefit was consistent across all subgroups. Overall survival data were immature. The median duration of response with T-DXd plus pertuzumab was more than 3 years.

Grade ≥3 treatment-emergent adverse events occurred in 63.5% of patients in the T-DXd plus pertuzumab group and 62.3% in the THP group, and serious adverse events occurred in 27.0% and 25.1%, respectively. Adjudicated drug-related ILD/pneumonitis occurred in 46 patients (12.1%; predominantly type 1/2; n =2 [0.5%] type 5) in the T-DXd + pertuzumab group and 4 patients (1.0%; all type 1/2) in the THP group. No new safety signals were identified.

Conclusions: T-DXd + pertuzumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with THP, which was consistent across all subgroups and may represent a new standard of care for first-line treatment of HER2+ advanced/metastatic breast cancer.

参考文献 Reference

Tolaney SM et al. J Clin Onc 2025 ; 43 [17, supplabstr LBA1008]

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2010-2019 年美国早发癌症发病率增加趋势 (6/29/2025)

Trends in early-onset cancer incidence in the United States, 2010–2019

摘要: 研究者估算了美国2010-2019年的年龄标准化癌症发病率和死亡率，以探究癌症发病率是否在低龄化中上升。14种癌症在至少一个早发年龄组（即15-29岁, 30-39岁和40-49岁）的发病率有所上升，其中9种癌症在至少一个高发年龄组（即50-59岁, 60-69岁和70-79岁；包括女性乳腺癌、结直肠癌、肾癌、睾丸癌、子宫癌和胰腺癌，以及几种淋巴系统肿瘤）的发病率也有所上升。与基于2010年发病率的预期诊断相比，2019年绝对增幅最大的是女性乳腺癌（新增4,834例癌症）, 结直肠癌（新增2,099例）, 肾癌（新增1,793例）和子宫癌（新增1,209例）。虽然大多数癌症的死亡率并未同步上升，但早发年龄组的结直肠癌、子宫癌和睾丸癌死亡率有所上升。发病率上升的驱动因素与癌症相关，可能包括既定病因和可能新增的病因，以及检测率的提高。

意义： 在美国，某些癌症在早发年龄组的发病率有所上升。其中许多癌症在老年群体中的发病率也有所上升，这表明风险因素患病率的变化和/或检测率的提高可能会影响整个年龄段的发病风险。

The researchers estimated age-standardized cancer incidence and mortality rates in the United States from 2010 to 2019 to examine whether cancer incidence is increasing at younger ages. The incidence of 14 cancers increased in at least one early-onset age group (i.e., 15-29 years, 30-39 years, and 40-49 years), and nine cancers also increased in at least one older-onset age group (i.e., 50-59 years, 60-69 years, and 70-79 years; including female breast cancer, colorectal cancer, kidney cancer, testicular cancer, uterine cancer, and pancreatic cancer, as well as several lymphoid system tumors). The largest absolute increases in 2019 compared with expected diagnoses based on 2010 incidence rates were for female breast cancer (4,834 additional cancers), colorectal cancer (2,099 additional cases), kidney cancer (1,793 additional cases), and uterine cancer (1,209 additional cases). Although mortality rates for most cancers did not increase synchronously, mortality rates for colorectal, uterine, and testicular cancers increased in earlier-onset age groups. Drivers of the increase are cancer-related and may include established and possibly novel causes, as well as increased detection rates.

Significance: Incidence rates of some cancers have increased in earlier-onset age groups in the United States. Incidence rates of many of these cancers have also increased in older age groups, suggesting that changes in risk factor prevalence and/or increased detection rates may affect risk across age groups.

参考文献 Reference

Shields MS et al. Cancer disc 2025; https//doi.org/10.1158/2159-8290.CD-24-1678

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非手术治疗错配修复缺陷型肿瘤 (6/28/2025)

Nonoperative management of mismatch repair–deficient (dMMR) tumors

方法: 研究者开展了一项 II 期临床试验（NCT04165772），纳入 I, II 或 III 期 dMMR 实体瘤患者，这些患者均可接受根治性手术，并接受 6 个月的新辅助治疗，该治疗方案为PD-1 阻断剂 dostarlimab。试验分为两组，评估了患者的治疗反应：第一组为 dMMR 局部晚期直肠癌患者，第二组为 dMMR 非直肠实体瘤患者。临床完全响应的患者可选择继续进行非手术治疗；残留病灶的患者则需接受手术切除。在本分析中，队列 1 评估的主要终点是 12 个月时的持续临床完全响应 (SCR)。同时评估了无复发生存率和安全性。   

结果: 共纳入 117 例患者。在队列 1 中，所有 49 例完成治疗的患者均获得临床完全响应并选择继续非手术治疗。共有 37 例患者在 12 个月时获得持续临床完全响应，这一结果符合疗效标准。在队列 2 中，54 例完成治疗的患者中，共有 35 例获得临床完全响应，33 例选择继续非手术治疗。在两个队列均完成治疗的 103 例患者中，84 例获得临床完全响应，82 例未接受手术。在总共 117 例患者中，2 年无复发生存率为 92%（95% 置信区间，86-99）；复发随访中位时间为20.0个月（范围：0至60.8个月）。大多数患者（95%）出现可逆性1级或2级不良事件（60%），或无不良事件（35%）。所有患者在治疗期间或治疗后均未出现根治性切除术。

结论: 对于适合根治性手术的早期dMMR实体瘤患者，新辅助PD-1阻断疗法可使较高比例的患者器官保留。

Methods: The researchers conducted a phase II clinical trial (NCT04165772) that enrolled patients with stage I, II, or III dMMR solid tumors who were eligible for curative surgery and received 6 months of neoadjuvant therapy with the PD-1 blocker dostarlimab. The trial evaluated the treatment response in two groups: patients with dMMR locally advanced rectal cancer in the first group and patients with dMMR non-rectal solid tumors in the second group. Patients with a clinical complete response could choose to continue nonsurgical treatment; patients with residual disease underwent surgical resection. In this analysis, the primary endpoint evaluated in cohort 1 was sustained clinical complete response at 12 months. Relapse-free survival and safety were also evaluated.

Results: A total of 117 patients were included. In cohort 1, all 49 patients who completed treatment achieved a clinical complete response and chose to continue nonsurgical treatment. A total of 37 patients achieved a sustained clinical complete response at 12 months, a result that met the efficacy criteria. In cohort 2, a total of 35 of 54 patients who completed treatment achieved a clinical complete response, and 33 chose to continue nonsurgical treatment. Of the 103 patients who completed treatment in both cohorts, 84 achieved a clinical complete response, and 82 did not undergo surgery. Among a total of 117 patients, the 2-year relapse-free survival rate was 92% (95% confidence interval, 86-99); the median follow-up time for relapse was 20.0 months (range: 0 to 60.8 months). Most patients (95%) experienced reversible grade 1 or 2 adverse events (60%) or no adverse events (35%). No patient underwent radical resection during or after treatment. Conclusion: Neoadjuvant PD-1 blockade therapy can achieve organ preservation in a high proportion of patients with early-stage dMMR solid tumors who are suitable for radical surgery.

参考文献 Reference

Cercek A et al. N Engl J Med 2025; 392:2297

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FDA 批准帕博利珠单抗用于可切除局部晚期头颈癌的新辅助和辅助治疗 (6/22/2025)

FDA approves neoadjuvant and adjuvant pembrolizumab for resectable, locally advanced head and neck cancer

2025年6月12日，FDA批准帕博利珠单抗用于治疗PD-L1[(CPS) ≥ 1]的可切除局部晚期头颈部鳞状细胞癌成人患者。帕博利珠单抗可作为新辅助治疗的单药，术后可与放疗（联合或不联合顺铂）联合使用，并可作为单药继续治疗。

这是一项随机, 多中心, 开放标签临床试验（KEYNOTE-689, NCT03765918），纳入了 714 例可切除局部晚期（III-IVA 期）头颈部鳞状细胞癌患者。患者按 1:1 的比例随机分配接受以下方案之一： 新辅助帕博利珠单抗治疗，每 3 周 1 次，共 2 个周期；随后辅助帕博利珠单抗治疗，每 3 周 1 次，共 3 个周期，联合放疗（联合或不联合顺铂）；之后每 3 周 1  次，共 12 个周期， 帕博利珠单抗单药治疗。 术前无需新辅助治疗，随后接受辅助放疗（联合或不联合顺铂）。 在两个治疗组中，如果患者在手术中存在高危病理特征（即阳性切缘<1 mm或结外扩散），则接受顺铂联合辅助放疗。 主要疗效指标是通过盲法独立中心审查确定的无事件生存期，定义为从随机分组到首次发生以下任何事件的时间：疾病进展导致无法进行确定性手术；局部或远处疾病进展或复发；或任何原因导致的死亡。另一项疗效结果指标是总生存期。

对于肿瘤表达 PD-L1 CPS ≥ 1 的患者（n = 682），帕博利珠单抗组的中位无事件生存期为 59.7 个月（95% 置信区间 [CI] = 37.9 个月至未达到），对照组为 29.6 个月（95% CI = 19.5-41.9 个月）（风险比 = 0.70，95% CI = 0.55-0.89，P = 0.00140）。 总生存期结果尚不成熟。

在接受帕博利珠单抗新辅助治疗的患者中，1.4% 的患者因不良反应而无法接受手术，而对照组这一比例为 1.4%。派姆单抗的处方信息包含针对免疫介导不良反应、输注相关反应和胚胎毒性的警告和注意事项。不良反应与派姆单抗的既往经验一致。 派姆单抗的推荐剂量为每3周200毫克或每6周400毫克。如果派姆单抗与化疗同日给药，则应在化疗前给药。

On June 12, 2025, the FDA approved pembrolizumab for the treatment of adult patients with resectable locally advanced head and neck squamous cell carcinoma with PD-L1 [(CPS) ≥ 1]. Pembrolizumab can be used as a single agent in neoadjuvant therapy, combined with radiotherapy (with or without cisplatin) after surgery, and can be continued as a single agent.

This is a randomized, multicenter, open-label clinical trial (KEYNOTE-689, NCT03765918) that enrolled 714 patients with resectable locally advanced (stage III-IVA) head and neck squamous cell carcinoma. Patients were randomly assigned in a 1:1 ratio to receive one of the following regimens: neoadjuvant pembrolizumab every 3 weeks for 2 cycles; followed by adjuvant pembrolizumab every 3 weeks for 3 cycles with or without cisplatin; followed by pembrolizumab monotherapy every 3 weeks for 12 cycles. No neoadjuvant therapy was required before surgery, followed by adjuvant radiotherapy with or without cisplatin. In both treatment groups, patients received cisplatin plus adjuvant radiotherapy if they had high-risk pathological features at surgery (i.e., positive margins <1 mm or extranodal spread). The primary efficacy measure was event-free survival as determined by blinded independent central review, defined as the time from randomization to the first occurrence of any of the following events: disease progression that precluded definitive surgery; local or distant disease progression or recurrence; or death from any cause. Another efficacy outcome measure was overall survival.

For patients whose tumors expressed PD-L1 CPS ≥ 1 (n = 682), median event-free survival was 59.7 months (95% confidence interval [CI] = 37.9 months to not reached) in the pembrolizumab group and 29.6 months (95% CI = 19.5-41.9 months) in the control group (hazard ratio = 0.70, 95% CI = 0.55-0.89, P = 0.00140). Overall survival results are immature.

Among patients who received neoadjuvant pembrolizumab, 1.4% of patients were unable to undergo surgery due to adverse reactions, compared with 1.4% of patients in the control group. The prescribing information for pembrolizumab contains warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, and embryotoxicity. Adverse reactions were consistent with previous experience with pembrolizumab.

The recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks. If pembrolizumab is given on the same day as chemotherapy, it should be given before chemotherapy.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-and-adjuvant-pembrolizumab-resectable-locally-advanced-head-and-neck

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Amivantamab 联合 lazertinib 与 osimertinib 治疗 EGFR 突变非小细胞肺癌的疗效对比 (6/21/2025)

Amivantamab plus lazertinib vs osimertinib in EGFR-mutated NSCLC: MARIPOSA trial

Amivantamab-vmkw是双特异性 EGF 受体 (EGFR) 和 MET 受体单克隆抗体, Lazertini 是 EGFR 酪氨酸激酶抑制剂。

这是一项III期临床试验（MARIPOSA），纳入了 1,074 名携带 EGFR 外显子 19 缺失或 L858R 置换突变的局部晚期或转移性非小细胞肺癌患者, 比较Amivantamab-vmkw 联合 lazertinbi 相对于奥希替尼对生存期的结果。

结果: 接受Amivantamab联合lazertinib（联合方案）一线治疗的患者总生存期显著长于接受奥希替尼 (osimertinib) 治疗的患者（风险比 [HR] = 0.75；95% 置信区间 [CI] = 0.61–0.92；P < .005）。联合治疗的中位总生存期尚未达到（95% CI = 42.9 个月至未达到）。相比之下，接受奥希替尼治疗的患者的中位总生存期为 36.7 个月（95% CI = 33.4–41.0 个月），这与先前对奥希替尼的研究结果一致。接受联合治疗的患者中，66% 的患者在 3.5 年时存活，而接受奥希替尼治疗的患者中，这一比例仅为 44%。 此外，与奥希替尼相比，联合治疗的多个次要终点指标均有所改善，包括颅内无进展生存期、颅内响应持续时间和颅内总体响应率。值得注意的是，联合治疗组的疾病进展时间（从随机分组到出现肺癌症状）比奥希替尼治疗组更长（43.6 个月 vs 29.3 个月；HR = 0.69；95% CI = 0.57-0.83；P < .001）。  

联合治疗组的安全性与初步分析结果一致。后续随访未发现新的安全性信号。联合治疗的大多数不良事件均在治疗早期报告。

预计中位总生存期将比奥希替尼的中位生存期 3 年多 1 年，但尚未达到。

Amivantamab-vmjw is a bispecific monoclonal antibody for EGF receptor (EGFR) and MET receptor; lazertinib is an EGFR tyrosine kinase inhibitor. This is a phase III clinical trial (MARIPOSA) that enrolled 1,074 patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletion or L858R substitution mutations. The trial compared the impact of amivantamab-vmkw plus lazertinbi versus osimertinib on survival. The median follow-up was 37.8 months.

Results: Overall survival was significantly longer in patients who received amivantamab plus lazertinib (combination regimen) as first-line therapy than in those who received osimertinib (hazard ratio [HR] = 0.75; 95% confidence interval [CI] = 0.61–0.92; P < .005). The median overall survival with the combination therapy was not yet reached (95% CI = 42.9 months to not reached). In contrast, the median overall survival for patients treated with osimertinib was 36.7 months (95% CI = 33.4–41.0 months), which is consistent with previous studies of osimertinib. Of the patients who received the combination, 66% were alive at 3.5 years, compared with 44% of those who received osimertinib. In addition, the combination improved several secondary endpoints compared with osimertinib, including intracranial progression-free survival, duration of intracranial response, and intracranial overall response rate. Notably, the time to disease progression (from randomization to the onset of lung cancer symptoms) was longer in the combination group than in the osimertinib group (43.6 months vs 29.3 months; HR = 0.69; 95% CI = 0.57-0.83; P < .001).

The safety profile of the combination group was consistent with the primary analysis. No new safety signals were identified during follow-up. Most adverse events with the combination were reported early in treatment.

Median overall survival is expected to be 1 year longer than the 3 years median survival with osimertinib but has not yet been reached.

参考文献 Reference

Yang JCH et al. Eur Lung Cancer Cong 2025; Abstr 4O

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Relacorilant 联合白蛋白结合型紫杉醇治疗铂耐药性卵巢癌患者 (6/15/2025)

Relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer: ROSELLA trial

Relacorilant 是一种首创的选择性糖皮质激素受体拮抗剂，它通过降低皮质醇信号传导来增强肿瘤对化疗的敏感性。

方法: 这项随机对照, 开放标签, III 期临床试验 (ROSELLA [GOG-3073/ENGOT-ov72], NCT05257408) 在澳大利亚, 欧洲, 拉丁美洲, 北美和韩国等 14 个国家的 117 家医院和社区肿瘤治疗中心开展。患者必须确诊为铂耐药, 上皮性（即高级别浆液性, 子宫内膜样或癌肉瘤，上皮成分≥30%）卵巢癌, 原发性腹膜癌或输卵管癌；之前接受过多达三种抗癌疗法和之前使用过贝伐单抗。患者按1:1比例分配接受Relacorilant（分别于白蛋白结合型紫杉醇输注前一天, 输注当日和输注后各口服150毫克）联合白蛋白结合型紫杉醇（每28天为一个周期，第1, 8和15天静脉注射80毫克/平方米）或白蛋白结合型紫杉醇单药治疗（按上述方案静脉注射100毫克/平方米）。两个主要终点是无进展生存期和总生存期，并根据意向性治疗在所有随机分配的患者中进行评估。安全性人群包括所有接受至少一剂指定治疗的随机分配患者。

结果: 2023年1月5日至2024年4月8日期间，381例患者被随机分配至联合治疗组（n=188）或白蛋白结合型紫杉醇单药治疗组（n=193）。经盲法独立中心审查评估，接受Relacorilant联合白蛋白结合型紫杉醇治疗的患者与接受白蛋白结合型紫杉醇单药治疗的患者相比，无进展生存期显著延长（风险比0.70 [95% CI 0.54–0.91]；中位生存期6.54个月[95% CI 5.55–7.43] 相对于 5.52个月[3.94–5.88]；分层对数秩检验p =0.0076）。在计划的中期分析中，Relacorilant 联合白蛋白结合型紫杉醇治疗组的总生存期与对照组存在具有临床意义的差异（0.69 [95% CI 0.52–0.92]；15.97 个月 [95% CI 13.47 – 未达到] 相对于11.50 个月 [10.02–13.57]；对数秩检验 p =0.0121）。调整白蛋白结合型紫杉醇暴露量后，各研究组的不良事件相似；未观察到新的安全性信号。

解读: Relacorilant联合白蛋白结合型紫杉醇治疗延长了无进展生存期，中期结果也显示总生存期有所改善。该研究结果将Relacorilant联合白蛋白结合型紫杉醇治疗定位为铂类耐药卵巢癌患者的潜在新标准治疗方案。

Relacorilant is a first-in-class, selective glucocorticoid receptor antagonist that enhances tumor sensitivity to chemotherapy by reducing cortisol signaling.

Methods: This randomized, controlled, open-label, phase III clinical trial (ROSELLA [GOG-3073/ENGOT-ov72], NCT05257408) was conducted at 117 hospitals and community cancer centers in 14 countries including Australia, Europe, Latin America, North America, and South Korea. Patients had to have a diagnosis of platinum-resistant, epithelial (i.e., high-grade serous, endometrioid, or carcinosarcoma with ≥30% epithelial component) ovarian, primary peritoneal, or fallopian tube cancer; had received up to three prior anticancer therapies and had received prior bevacizumab. Patients were assigned in a 1:1 ratio to receive relacorilant (150 mg orally on the day before, on the day of, and after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel alone (100 mg/m2 intravenously as above). The two primary endpoints were progression-free survival and overall survival and were assessed in all randomly assigned patients by intention to treat. The safety population included all randomly assigned patients who received at least one dose of assigned treatment.

Results: Between January 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the combination group (n=188) or nab-paclitaxel alone (n=193). Patients treated with relacorilant plus nab-paclitaxel had significantly longer progression-free survival than those treated with nab-paclitaxel alone, as assessed by blinded independent central review (hazard ratio, 0.70 [95% CI, 0.54–0.91]; median survival, 6.54 months [95% CI, 5.55–7.43] vs. 5.52 months [3.94–5.88]; p = 0.0076 by stratified log-rank test). At the planned interim analysis, a clinically meaningful difference in overall survival was observed in the relacorilant plus nab-paclitaxel group compared with the control group (0.69 [95% CI, 0.52–0.92]; 15.97 months [95% CI, 13.47 – not reached] vs. 11.50 months [10.02–13.57]; p = 0.0121 by log-rank test).

Adverse events were similar across study groups after adjustment for nab-paclitaxel exposure; no new safety signals were observed.

Interpretation: Relacorilant combined with nab-paclitaxel prolonged progression-free survival, and interim results also showed improved overall survival. The results provided data to support relacorilant in combination with nab-paclitaxel as a potential new standard of care for patients with platinum-resistant ovarian cancer.

参考文献 Reference

Olawaiye AB et al. Lancet published June 2 , 2025; DOI: 10.1016/S0140-6736(25)01040-2

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CAR T治疗晚期透明细胞肾细胞癌 (ccRCC)：1 期 TRAVERSE 研究 (6/14/2025)

ALLO-316 in advanced clear cell renal cell carcinoma (ccRCC): Phase I TRAVERSE study

背景： CD70 在 ccRCC 上高表达。ALLO-316 是一款来自健康供体的同种异体 CD70 CAR T 细胞产品，旨在识别并杀灭 CD70 阳性肿瘤细胞和导致同种异体排斥的 CD70 阳性宿主 T 细胞。多中心Ia/b期TRAVERSE研究（NCT04696731）的初步数据显示，ALLO-316具有可控的安全性和良好的抗肿瘤活性。

方法： 患有晚期ccRCC，且在接受免疫检查点抑制剂和血管内皮生长因子(VEGF)靶向治疗后病情进展。患者接受氟达拉滨和环磷酰胺±ALLO-647（抗CD52）淋巴细胞清除治疗后，按照3+3方案单次输注ALLO-316（40-240 × 10⁶个同种异体CAR+ T细胞）。主要终点为剂量限制性毒性和不良事件发生率。客观响应率为次要终点。

结果：44例接受淋巴细胞清除治疗的患者中，39例接受了ALLO-316治疗，其中38例可评估疾病结局。患者中位年龄为60岁，既往接受过3种治疗（范围：1-8种），36例（82%）患者为CD70阳性ccRCC。截至2025年1月2日，中位随访时间为6.8个月（范围：0.8-39.5个月）。2例患者出现剂量限制性毒性（自身免疫性肝炎和多器官衰竭导致的心源性休克）。42例患者（96%；≥3级，37例[84%]）出现治疗中出现的不良事件。 1例患者（2%；任意级别，25例[57%]）发生≥3级细胞因子释放综合征，0例患者（任意级别，4例[9%]）发生≥3级ICANS，1例患者（2%；任意级别，8例[18%]）发生≥3级IEC-HS。未发生移植物抗宿主病。如先前报告，3例5级不良事件与ALLO-316相关（心源性休克, 发育不良和脓毒症）。对于CD70阳性肿瘤患者，所有淋巴细胞清除治疗方案的客观响应率总体为20%（6/30）。对于接受1b期方案治疗的CD70≥50%患者，确认的客观响应为33%（3/9）；所有确认的响应均持续存在（数据截止时分别为2.1个月、6.7个月和8.4个月）。

结论： 中位随访时间为6.8个月，单次输注ALLO-316对于接受过大量治疗的患者具有可控的安全性和令人鼓舞的抗肿瘤活性。

Background: CD70 is highly expressed on ccRCC. ALLO-316 is an allogeneic CD70 CAR T cell product from healthy donors designed to recognize and kill CD70-positive tumor cells and CD70-positive host T cells that cause allogeneic rejection. Preliminary data from the multicenter phase Ia/b TRAVERSE study (NCT04696731) showed that ALLO-316 has a manageable safety profile and good anti-tumor activity.

Methods: Patients with advanced ccRCC who progressed after immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) targeted therapy. After lymphodepletion with fludarabine and cyclophosphamide ± ALLO-647 (anti-CD52), patients received a single infusion of ALLO-316 (40-240 × 10⁶ allogeneic CAR+ T cells) according to the 3+3 regimen. The primary endpoints were dose-limiting toxicity and adverse event rates. Objective response rate was a secondary endpoint.

Results: Of the 44 patients who underwent lymphodepletion, 39 received ALLO-316, and 38 were evaluable for disease outcome. The median age of the patients was 60 years, and they had received 3 previous therapies (range: 1-8), and 36 patients (82%) had CD70-positive ccRCC. As of January 2, 2025, the median follow-up was 6.8 months (range: 0.8-39.5 months). Two patients experienced dose-limiting toxicity (autoimmune hepatitis and cardiogenic shock due to multiorgan failure). Forty-two patients (96%; ≥ grade 3, 37 [84%]) experienced treatment-emergent adverse events. One patient (2%; any grade, 25 [57%]) developed ≥ grade 3 cytokine releasing syndrome, 0 patients (any grade, 4 [9%]) developed ≥ grade 3 ICANS, and 1 patient (2%; any grade, 8 [18%]) developed ≥ grade 3 IEC-HS. No graft-versus-host disease occurred. As previously reported, 3 grade 5 adverse events were related to ALLO-316 (cardiogenic shock, dysplasia, and sepsis). For patients with CD70-positive tumors, the overall objective response rate was 20% (6/30) across all lymphodepleting regimens. For patients with CD70 ≥ 50% treated with the phase 1b regimen, the confirmed objective response was 33% (3/9); all confirmed responses were durable (2.1, 6.7, and 8.4 months at data cutoff, respectively).

Conclusions: With a median follow-up of 6.8 months, a single infusion of ALLO-316 had a manageable safety profile and encouraging antitumor activity in heavily pretreated patients.

参考文献 Reference

Srour SA et al. 2025 ASCO meeting abstr 4508

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树脂毒素治疗顽固性癌痛 (6/8/2025)

Treatment of intractable cancer pain with resiniferatoxin

本文评估了一种非阿片类镇痛药树脂毒素 (resiniferatoxin , RTX)，它是瞬时受体电位香草酸1 离子通道的强效激动剂，可选择性阻断由背根神经节神经元亚群传递的痛觉活动。

方法: 在这项首次人体试验、开放标签, I期临床试验(NCT00804154)的中期分析中，19名患有顽固性腹部和/或下肢癌痛的患者接受了一次鞘内注射RTX。主要结局指标是安全性。次要结局指标是研究期间的疗效评估，使用数值评定量表测量24小时内“最严重疼痛”。这是一个从0到10的量表，其中0表示“无痛”，10表示“能想象到的最剧烈的疼痛”。阿片类药物的消耗量以控制疼痛的吗啡当量来衡量。

结果: 在RTX注射后的188天内，19名接受治疗的患者共报告了213起治疗中出现的不良事件，其中14名患者报告了37起严重不良事件。9例患者平均在治疗后70天（范围从11天到140天）死亡。其中许多事件（包括死亡）与晚期癌症的病程相符。19名患者均至少出现一例不良事件。3名患者暴露于RTX的皮区热敏感性丧失（I级和II级）。7名患者出现持续超过24小时的尿潴留（3例为III级）。5名患者出现与心电图QT间期一过性增加相关的不良事件，该事件在24小时内缓解（I级和II级）。唯一的IV级不良事件是无法分期的褥疮。RTX使“最严重”疼痛强度降低38%（治疗前8.4±0.4 vs. 治疗后5.2±0.6），并在治疗后第15天测量阿片类药物消耗量减少57%。

结论: 鞘内注射RTX是一种单次给药、不增加阿片类药物用量的镇痛药，适用于难治性癌痛患者。本研究出现了不同程度的预期和非预期不良事件，但对疼痛的初始疗效令人鼓舞。

The researchers evaluated a nonopioid analgesic, resiniferatoxin (RTX), which is a potent agonist of transient receptor potential vanilloid 1 ion channels and selectively blocks pain activity transmitted by a subset of dorsal root ganglion neurons.

Methods: In an interim analysis of this first-in-human, open-label, phase I clinical trial (NCT00804154), 19 patients with intractable abdominal and/or lower extremity cancer pain received a single intrathecal injection of RTX. The primary outcome measure was safety. Secondary outcomes were efficacy assessments during the study period, using a numerical rating scale to measure “worst pain” within 24 hours. This is a scale from 0 to 10, with 0 indicating “no pain” and 10 indicating “the worst pain imaginable.” Opioid consumption was measured as morphine equivalents for pain control.

Results: Within 188 days after RTX injection, 213 treatment-emergent adverse events were reported by 19 treated patients, of which 37 serious adverse events were reported by 14 patients. Nine patients died at a mean of 70 days after treatment (range, 11 to 140 days). Many of these events, including death, were consistent with the course of advanced cancer. All 19 patients experienced at least one adverse event. Three patients had loss of dermatomal thermal sensitivity (grades I and II) exposed to RTX. Seven patients had urinary retention lasting more than 24 hours (grade III in three). Five patients had an adverse event associated with a transient increase in the QT interval on the electrocardiogram that resolved within 24 hours (grades I and II). The only grade IV adverse event was an unstageable decubitus ulcer. RTX reduced “worst” pain intensity by 38% (8.4±0.4 before treatment vs. 5.2±0.6 after treatment) and reduced opioid consumption by 57% measured on day 15 after treatment.

Conclusions: Intrathecal RTX is a single-dose, opioid-free analgesic for patients with refractory cancer pain. This study was accompanied by varying degrees of expected and unexpected adverse events, but the initial efficacy for pain was encouraging.

参考文献 Reference

Manners AJ et al. NEJM Evid 2025 ; 4(6)

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Trastuzumab deruxtecan 对比 ramucirumab + 紫杉醇在HER 2 阳性转移性胃癌/胃食管腺癌二线治疗的疗效 (6/7/2025)

Trastuzumab deruxtecan vs ramucirumab + paclitaxel in second-line treatment of HER2-positive metastatic gastric cancer or GE junction adenocarcinoma: phase III DESTINY-Gastric04

DESTINY-Gastric04是一项全球性, 随机, 多中心, 开放标签的III期临床试验。

方法： 经活检确认HER2阳性后，患者按1:1的比例随机分配至Trastuzumab deruxtecan (T-DXd) 6.4 mg/kg或ramucirumab (RAM) + 紫杉醇方案。主要终点是总生存期。研究者评估的次要终点包括无进展生存期, 客观响应率, 疾病控制率和安全性。

结果： 截至数据截止（2024年10月24日），共纳入494例患者（T-DXd组，n = 246；RAM + 紫杉醇组 [对照组]，n = 248）。基于观察到的266总生存期事件（信息分数 = 78.5%），疗效优于其他组（双侧P < 0.0228）。T-DXd组的中位总生存期随访期95% CI）为16.8个月（14.0-20.0个月），对照组为14.4个月（13.1-19.7个月）。T-DXd组的中位总生存期（95% CI）为14.7个月（12.1-16.6个月），对照组为11.4个月 （9.9-15.5个月）（风险比[HR]，0.70；P = 0.0044）。T-DXd 组和对照组的中位治疗持续时间分别为 5.4 个月 (0.7-30.3 个月) 和 4.6 个月 (0.9-34.9 个月)。

T-DXd 组报告治疗中出现的不良事件发生率为 244/244 (100%)，对照组报告的发生率为 228/233 (97.9%)；≥3级事件发生率分别为 68.0% 和 73.8%。T-DXd 组和对照组的严重不良事件发生率分别为 41.0% 和 43.3%；与停药相关的不良事件发生率分别为 14.3% 和 17.2%。经独立裁定，T-DXd 组 34 例患者（13.9%）（1 例3级，0 例4/5级）发生了药物相关性间质性肺疾病/肺炎，而对照组 3 例患者（1.3%）（2 例3级，1 例5级）。

结论： 对于 HER2+ 不可切除/转移性胃癌/胃食管癌患者，T-DXd 较对照组总生存期改善显著，且具有临床意义，T-DXd 6.4 mg/kg 的安全性与胃癌/胃食管癌患者中已知的 T-DXd 安全性一致，未出现新的安全性信号。

DESTINY-Gastric04 is a global, randomized, multicenter, open-label, phase III clinical trial. Methods: After biopsy confirmation of HER2 positivity, patients were randomly assigned in a 1:1 ratio to trastuzumab deruxtecan (T-DXd) 6.4 mg/kg or ramucirumab (RAM) + paclitaxel regimen. The primary endpoint was overall survival. Secondary endpoints assessed by investigators included progression-free survival, objective response rate, disease control rate, and safety. Results: As of data cutoff (October 24, 2024), a total of 494 patients were included (T-DXd group, n = 246; RAM + paclitaxel group [control group], n = 248). Based on the observed 266 overall survival events (information score = 78.5%), the efficacy was superior to the other groups (two-sided P < 0.0228). The median overall survival (95% CI) was 16.8 months (14.0-20.0 months) in the T-DXd group and 14.4 months (13.1-19.7 months) in the control group. The median overall survival (95% CI) was 14.7 months (12.1-16.6 months) in the T-DXd group and 11.4 months (9.9-15.5 months) in the control group (hazard ratio [HR], 0.70; P = 0.0044). The median duration of treatment was 5.4 months (0.7-30.3 months) in the T-DXd group and 4.6 months (0.9-34.9 months) in the control group, respectively. Treatment-emergent adverse events were reported in 244/244 (100%) patients in the T-DXd group and 228/233 (97.9%) patients in the control group; grade ≥3 events occurred in 68.0% and 73.8%, respectively. Serious adverse events occurred in 41.0% and 43.3% of the T-DXd and control groups, respectively; and adverse events related to discontinuation occurred in 14.3% and 17.2%, respectively. Drug-related interstitial lung disease/pneumonitis was independently adjudicated in 34 patients (13.9%) in the T-DXd group (1 grade 3, 0 grade 4/5) and in 3 patients (1.3%) in the control group (2 grade 3, 1 grade 5). Conclusion: For patients with HER2+ unresectable/metastatic gastric cancer/gastroesophageal cancer, T-DXd significantly improved overall survival compared with the control group, which was clinically significant. The safety of T-DXd 6.4 mg/kg was consistent with the known safety of T-DXd in patients with gastric cancer/gastroesophageal cancer, and no new safety signals emerged.

参考文献 Reference

Shitara K et al. J Clin Onc 2025; 43 [17, suppl Abstr LBA4002]

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FDA 批准 retifanlimab-dlwr 与卡铂和紫杉醇联合治疗肛管鳞状细胞癌 (6/1/2025)

FDA approves retifanlimab-dlwr in combination with carboplatin and paclitaxel for anal squamous cell carcinoma

2025 年 5 月 15 日，FDA 批准 retifanlimab与卡铂和紫杉醇联合治疗，用于无法手术的局部复发或转移性肛管鳞状细胞癌的一线治疗。FDA 还批准 retifanlimab 作为单药治疗，用于治疗在铂类化疗后病情进展或不耐受的局部复发或转移性肛管鳞状细胞癌。POD1UM-303/InterAACT 2 (NCT04472429) 是一项随机, 多中心, 双盲试验，纳入了308例未接受过化疗且无法手术的局部复发或转移性鳞状细胞癌患者，评估了 retifanlimab联合卡铂和紫杉醇的疗效。患者在第1天接受卡铂AUC 5的治疗，在第1, 8和15天接受紫杉醇80 mg/m²的治疗，共6个周期。患者按1:1的比例随机分配接受以下治疗： retifanlimab 500 mg，每4周静脉注射一次；或 安慰剂，每4周静脉注射一次。 主要疗效结局指标是无进展生存期。总生存期是关键的次要终点。其他疗效结局指标包括总体响应率和响应持续时间。

Retifanlimab组的中位无进展生存期为9.3个月（95% CI: 7.5, 11.3），安慰剂组为7.4个月（95% CI: 7.1, 7.7）（风险比0.63 [95% CI: 0.47, 0.84]，p值0.0006）。中期总生存期结果无统计学意义：两组的中位总生存期分别为29.2个月（95% CI: 24.2，无法估计[NE]）和23个月（95% CI: 15.1, 27.9）（风险比0.70 [95% CI: 0.49, 1.01]）。 45% 的安慰剂组患者在病情进展后接受了 retifanlimab治疗。两组的总体响应率分别为 56%（95% CI：48, 64）和 44%（95% CI：36, 52）。

POD1UM-202 (NCT03597295) 是一项开放标签, 多中心, 单组试验，纳入了 94 例局部复发或转移性鳞状细胞癌患者，这些患者在铂类化疗期间病情进展或对铂类化疗不耐受。患者每 4 周接受 500 毫克 retifanlimab静脉注射，直至病情进展、出现不可接受的毒性反应或最长 24 个月。主要疗效指标是总体响应率和响应持续时间。 总体响应率为 14% (95% CI: 8, 23)，中位响应持续时间为 9.5 个月 (95% CI: 4.4，无法估计 [NE])。

Retifanlimab的处方信息包含对严重及致命的免疫介导不良反应, 输注相关反应, 异基因造血干细胞移植并发症以及胚胎-胎儿毒性的警告和注意事项。 Retifanlimab与卡铂和紫杉醇联合治疗的推荐剂量为每 4 周 500 毫克，直至病情进展、出现不可接受的毒性或最长 12 个月。Retifanlimab单药治疗的推荐剂量为每 4 周 500 毫克，直至病情进展、出现不可接受的毒性或最长 24 个月。

On May 15, 2025, the FDA approved retifanlimab in combination with carboplatin and paclitaxel for the first-line treatment of inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal. The FDA also approved retifanlimab as a single-agent therapy for the treatment of locally recurrent or metastatic squamous cell carcinoma of the anal canal that has progressed after or is intolerant of platinum-based chemotherapy.  

POD1UM-303/InterAACT 2 (NCT04472429) was a randomized, multicenter, double-blind trial that enrolled 308 patients with chemotherapy-naive, inoperable locally recurrent or metastatic squamous cell carcinoma to evaluate the efficacy of retifanlimab in combination with carboplatin and paclitaxel. Patients received carboplatin AUC 5 on day 1 and paclitaxel 80 mg/m² on days 1, 8, and 15 for a total of 6 cycles. Patients were randomized in a 1:1 ratio to receive either retifanlimab 500 mg intravenously every 4 weeks or placebo intravenously every 4 weeks. The primary efficacy outcome measure was progression-free survival. Overall survival was a key secondary endpoint. Other efficacy outcomes included overall response rate and duration of response. The median progression-free survival was 9.3 months (95% CI: 7.5, 11.3) in the retifanlimab group and 7.4 months (95% CI: 7.1, 7.7) in the placebo group (hazard ratio 0.63 [95% CI: 0.47, 0.84], p-value 0.0006). Interim overall survival results were not statistically significant: median overall survival was 29.2 months (95% CI: 24.2, not estimable [NE]) and 23 months (95% CI: 15.1, 27.9), respectively (hazard ratio 0.70 [95% CI: 0.49, 1.01]). Forty-five percent of patients in the placebo group received retifanlimab after disease progression. The overall response rate was 56% (95% CI: 48, 64) and 44% (95% CI: 36, 52), respectively.

POD1UM-202 (NCT03597295) was an open-label, multicenter, single-arm trial that enrolled 94 patients with locally recurrent or metastatic squamous cell carcinoma who had progressed during or were intolerant of platinum-based chemotherapy. Patients received 500 mg of retifanlimab intravenously every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. The primary efficacy endpoints were overall response rate and duration of response. The overall response rate was 14% (95% CI: 8, 23), and the median duration of response was 9.5 months (95% CI: 4.4, not estimable [NE]).

The prescribing information for retifanlimab contains warnings and precautions for serious and fatal immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. The recommended dose of retifanlimab in combination with carboplatin and paclitaxel is 500 mg every 4 weeks until disease progression, unacceptable toxicity, or up to 12 months. The recommended dose of retifanlimab monotherapy is 500 mg every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months.

参考文献 Reference

www.fda/gov/drugs/development&approvalprocess/ FDA approves retifanlimab-dlwr with carboplatin and paclitaxel

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Niraparib 治疗伴同源重组途径基因突变的晚期黑色素瘤患者 (5/31/2025)

Niraparib treating advanced melanoma with homologous recombination pathway gene mutations

目的: 转移性黑色素瘤患者在接受检查点抑制剂和BRAF靶向药物治疗后病情进展，治疗选择有限。高达三分之一的黑色素瘤在同源重组 (HR) 途径中存在至少一个分子畸变，导致HR功能缺陷。

方法: 在这项单组试验中，研究者评估了尼拉帕利对转移性黑色素瘤患者的总体响应率。这些患者携带HR通路（ARID1A/B、ARID2、ATM、ATR、ATRX、BARD1、BRCA1/2、BAP1、BRIP1、CHEK2、FANCD2、MRE11A、RAD50、RAD51、RAD54B或PALB2）的基因变异，且在接受PD-1阻断治疗或BRAF/MEK抑制剂（如果存在BRAF突变）治疗后病情出现进展。尼拉帕利的给药剂量为每日300毫克或200毫克，具体剂量取决于体重和血小板计数。

结果: 本试验共纳入14名患者，但由于患者入组缓慢而终止。患者中位年龄为71岁。11 例患者的乳酸脱氢酶水平升高。10 例患者患有非葡萄膜黑色素瘤，4 例患者患有葡萄膜黑色素瘤。2 例（14%）达到部分响应，7 例（50%）病情稳定，疾病控制率为 64%。中位无进展生存期为 16 周。在非葡萄膜黑色素瘤患者中，2 例（20%）达到部分响应，至进展时间分别为 32 和 24 周，5 例（50%）病情稳定，持续 16-98 周。4 例葡萄膜黑色素瘤患者均未达到响应。未发生与尼拉帕尼治疗相关的意外不良事件。值得注意的是，1 例具有 ARID1A 突变的响应患者在基线时可检测到循环肿瘤 DNA，但在治疗期间无法检测到。

结论: 尽管样本量较小，但结果显示，对于既往接受过治疗且伴有 HR 基因突变的非葡萄膜转移性黑色素瘤患者，尼拉帕利单药疗法具有良好的疗效。

Objective: Patients with metastatic melanoma who have progressed after treatment with checkpoint inhibitors and BRAF-targeted agents have limited treatment options. Up to one-third of melanomas harbor at least one molecular aberration in the homologous recombination (HR) pathway, resulting in defective HR function.

Methods: In this single-arm trial, the researchers evaluated the overall response rate to niraparib in patients with metastatic melanoma who harbored genetic alterations in the HR pathway (ARID1A/B, ARID2, ATM, ATR, ATRX, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCD2, MRE11A, RAD50, RAD51, RAD54B, or PALB2) and who had progressed after treatment with PD-1 blockade or BRAF/MEK inhibitors if a BRAF mutation was present. Niraparib was administered at a dose of 300 mg or 200 mg daily, depending on body weight and platelet count. Results: A total of 14 patients were enrolled in this trial, but it was terminated due to slow patient enrollment. The median age of the patients was 71 years. Eleven patients had elevated lactate dehydrogenase levels. Ten patients had non-uveal melanoma and four had uveal melanoma. Two patients (14%) achieved partial responses and seven patients (50%) had stable disease, with a disease control rate of 64%. The median progression-free survival was 16 weeks. Among patients with non-uveal melanoma, two patients (20%) achieved partial responses with a time to progression of 32 and 24 weeks, respectively, and five patients (50%) had stable disease lasting 16-98 weeks. None of the four patients with uveal melanoma achieved a response. No unexpected adverse events related to niraparib treatment occurred. Of note, one responding patient with an ARID1A mutation had detectable circulating tumor DNA at baseline but not during treatment. Conclusions: Despite the small sample size, the results show that niraparib monotherapy has an efficacy in patients with previously treated non-uveal metastatic melanoma with HR gene mutations.

参考文献 Reference

Kim KB et al. J Clin Onc Precision Onc  2025;  Ma 15.

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乳腺癌患者的手术延迟与死亡风险因亚型而异 (5/25/2025)

Delayed surgery and mortality risk vary by breast cancer subtype

这项回顾性队列研究旨在使用 SEER (Surveillance, Epidemiology, and End Results)-Medicare 数据库评估在 2010 年至 2017 年期间接受手术作为首次治疗的局部区域乳腺癌患者中 (548,808人)，延迟手术对生存的影响是否因亚型（激素 [HR] + / HER2 -, HR – / HER2 – 和 HER2 +）而异。

所有亚型的调整后乳腺癌死亡率风险都随着从诊断活检到手术的持续天数 (TTS) 的增加而增加；然而，关联的模式和程度各不相同。 HR + / HER2 – 患者的乳腺癌死亡率风险与TTS相关的增加最为明显，42 天后呈指数增长，调整后的亚分布风险比 (sHR) 在 TTS = 60 天时为 1.21 (95% CI: 1.06–1.37)，在 TTS = 90 天时为 1.79 (95% CI: 1.40–2.29)，在 TTS = 120 天时为 2.83 (95% CI: 1.76–4.55)。相反，HER2 + 和 HR – / HER2 – 患者的 sHR 均显示较慢的、近似线性的增长，尽管 HR – HER2 – 的 sHR 增长不显著。 

受延迟手术影响最大的乳腺癌亚型往往是预后最好的亚型，包括激素受体阳性乳腺癌和HER2阴性乳腺癌。在未手术的情况下，患者的风险在42天后就开始增加。到60、90和120天时，患者的死亡风险分别增加了21%、79%和183%。相比之下，激素受体阴性和三阴性乳腺癌亚型在治疗延迟期间变化较小。

This retrospective cohort study aimed to evaluate whether the effect of delayed surgery on survival differed by subtype (hormone [HR] + / HER2 -, HR – / HER2 -, and HER2 +) among patients with locoregional breast cancer who underwent surgery as first treatment between 2010 and 2017 (n=548,808) using the SEER (Surveillance, Epidemiology, and End Results)-Medicare database. The adjusted breast cancer mortality risk increased with increasing days from diagnostic biopsy to surgery (TTS)  for all subtypes. However, the pattern and magnitude of the association varied. The TTS-related increase in breast cancer mortality risk was most pronounced in HR + / HER2 – patients, increasing exponentially after 42 days, with adjusted subdistribution hazard ratios (sHR) of 1.21 (95% CI: 1.06–1.37) at TTS = 60 days, 1.79 (95% CI: 1.40–2.29) at TTS = 90 days, and 2.83 (95% CI: 1.76–4.55) at TTS = 120 days. In contrast, both HER2 + and HR – / HER2 – patients showed a slower, nearly linear increase in sHR, although the increase in sHR for HR – HER2 – was not significant. The breast cancer subtypes most affected by delayed surgery tended to be those with the best prognosis, including hormone receptor-positive breast cancer and HER2-negative breast cancer. In the absence of surgery, patients’ risk began to increase after 42 days. By 60, 90, and 120 days, patients’ risk of death increased by 21%, 79%, and 183%, respectively.

参考文献 Reference

Salewon ML et al. Breast Can Res 202 ; 26 : 191

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Tocilizumab联合化疗作为晚期胰腺癌一线治疗: 生存期和恶病质 (5/24/2025)

Tocilizumab as first-line treatment in advanced pancreatic cancer: survival and cachexia

方法: 这是一项随机II期临床试验（NCT02767557）, 比较了吉西他滨/白蛋白结合型紫杉醇（Nab）联合或不联合抗白细胞介素-6 (IL-6) 受体抗体托珠单抗 Tocilizumab治疗晚期胰腺癌的疗效。 安全队列参与者在第1, 8和15天接受吉西他滨 1,000 mg/m²和Nab 125 mg/m²的治疗，第1天接受Tocilizumab 8 mg/kg的治疗，每个28天为一个周期。参与者按1:1的比例随机分配接受吉西他滨/白蛋白结合型紫杉醇/Tocilizumab(试验组)或吉西他滨/白蛋白结合型紫杉醇(对照组)方案治疗。主要终点是6个月总生存率。次要终点是无进展生存率, 总响应率和安全性。探索性终点包括恶病质, 生活质量和生物标志物，包括促恶病质蛋白生长分化因子15(GDF15)。  

结果: 共147例患者接受治疗，其中包括6例安全队列参与者。中位随访期为8.1个月（四分位距(IQR)，4.2-13.9）。 试验组6个月总生存率为68.6%（95% CI，56.3-78.1），对照组为62.0%（49.6-72.1）（P = 0.409）。试验组与对照组相比，18个月时的总生存率有所改善（27.1% vs 7.0%，P = 0.001）。中位总生存率, 无进展生存率, 总响应率和安全性均无差异。试验组3级及以上治疗相关不良事件发生率为88.1%，对照组为63.4%（P < 0.001）。与对照组相比，试验组肌肉损失减少，2个月时中位数变化量分别为+0.1013%和-3.430%（P =0.0012），4个月时中位数变化量分别为+0.7044和-3.353%（P=0.036）。2个月时，试验组的肌肉损失发生率为43.48%，对照组为73.52%（P=0.0045）；4个月时，试验组的肌肉损失发生率为41.82%，对照组为68.75%（P=0.0062）。对照组和试验组均未改变GDF15。

结论: 尽管Tocilizumab组未达到主要终点且治疗相关不良事件发生率增加，但18个月生存率的提高和肌萎缩的减少支持了IL-6阻断剂独立于GDF15的抗恶病质作用。

Methods: This was a randomized phase II clinical trial (NCT02767557) comparing gemcitabine/nab-paclitaxel (Nab) with or without the anti-interleukin-6 (IL-6) receptor antibody Tocilizumab in patients with advanced pancreatic cancer. Participants in the safety cohort received gemcitabine 1,000 mg/m² and Nab 125 mg/m² on days 1, 8, and 15 and Tocilizumab 8 mg/kg on day 1, each 28-day cycle. Participants were randomly assigned in a 1:1 ratio to receive gemcitabine/nab-paclitaxel/tocilizumab (experimental group) or gemcitabine/nab-paclitaxel (control group). The primary endpoint was 6-month overall survival. Secondary endpoints were progression-free survival, overall response rate, and safety. Exploratory endpoints included cachexia, quality of life, and biomarkers, including the cachexia-promoting protein growth differentiation factor 15 (GDF15).  

Results: A total of 147 patients were treated, including 6 participants in the safety cohort. The median follow-up was 8.1 months (interquartile range (IQR), 4.2-13.9). The 6-month overall survival rate was 68.6% (95% CI, 56.3-78.1) in the experiment group and 62.0% (49.6-72.1) in the control group (P = 0.409). The overall survival rate at 18 months was improved in the experiment group compared with the control group (27.1% vs 7.0%, P = 0.001). There were no differences in median overall survival, progression-free survival, overall response rate, and safety. The incidence of grade 3 or higher treatment-related adverse events was 88.1% in the experiment group and 63.4% in the control group (P < 0.001). Compared with the control group, the experimental group had reduced muscle loss, with median changes of +0.1013% and -3.430% at 2 months (P = 0.0012) and +0.7044 and -3.353% at 4 months (P = 0.036). At 2 months, the incidence of muscle loss was 43.48% in the experiment group and 73.52% in the control group (P = 0.0045); at 4 months, the incidence of muscle loss was 41.82% in the experiment group and 68.75% in the control group (P = 0.0062). GDF15 was not altered in either the control or experiment group.

Conclusion: Although the primary endpoint was not achieved and the incidence of treatment-related adverse events was increased in the Tocilizumab group, the improved 18-month survival rate and reduced muscle atrophy support the anti-cachexia effect of IL-6 blockade independent of GDF15.

参考文献 Reference

Chen IM et al. J Clin Onc 2025: May 12 https://doi.org/10.1200/JCO.23.019

Casdatifan 单药治疗既往接受过治疗的透明细胞肾细胞癌: I期试验 (5/18/2025)

Casdatifan in previously treated clear cell renal cell carcinoma, a phase I study

Casdatifan  是一种口服生物可利用的小分子 HIF-2α 抑制剂，可有效抑制 HIF-2α 依赖性基因的转录。

方法：ARC-20 (NCT05536141) 是一项 I 期开放标签研究，旨在评估Casdatifa 单药治疗既往接受过 HIF-2α 抑制剂治疗且既往接受过抗 PD-(L)1 和 VEGFR-TKI 治疗的透明细胞肾细胞癌患者的效果。试验终点包括治疗中出现的不良事件发生率和客观响应率。

结果：剂量扩展前，4 名患有透明细胞肾细胞癌的患者（3 名患者 50 mg，每日两次；1 名患者 50 mg，每日一次）出现了剂量递增，其中 2 名患者疾病稳定，1 名患者出现部分响应，截至 2024 年 8 月 30 日，还有 2 名患者仍在研究中。在剂量扩展中，64 名患者接受了Casdatifan治疗（33 名患者 50 mg，每日两次，31 名患者 50 mg，每日一次）。各个剂量组的既往治疗线数中位数为 3（范围为 1-7）。50 mg BID 和 50 mg QD 组的中位随访时间（月，范围）分别为 11（3-15+）和 8（4-10+）。 Casdatifan相关 ≥3 级治疗中出现的不良事件 发生率分别为 42%（n=14）和 36%（n=11）的患者。值得注意的是，无论剂量多少，36% 的患者出现 3 级贫血，9% 和 6% 的患者出现 3 级缺氧。未发生 ≥4 级治疗中出现的不良事件。所有 IMDC（国际转移性肾细胞癌数据库联盟）风险组（无论剂量多少）以及有或无先前使用 mTOR 抑制剂的患者均观察到活性。Casdatifan 100 毫克表现出最佳的持续 EPO 降低作用。

结论：对于接受过大量治疗的透明细胞肾细胞癌患者，Casdatifan单药治疗耐受性良好，并在 IMDC 风险组中显示出良好的早期临床活性。 Casdatifan 每天 100 mg 将在 3 期 PEAK-1 试验中与 VEGFR-TKI（卡博替尼）联合使用，并在即将开展的另一项一线试验中与免疫疗法（volrustomig）联合使用。

Casdatifan is an orally bioavailable small molecule HIF-2α inhibitor that effectively inhibits the transcription of HIF-2α-dependent genes.

Methods: ARC-20 (NCT05536141) is a phase I open-label study designed to evaluate the effect of casdatifa monotherapy in patients with clear cell renal cell carcinoma who have received prior HIF-2α inhibitor therapy and have received prior anti-PD-(L)1 and VEGFR-TKI therapy. Trial endpoints included the incidence of treatment-emergent adverse events and objective response rate.

Results: Before dose expansion, 4 patients with clear cell renal cell carcinoma (3 patients 50 mg twice daily; 1 patient 50 mg once daily) had dose escalation, 2 patients had stable disease, 1 patient had a partial response, and 2 patients remained on study as of August 30, 2024. In dose expansion, 64 patients were treated with casdatifan (33 patients 50 mg twice daily and 31 patients 50 mg once daily). The median number of prior lines of therapy was 3 (range 1-7) across dose groups. The median follow-up (months, range) was 11 (3-15+) and 8 (4-10+) for the 50 mg BID and 50 mg QD groups, respectively. Casdatifan-related grade ≥3 treatment-emergent adverse events occurred in 42% (n=14) and 36% (n=11) of patients, respectively. Notably, grade 3 anemia occurred in 36% of patients, and grade 3 hypoxia in 9% and 6% of patients, regardless of dose. No grade ≥4 treatment-emergent adverse events occurred. Activity was observed across all IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) risk groups, regardless of dose, and in patients with or without prior mTOR inhibitor use. Casdatifan 100 mg demonstrated the best sustained EPO lowering effect.

Conclusions: Casdatifan monotherapy was well tolerated and showed promising early clinical activity across IMDC risk groups in heavily pretreated clear cell renal cell carcinoma patients. Casdatifan 100 mg daily will be used in combination with a VEGFR-TKI (cabozantinib) in the phase 3 PEAK-1 trial and in combination with immunotherapy (volrustomig) in another upcoming first-line trial.

参考文献 Reference

Choueiri TK et al. J Clin Onc 2025 ; 43 [5, suppl abstr 441

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III 期临床试验 TFOX 对比 FOLFOX 在晚期胃或胃食管交界处腺癌者的一线治疗 (5/16/2025)

TFOX versus FOLFOX in first-line treatment in advanced gastric or GE junction adenocarcinoma, a phase III trial

方法: PRODIGE 51-FFCD-GASTFOX(NCT03006432) 是一项在法国 96 家医疗中心开展的开放标签, 多中心, 随机, III 期临床试验。符合条件的为 HER2 阴性胃腺癌或胃食管交界处腺癌，局部晚期不可切除或转移性且先前未接受过治疗，患者按1:1的比例随机分配，接受FOLFOX方案（亚叶酸400 mg/m2，奥沙利铂85 mg/m2，5-氟尿嘧啶400 mg/m2推注，随后5-氟尿嘧啶2400 mg/m2，每2周持续输注46小时）或TFOX方案（多西他赛50 mg/m2，亚叶酸400 mg/m2，奥沙利铂85 mg/m2，随后5-氟尿嘧啶2,400 mg/m2，每2周持续输注46小时）。主要终点是无进展生存期，定义为从随机分组至首次出现放射学或临床进展（或两者兼有）或任何原因死亡的时间。次要终点包括总生存期和客观响应率（定义为达到最佳总体完全或部分响应的患者比例）。风险比和 95% 置信区间 (CI) 使用未分层 Cox 比例风险模型估算。

结果: 2016年12月19日至2022年12月26日，507例患者被随机分配（TFOX组254例，FOLFOX组253例）。中位年龄为64.2岁（IQR 56.7–70.8），其中399例（79%）为男性，108例（21%）为女性。中位随访时间为42.8个月（25.8–49.9个月），TFOX组的中位无进展生存期为7.59个月（95% CI 7.06–7.95），FOLFOX组为5.98个月（5.65–6.97）（p =0.013）；因此，计算出 12 个月限制性平均无进展生存期：TFOX 组为 7.52 个月（7.06 ～ 7.97 个 月），FOLFOX 组为 6.62 个月（6.16 ～ 7.09 个月）（p =0.0072）。中位总生存期：TFOX 组为 15.08 个月（13.70 ～ 16.72 个月），FOLFOX 组为 12.65 个月（10.94 ～ 14.00 个月）（HR 0.82  [0.68 ～ 0.99]；p =0.048），客观响应率：62.3（56.0 ～ 68.3%）vs 53.4%（47.0 ～ 59.8 个月；p =0.045）。

最常见的3级和4级治疗中出现的不良事件包括腹泻（TFOX组37例[15%] vs FOLFOX组18例[7%]）、周围神经病变（80例[32%] vs 49例[20%]）、中性粒细胞减少症（67例[27%] vs 44例[18%]）和疲劳（40例[16%] vs 20例[8%]）。TFOX组有66例（27%）患者发生了严重的治疗相关不良事件，FOLFOX组有33例（13%）患者发生了严重的治疗相关不良事件。TFOX组有2例（<1%）患者死亡（1例死于感染性休克，1例死于胃肠道穿孔），FOLFOX组有1例（<1%）患者死亡（死于感染性休克）。

解读: 与FOLFOX方案相比，改良FLOT/TFOX方案显著改善了既往未接受治疗的HER2阴性晚期胃癌和胃食管交界部腺癌患者的无进展生存期, 总生存期和客观响应率。对于适合接受多西他赛三联化疗的患者，改良FLOT/TFOX方案可能成为一种新的一线治疗选择。

编者：一项使用 FLOT（类似于 TFOX）作为转移性胃/胃食管交界处腺癌一线治疗的 II 期研究早在2008 年报告过

Methods: PRODIGE 51-FFCD-GASTFOX (NCT03006432) was an open-label, multicenter, randomized, phase III clinical trial conducted in 96 centers in France. Eligible patients with HER2-negative untreated gastric or GE junction adenocarcinoma, locally advanced unresectable or metastatic disease, were randomly assigned in a 1:1 ratio to receive FOLFOX (leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, 5-fluorouracil 400 mg/m2 bolus followed by 5-fluorouracil 2400 mg/m2 infused over 46 hours every 2 weeks) or TFOX (docetaxel 50 mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2 followed by 5-fluorouracil 2,400 mg/m2 infused over 46 hours every 2 weeks). The primary end point was progression-free survival, defined as the time from randomization to the first occurrence of radiographic or clinical progression (or both) or death from any cause. Secondary end points included overall survival and objective response rate. Hazard ratios and 95% confidence intervals (CIs) were estimated using unstratified Cox proportional hazards models.

Results: Between Dec 19, 2016, and Dec 26, 2022, 507 patients were randomly assigned (254 to TFOX and 253 to FOLFOX). The median age was 64.2 years (IQR 56.7–70.8), of whom 399 (79%) were men and 108 (21%) were women. With a median follow-up of 42.8 months (25.8–49.9 months), the median progression-free survival was 7.59 months (95% CI 7.06–7.95) in the TFOX group and 5.98 months (5.65–6.97) in the FOLFOX group (p = 0.013); thus, the 12-month restricted mean progression-free survival was calculated to be 7.52 months (7.06–7.97 months) in the TFOX group and 6.62 months (6.16–7.09 months) in the FOLFOX group (p = 0.0072). Median overall survival: 15.08 months (13.70-16.72 months) in the TFOX group and 12.65 months (10.94-14.00 months) in the FOLFOX group (HR 0.82 [0.68-0.99]; p = 0.048), objective response rate: 62.3 (56.0-68.3%) vs 53.4% ​​(47.0-59.8 months; p = 0.045).

The most common grade 3 and 4 treatment-emergent adverse events were diarrhea (37 patients [15%] in the TFOX group vs 18 patients [7%] in the FOLFOX group), peripheral neuropathy (80 patients [32%] vs 49 patients [20%]), neutropenia (67 patients [27%] vs 44 patients [18%]), and fatigue (40 patients [16%] vs 20 patients [8%]). Serious treatment-related adverse events occurred in 66 patients (27%) in the TFOX group and in 33 patients (13%) in the FOLFOX group. Two patients (<1%) in the TFOX group died (one from septic shock and one from gastrointestinal perforation), and one patient (<1%) in the FOLFOX group died (from septic shock).

Interpretation: Compared with FOLFOX, modified FLOT/TFOX significantly improved progression-free survival, overall survival, and objective response rate in patients with HER2-negative advanced gastric cancer and gastroesophageal junction adenocarcinoma who had not received previous treatment. Modified FLOT/TFOX may become a new first-line treatment option for patients who are suitable for docetaxel triple chemotherapy.

Editor: A phase II study using FLOT (similar to TFOX) as first -line in metastatic gastric/GE junction cancer was conducted in 2008.

参考文献 Reference

Zaanan A et al/ Lancet Onc 2025 ; doi: 10.1016/S1470-2045(25)00130-5

Al-Batran S-E et al. Ann Onc 2008; 19:1882

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FDA 批准 avutometinib 和 defactinib 联合治疗 KRAS 突变复发性低级别浆液性卵巢癌 (5/11/2025)

FDA approved avutometinib plus defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer

2025年5月8日，FDA加速批准avutometinib和defactinib联合疗法，用于治疗既往接受过全身治疗的KRAS突变复发性低级别浆液性卵巢癌（LGSOC）成年患者。RAMP-201（NCT04625270）是一项开放标签, 多中心临床试验，纳入了57名可测量KRAS突变复发性低级别浆液性卵巢癌成年患者，评估了其疗效。患者需接受过至少一项既往全身治疗，包括含铂方案。 KRAS 突变状态通过前瞻性局部肿瘤组织检测确定。患者接受每周两次口服 3.2 mg avutometinib（第 1 天和第 4 天）和每日两次口服 200 mg defactinib，均持续服用3 周，休息一周, 每 4 周为一个疗程,，直至病情进展或出现不可接受的毒性。 主要疗效指标是总响应率。另一项疗效指标是响应持续时间 。

确认的总响应率为 44%（95% CI: 31, 58），响应持续时间范围为 3.3 个月至 31.1 个月。

最常见的不良反应（≥25%），包括实验室检查异常，包括肌酸磷酸激酶升高、恶心、疲劳、天冬氨酸氨基转移酶升高、皮疹、腹泻、肌肉骨骼疼痛、水肿、血红蛋白降低、丙氨酸氨基转移酶升高、呕吐、血胆红素升高、甘油三酯升高、淋巴细胞计数减少、腹痛、消化不良、痤疮样皮炎、玻璃体视网膜疾病、碱性磷酸酶升高、口腔炎、瘙痒、视力障碍、血小板计数减少、便秘、皮肤干燥、呼吸困难、咳嗽、尿路感染和中性粒细胞计数减少。 Avutometinib 的推荐剂量为 3.2 毫克（四粒 0.8 毫克胶囊），每周口服两次（第 1 天和第 4 天），均持续服用3 周，休息一周, 每 4 周为一个疗程，直至病情进展或出现不可接受的毒性。Defactinib 的推荐剂量为 200 毫克（一片），每日口服两次，均持续服用3 周，休息一周, 每 4 周为一个疗程，直至病情进展或出现不可接受的毒性。

On May 8, 2025, the FDA granted the approval of avutometinib and defactinib combination therapy for the treatment of adult patients with recurrent low-grade serous ovarian cancer with KRAS mutations who had previously received systemic treatment. RAMP-201 (NCT04625270) is an open-label, multicenter clinical trial that enrolled 57 adult patients with recurrent low-grade serous ovarian cancer with measurable KRAS mutations to evaluate the efficacy. Patients were required to have received at least one previous systemic treatment, including a platinum-containing regimen. KRAS mutation status was determined by prospective local tumor tissue testing. Patients received 3.2 mg avutometinib orally twice a week (day 1 and day 4) and 200 mg defactinib orally twice a day, both taken for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. The major efficacy outcome measure was the overall response rate. Another efficacy indicator was the duration of response.

The confirmed overall response rate was 44% (95% CI: 31, 58), and the duration of response ranged from 3.3 months to 31.1 months.

The most common adverse reactions (≥25%) included laboratory abnormalities, including increased creatine phosphokinase, nausea, fatigue, increased aspartate aminotransferase, rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, increased alanine aminotransferase, vomiting, increased blood bilirubin, increased triglycerides, decreased lymphocyte count, abdominal pain, dyspepsia, acneiform dermatitis, vitreoretinal disease, increased alkaline phosphatase, stomatitis, pruritus, visual disturbances, decreased platelet count, constipation, dry skin, dyspnea, cough, urinary tract infection, and decreased neutrophil count.

The recommended dose of Avutometinib is 3.2 mg (four 0.8 mg capsules) taken orally twice a week (Day 1 and Day 4), taken for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. The recommended dose of Defactinib is 200 mg (one tablet) taken orally twice a day taken for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-combination-avutometinib-and-defactinib-kras-mutated-recurrent-low

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靶向CD46的抗体-药物（FG-3246）首次用于人类转移性前列腺癌的 I 期试验 (5/10/2025)

First human phase I trial of antibody-drugs conjugate targeting CD46 (FG-3246)  used in metastatic prostate cancer

For46（FG-3246）是一种与单甲基auristatin E共轭的完全人类抗体，它靶向CD46的肿瘤选择表位，该表位在转移性去势抵抗性的前列腺癌(mCRPC)中过表达。 For46在耐enzalutamide耐药的CRPC模型中表现出有效的非临床活性。

方法: 这是一项I期，剂量升级/扩张试验（ClinicalTrials.govs.gov identifier: NCT03575819), 旨在治疗经过大于一种雄激素信号抑制剂后疾病进行的mCRPC患者。每3周静脉注射一次，For46的起始剂量为0.1 mg/kg。主要目的是确定最大耐受剂量。全血质量细胞仪用于表征CRPC组织中周围免疫反应和CD46表达。

结果: 56例患者被招募。剂量限制毒性包括中性粒细胞减少症（n = 4），发热性中性粒细胞减少症（n = 1）和疲劳（n = 1）。使用调整后的体重，最大耐受剂量为2.7 mg/kg。所有剂量水平的最常见 > 3级不良事件是中性粒细胞减少症（59％），白细胞减少症（27％），淋巴细胞减少症（7％），贫血（7％）和疲劳（5％）。观察到一个3级的发热性中性粒细胞减少事件。没有与治疗有关的死亡。

在可评估的亚组的功效中（腺癌患者接受起始剂量 > 1.2mg/kg，n = 40），中位无放射线学进展生存期为8.7个月（范围为0.1-33.9）。 39名可评估患者中有14名（36％）达到了PSA50反应。确认的客观响应率为20％（25例可评估患者中的5个）。响应的中间持续时间为7.5个月。响应者的循环效应CD8+ T细胞的频率更高。  

结论: For46表现出具有安全性可管的初步临床活性。靶向CD46引起了与临床效应相关的免疫启动作用。

For46 (FG-3246) is a fully human antibody conjugated with monomethyl auristatin E, which targets the tumor-selective epitope of CD46, which is overexpressed in metastatic castration-resistant prostate cancer (mCRPC). For46 exhibits effective nonclinical activity in CRPC models that are resistant to enzalutamide.

Methods: This is a phase I, dose escalation/expansion trial (ClinicalTrials.gov identifier: NCT03575819), in patients with progressive mCRPC after treatment of >  one androgen signaling inhibitor. The initial dose of For46 was 0.1 mg/kg every 3 weeks. The main purpose is to determine the maximum tolerated dose. Whole blood mass cytometer was used to characterize peripheral immune responses and CD46 expression in CRPC tissues.

Results: 56 patients were recruited. Dosage-limiting toxicities include neutropenia (n = 4), febrile neutropenia (n = 1), and fatigue (n = 1). The maximum tolerated dose was 2.7 mg/kg using the adjusted weight. The most common grade  > 3 adverse events at all dose levels were neutropenia (59%), leukopenia (27%), lymphopenia (7%), anemia (7%), and fatigue (5%). A grade 3 febrile neutropenic event was observed. No treatment-related deaths.

In the efficacy evaluable subset (patients with adenocarcinoma received an initial dose > 1.2 mg/kg, n = 40), the median radiological progression-free survival was 8.7 months (range 0.1-33.9). 14 of the 39 evaluable patients (36%) achieved a PSA50 response. The confirmed objective response rate was 20% (5 out of 25 evaluable patients). The median duration of response was 7.5 months. Responders had a higher on-treatment frequency of circulating effector CD8+ T cells. Conclusion: For46 exhibits preliminary clinical activity with manageable safety profile. Targeting CD46 initiated an immune priming effect related to clinical outcomes.

参考文献 Reference

Aggarwal RR et al. J Clin Onc 2025 ; https://doi.org/10.1200/JCO-24-01989

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ICAM-1 CAR-T 细胞 (AIC100) 治疗晚期甲状腺癌的I 期研究 (5/4/2025)

Phase I study of ICAM-1 CAR-T cells (AIC100) in advanced thyroid cancer

ICAM-1 是一种细胞表面糖蛋白(CD54)，在包括甲状腺癌在内的多种癌症中过表达，并在肿瘤发生中起关键作用。AIC100 是第三代 ICAM-1 靶向 CAR-T 细胞产品，可选择性结合并杀死肿瘤细胞，从而提高安全性。而且它与生长抑素受体 2 共表达，可通过 DOTATATE PET 扫描监测 CAR-T 细胞。

方法： 这项多中心研究旨在探索 AIC100 的三个剂量水平，分别为 1x 10⁷、1 x 10⁸ 和 5 x 10⁸。由于之前未观察到剂量限制性毒性，因此研究了额外的剂量水平4 (7.5 x 10⁸)。关键入选者包括新诊断或复发性/难治性间变性(anaplastic ) 甲状腺癌或复发性/难治性低分化甲状腺癌患者，病灶可测量。在完成淋巴细胞清除（氟达拉滨/环磷酰胺 x 3 天）后 48 小时静脉输注 AIC100。主要目标包括 AIC100 输注后 30 天内的安全性评估/剂量限制性毒性，并确定推荐的 II 期临床试验剂量。

结果： 截至 2024 年 12 月 12 日，共入组 24 例患者，其中 15 例（8 例间变性甲状腺癌；7 例低分化甲状腺癌 ），中位年龄 59 岁（范围：47-69 岁），接受了 4 次剂量水平输注 AIC100。患者主要是男性（N = 11），既往全身治疗线数中位数为 2（范围，1-4）。在最初计划的剂量水平 1-3 中未观察到剂量限制性毒性。探索性剂量水平4 中的两名患者出现了 3 级肺炎。10 名（66.7%）患者出现了 1/2 级细胞因子释放综合征。在剂量水平 1-3 中未发生与 AIC100 相关的 ICANS。

输注后第 42 天，剂量水平 1-3 中有 11 名患者的疗效可评估；每个研究中心都评估了响应。在剂量水平1 中未观察到响应。对于剂量水平 2 和 3 中可评估的患者（n = 9），客观响应率和疾病控制率，定义为客观响应率 + 稳定疾病分别为 22% 和 56%。对剂量水平2剂量水平3期的间变性甲状腺癌患者（N=4），客观响应率为50% [剂量水平2期和剂量水平3期分别有1例部分响应和完全响应。对于剂量水平2-剂量水平3期的低分化甲状腺癌患者（N=5）疾病控制率为60%。所有患者均观察到AIC100扩增。基于安全性和有效性，5 x 10⁸（剂量水平3期）被宣布为推荐的 II 期临床试验剂量。  

 结论： AIC100是一种首次在人体中靶向ICAM-1的CAR-T细胞疗法，在复发/难治性例间变性甲状腺癌/低分化甲状腺癌患者中表现出可接受的安全性。剂量水平2剂量水平3期观察到的持久响应，并为AIC100在侵袭性甲状腺癌患者和其他晚期癌症患者中的潜在作用提供了概念验证。

ICAM-1 is a cell surface glycoprotein (CD54) that is overexpressed in a variety of cancers, including thyroid cancer, and plays a key role in tumorigenesis. AIC100 is a third-generation ICAM-1-targeted CAR-T cell product that selectively binds to and kills tumor cells, thereby improving safety. It is also co-expressed with somatostatin receptor 2, allowing CAR-T cells to be monitored by DOTATATE PET scanning.

Methods: This multicenter study was designed to explore three dose levels of AIC100, 1x 10⁷, 1 x 10⁸, and 5 x 10⁸. As no dose-limiting toxicity was previously observed, an additional dose level 4 (7.5 x 10⁸) was investigated. Key eligibilities included adult patients with newly diagnosed or relapsed/refractory anaplastic thyroid cancer or relapsed/refractory poorly differentiated thyroid cancer with measurable lesions. AIC100 was infused intravenously 48 hours after completion of lymphodepletion (fludarabine/cyclophosphamide x 3 days). Primary objectives included safety assessment/dose-limiting toxicity within 30 days after AIC100 infusion and determination of the recommended phase II clinical trial dose.

Results: As of December 12, 2024, a total of 24 patients were enrolled, of whom 15 (8 anaplastic thyroid cancer; 7 poorly differentiated thyroid cancer) with a median age of 59 years (range: 47-69 years) received 4 dose level infusions of AIC100. Patients were primarily male (N = 11) with a median number of prior systemic treatment lines of 2 (range, 1-4). No dose-limiting toxicity was observed at the initially planned dose levels 1-3. Two patients in the exploratory dose level 4 experienced grade 3 pneumonitis. Grade 1/2 cytokine release syndrome occurred in 10 patients (66.7%). No AIC100-related ICANS occurred in dose levels 1-3.

Eleven patients in dose levels 1-3 were evaluable for efficacy at day 42 after infusion; responses were assessed at each site. No responses were observed in dose level 1. For evaluable patients in dose levels 2 and 3 (n = 9), the objective response rate and disease control rate, defined as objective response rate + stable disease, were 22% and 56%, respectively. For patients with anaplastic thyroid cancer at dose level 2 and dose level 3 (N = 4), the objective response rate was 50% [1 partial response and 1 complete response at dose level 2 and dose level 3, respectively. The disease control rate was 60% for patients with poorly differentiated thyroid cancer at dose levels 2-dose level 3 (N = 5). AIC100 amplification was observed in all patients. Based on safety and efficacy, 5 x 10⁸ (dose level 3) was announced as the recommended dose for phase II clinical trials.

 Conclusion: AIC100 is a first-in-human CAR-T cell therapy targeting ICAM-1 that demonstrated an acceptable safety profile in patients with relapsed/refractory anaplastic/poorly differentiated thyroid cancer. Durable responses were observed at dose level 2 and provide proof of concept for the potential role of AIC100 in patients with aggressive thyroid cancer and other advanced cancers.

参考文献 Reference

Srour SA et al. Cancer Res 2025 ; 85 (8_Suppl_2): CT206

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Zoldonrasib 用于 KRAS G12D 突变型 非小细胞肺癌 (5/3/2025)

Zoldonrasib in patients with KRAS G12D–mutated NSCLC

约4% 的非小胞肺癌携带KRAS G12D突变，目前尚无有效的靶向疗法。Zoldonrasib是一种新型RAS(ON)三重复合物抑制剂，可选择性靶向KRAS G12D突变。与目前获批的KRAS G12C靶向疗法不同，该疗法将突变的KRAS锁定在非活性构象，而Zoldonrasi则靶向KRAS的活性构象。这可能会延缓或预防治疗耐药性，因为细胞无法通过增强上游信号传导来规避阻断，从而维持KRAS的活性构象。   

这是一项I期临床试验，研究人员分析了Zoldonrasib在211例KRAS G12D突变实体瘤患者中的安全性和有效性，这些患者至少接受过一线治疗。其中90例患者接受了II期临床试验的推荐剂量，即每日1,200毫克。未达到最大耐受剂量。 研究人员报告称，未出现 4 级或 5 级治疗相关不良反应。然而，在接受 1,200 毫克剂量的患者中，1 例患者停止治疗，4 例患者减少剂量，8 例患者因治疗相关不良反应而中断治疗。但在Zoldonrasib治疗期间未观察到皮疹, 黏膜炎和转氨酶升高等不良反应。 Zoldonrasib在所有剂量水平下均具有良好的耐受性，包括每日一次 1,200 毫克剂量。最常见的[不良]反应是恶心, 腹泻和疲劳，通常程度较轻，可通过支持性药物控制。

在疗效分析中，研究人员纳入了 18 名非小胞肺癌患者，这些患者入组时间至少在数据截止前 8 周。在这些患者中，61% 的患者获得了客观响应，89% 的患者病情得到控制。

结论: Zoldonrasib选择性靶向 KRAS G12D 基因，是耐受性良好的口服疗法，有望改变此类非小细胞肺癌亚型患者的治疗。

Approximately 4% of non-small cell lung cancers carry KRAS G12D mutations, for which there are currently no approved targeted therapies. Zoldonrasib is a novel RAS(ON) triple complex inhibitor that selectively targets KRAS G12D mutations. Unlike currently approved KRAS G12C targeted therapies, which lock mutant KRAS in an inactive conformation, Zoldonrasib targets the active conformation of KRAS. This may delay or prevent treatment resistance because cells cannot circumvent blockade by enhancing upstream signaling to maintain the active conformation of KRAS.

This is a phase I clinical trial in which researchers analyzed the safety and efficacy of Zoldonrasib in 211 patients with KRAS G12D mutant solid tumors who had received at least one line of treatment. Of these, 90 patients received the recommended dose of the phase II clinical trial, 1,200 mg per day. The maximum tolerated dose was not reached. The researchers reported that there were no grade 4 or 5 treatment-related adverse reactions. However, among patients receiving the 1,200 mg dose, 1 patient discontinued treatment, 4 patients had their dose reduced, and 8 patients discontinued treatment due to treatment-related adverse reactions. However, adverse reactions such as rash, mucositis, and elevated transaminases were not observed during zoldonrasib treatment. Zoldonrasib was well tolerated at all dose levels, including the 1,200 mg dose once daily. The most common [adverse] reactions were nausea, diarrhea, and fatigue, which were generally mild and manageable with supportive medications.

In the efficacy analysis, the researchers included 18 patients with NSCLC who were enrolled at least 8 weeks before the data cutoff. Among these patients, 61% achieved an objective response and 89% had disease control.

Conclusion: Zoldonrasib selectively targets the KRAS G12D gene and is a well-tolerated oral therapy that is expected to change the treatment of patients with this subtype of NSCLC.

参考文献 Reference

Arbour KC et. 2025 AACR Abstr CT019

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人工智能触发的临床试验通知 (4/27/2025)

Clinical trial notifications triggered by artificial intelligence-detected cancer progression

历史上，只有不到10%的成年癌症患者参加了临床试验。目前已开发出一些计算工具来匹配患者与试验，但这些工具仅在患者需要新的治疗方案时才有意义。 本试验目的为评估告知肿瘤科医生针对癌症进展患者的基因组靶向临床试验（由人工智能 (AI) 检测）是否会影响临床试验的参与。   

方法： 这项单中心随机试验于2023年1月30日至2024年6月30日在一家三级学术癌症中心进行。参与者为精准肿瘤学临床试验匹配数据库中至少18岁的实体瘤患者，于2013年7月至2022年12月接受二代测序，且截至2023年1月30日仍存活。患者按2:1的比例随机分配到干预组或对照组。在干预组中，当患者癌症进展且基于应用于影像学报告的人工智能技术，开始新治疗的可能性增加时，会向其肿瘤科医生发送关于基因组匹配临床试验的通知。对照组则未发送此类通知。 主要结果是患者参与任何治疗性临床试验。预先设定的次要结果包括同意参与任何治疗性试验, 已确定为试验就绪的患者同意并参与试验的情况, 作为临床试验一部分的新全身治疗的比例，以及收到通知的临床医生的调查回复。

结果 在随机分组的20,707名患者中（57.26%为女性；测序时的中位年龄为60岁[四分位距，50-69岁]），13,802名患者随机分配至干预组，6,905名患者随机分配至对照组。干预对试验入组率没有显著影响（干预组为 2.20% [95% CI, 1.97%-2.46%]；对照组为 2.03% [95% CI, 1.72%-2.39%]；差异为 0.18 [95% CI, -0.25 至 0.58] 个百分点；P = .41）。同样，在已确定为准备参加试验的 2,127 名患者中，干预组和对照组的试验入组率也没有显著差异（18.05% [95% CI, 16.15%-20.12%] vs 18.50% [95% CI, 15.78%-21.56%]；差异，-0.45 [95% CI, -4.01 至 3.02] 个百分点；P = .80），在已开始新的全身治疗的 2,036 名患者中也没有显著差异（22.67% [95% CI, 20.51%-24.99%] vs 20.14% [95% CI, 17.33%-23.29%]；差异，2.53 [95% CI, -1.25 至 6.21] 个百分点；P = .19）。

结论: 在这项随机试验中，基于人工智能对影像报告的解读，向学术肿瘤学家提供针对肿瘤进展患者的基因组匹配治疗性临床试验的信息，并未增加治疗性试验的入组人数。研究结果表明，未来利用人工智能优化癌症临床试验入组应该涵盖预测治疗方案变化以外的任务，以及/或涵盖肿瘤已接受全面基因测序的人群以外的人群。

Historically, fewer than 10% of adult cancer patients have enrolled in clinical trials. Computational tools have been developed to match patients to trials, but these tools are only useful when patients need new treatment options. The aim of this trial was to assess whether informing oncologists of genomically targeted clinical trials (detected by artificial intelligence (AI)) for patients with cancer progression would affect clinical trial enrollment.

Methods: This single-center randomized trial was conducted at a tertiary academic cancer center from January 30, 2023, to June 30, 2024. Participants were patients who had solid tumors and and were in the Precision Oncology Clinical Trials Matching Database, underwent next-generation sequencing between July 2013 and December 2022, and were alive as of January 30, 2023. Patients were randomly assigned in a 2:1 ratio to an intervention or control group. In the intervention group, notification of a genomically matched clinical trial was sent to the patient’s oncologist when their cancer progressed and the likelihood of starting a new treatment increased based on artificial intelligence technology applied to the imaging report. No such notification was sent to the control group. The primary outcome was patient enrollment in any therapeutic clinical trial. Prespecified secondary outcomes included consent to participate in any therapeutic trial, consent and participation in trials among patients identified as trial-ready, the proportion of new systemic therapies initiated as part of a clinical trial, and survey responses by notified clinicians. Results Of the 20,707 patients who underwent randomization (57.26% women; median age at sequencing, 60 years [interquartile range, 50-69]), 13,802 were randomly assigned to the intervention group and 6,905 to the control group. The intervention did not significantly affect trial enrollment (2.20% [95% CI, 1.97%-2.46%] in the intervention group; 2.03% [95% CI, 1.72%-2.39%] in the control group; difference, 0.18 [95% CI, -0.25 to 0.58] percentage points; P = .41). Similarly, there was no significant difference in trial enrollment between the intervention and control groups among the 2,127 patients identified as ready to participate in the trial (18.05% [95% CI, 16.15%-20.12%] vs 18.50% [95% CI, 15.78%-21.56%]; difference, -0.45 [95% CI, -4.01 to 3.02] percentage points; P = .80) or among the 2,036 patients who started new systemic therapy (22.67% [95% CI, 20.51%-24.99%] vs 20.14% [95% CI, 17.33%-23.29%]; difference, 2.53 [95% CI, -1.25 to 6.21] percentage points; P = .19).

Conclusions: In this randomized trial, prompting academic oncologists with information about genomically matched therapeutic clinical trials for patients with progressive tumors based on artificial intelligence interpretation of imaging reports did not increase enrollment in therapeutic trials. Our findings suggest that future use of artificial intelligence to optimize enrollment in cancer clinical trials should include tasks beyond predicting changes in treatment regimens and/or include populations beyond those whose tumors have undergone comprehensive genetic sequencing.

参考文献 Reference

Mazor T et al. JAMA Network 2025 ; 8 :e252103

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奥拉帕尼用于BRCA1/BRCA2+且高危HER2阴性乳腺癌患者（新）辅助化疗后疗效的长期随访 (4/26/25)

Long-term follow-up of adjuvant olaparib after (neo)adjuvant chemotherapy in germline BRCA1/BRCA2+ & high risk HER2- breast cancer: OlympiA trial

背景：OlympiA试验 (NCT02032823) 是一项随机试验，纳入了1,836例携带BRCA1或BRCA2且患有高危HER- 阴性乳腺癌的患者，这些患者已完成所有（新）辅助化疗, 手术和放疗。第一个预设的中期分析显示，无侵袭性疾病生存期和远处无病生存期均有显著改善。第二个中期分析显示，总生存期显著改善，无论激素受体状态、既往铂类药物治疗情况。未观察到过量急性髓系白血病 (AML) 或骨髓增生异常综合征病例  (MDS)。本次更新的分析报告了第三个预设中期分析 的结果，中位随访期为 6.1 年（最长 9.6 年）。

方法：对长期随访结果进行描述性分析，比较两组的主要终点无侵袭性疾病生存期和 关键次要终点远处无病生存期和总生存期：口服12个月的奥拉帕尼 300 mg，每日两次相对于安慰剂。基于分层Cox比例风险模型估计的风险比及其95%置信区间，每个终点事件发生率均以6年中位随访期报告。安全性分析包括特别关注的不良事件和所有死亡事件。

结果：随着随访时间延长，奥拉帕尼在无侵袭性疾病生存期, 远处无病生存期和总生存期方面的获益得以维持，其效应大小与先前分析报告的效应大小相似。无侵袭性疾病生存期方面，HR=0.65（95% CI：0.53，0.78）；6年无侵袭性疾病生存期百分比（奥拉帕尼 vs 安慰剂）：79.6% vs 70.3%（差异9.4%；95% CI，5.1%，12.7%）。远处无病生存期方面，HR=0.65（95% CI：0.53，0.81）； 6年远处无病生存期百分比：83.5% vs 75.7%（差异7.8%；95% CI，3.8%，11.5%）。总生存期，HR 0.72（95% CI：0.56，0.93）；6年总生存期百分比：87.5% vs 83.2%（差异4.4%；95% CI，0.9%，6.7%）。奥拉帕尼组和安慰剂组 患者总死亡人数分别为107/921 vs 143/915。所有关键亚组，包括高危, 激素受体阳性患者， 奥拉帕尼获益均一致。奥拉帕尼组报告的BRCA相关癌症发生率低于安慰剂组：对侧浸润性乳腺癌（31 vs 40）；对侧非浸润性乳腺癌（3 vs 4）、新发原发性卵巢癌（3 vs 9）、新发原发性输卵管癌（1 vs 4）。奥拉帕尼组患者发生的不良事件的比例低于安慰剂组（6.3% vs 9.3%），包括MDS或AML（奥拉帕尼组，n=4；安慰剂组，n=6）、肺炎（奥拉帕尼组，n=9；安慰剂组，n=13），且新发原发癌数量较少（奥拉帕尼组，n=45；安慰剂组，n=68）。

 结论：在6.1年MFU（多中心生存率）时，（新）辅助化疗后进行一年的辅助奥拉帕尼治疗，对于携带BRCA1或BRCA2可能致病基因突变的高危HER2阴性原发性乳腺癌患者（包括所有关键亚组），其无侵袭性疾病生存期, 远处无病生存期和总生存期均显著改善，且毒性反应可接受，且无证据表明MDS或AML风险增加。这些数据再次强调检测BRCA1或BRCA2对于高危HER2阴性原发性乳腺癌的重要性。

患者入组试验标准; 三阴性乳腺癌患者必须为腋窝淋巴结阳性（任何肿瘤大小）或腋窝淋巴结阴性（pN0），且侵袭性原发性肿瘤病理大小 > 2 cm；ER 和/或 PgR 阳性/HER2 阴性患者必须有≥4个经病理证实的阳性淋巴结。总共有 82.2% 的患者呈三阴性。

Background: The OlympiA trial (NCT02032823) was a randomized trial that enrolled 1,836 patients with high-risk HER-negative breast cancer and pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 and they had completed all (neo)adjuvant chemotherapy, surgery, and radiotherapy. The first prespecified interim analysis showed significant improvements in invasive disease-free survival and distant disease-free survival. The second interim analysis showed significant improvements in overall survival, regardless of hormone receptor status or prior platinum therapy. No excess cases of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were observed. This updated analysis reports the results of the third prespecified interim analysis with a median follow-up of 6.1 years (maximum 9.6 years).

Methods: Descriptive analyses of long-term follow-up were performed to compare the primary endpoint of invasive disease-free survival and key secondary endpoints of distant disease-free survival and overall survival between the two groups: olaparib 300 mg orally twice daily for 12 months versus placebo. The analyses of each endpoint with rates reported at the median follow-up of 6 years were based on the hazard ratio and its 95% confidence interval estimated by the stratified Cox proportional hazards model. Safety analysis included adverse events of special interest and all deaths are highlighted.

Results: With the extension of follow-up time, the benefits of olaparib in invasive disease-free survival, distant disease-free survival, and overall survival were maintained, and the effect sizes were similar to that reported in previous analyses. In terms of invasive disease-free survival, HR=0.65 (95% CI: 0.53, 0.78); 6-year invasive disease-free survival percentage (olaparib vs placebo): 79.6% vs 70.3% (difference 9.4%; 95% CI, 5.1%, 12.7%). In terms of distant disease-free survival, HR=0.65 (95% CI: 0.53, 0.81); 6-year percentage of distant disease survival: 83.5% vs 75.7% (difference 7.8%; 95% CI, 3.8%, 11.5%). Overall survival, HR 0.72 (95% CI: 0.56, 0.93); 6-year overall survival percentage: 87.5% vs 83.2% (difference 4.4%; 95% CI, 0.9%, 6.7%). The total number of deaths in the olaparib group and the placebo group was 107/921 vs 143/915, respectively. The benefits of olaparib were consistent in all key subgroups, including high-risk, hormone receptor-positive patients. The incidence of BRCA-related cancers reported in the olaparib group was lower than that in the placebo group: contralateral invasive breast cancer (31 vs 40); contralateral non-invasive breast cancer (3 vs 4), new primary ovarian cancer (3 vs 9), and new primary fallopian tube cancer (1 vs 4). The proportion of adverse events of

special interest was lower in patients who received olaparib (6.3% vs 9.3%), including MDS or AML (olaparib group, n=4; placebo group, n=6), pneumonia (olaparib group, n=9; placebo group, n=13), and the number of new primary cancers (olaparib group, n=45; placebo group, n=68).

Conclusions: At the median follow up of 6.1 years, one year of adjuvant olaparib treatment after (neo)adjuvant chemotherapy significantly improved invasive disease-free survival, distant disease-free survival, and overall survival in patients with high-risk HER2-negative primary breast cancer carrying pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (including all key subgroups), with acceptable toxicity and no evidence of increased risk of MDS or AML. These data once again emphasize the importance of testing germline BRCA1 or BRCA2 in high-risk HER2-negative primary breast cancer patients.

Eligibility criteria: triple-negative breast cancer patients must have been axillary node-positive (any tumor size) or axillary node-negative with invasive primary tumor pathological size > 2 cm; ER and/or PR positive/HER 2 negative patients must have had ≥4 pathologically confirmed

positive lymph nodes. A total of 82.2% patients were triple-negative.

参考文献 Reference

Garber J et al. 2024 San Antonio Breast Cancer Symp Abstr GS1-09

Andrew NJ et al. New Engl J Med 2021 ;384 : 2394

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添加抗组胺药有利于转移性尿路上皮癌的免疫疗法 (4/20/2025)

Adding antihistamines benefited immunotherapy for metastatic urothelial carcinoma: IMvigor210 and IMvigor211 trials

临床前研究表明，抗组胺药可以逆转巨噬细胞免疫抑制，重新激活 T 细胞的细胞毒性，并增强免疫治疗反应。

方法: 基于 IMvigor210 试验（一项 II 期单组试验，比较二线阿替利珠单抗治疗转移性尿路上皮癌的效果）和 IMvigor211 试验（一项 III 期随机试验，比较二线阿替利珠单抗对比化疗治疗转移性尿路上皮癌的效果 ）中的个体患者数据,  在接受免疫肿瘤学 治疗的患者中，筛选出接受和未接受抗组胺药治疗的患者。使用多变量 Cox 或竞争风险回归模型预测无进展生存期, 总生存期和癌症特异性生存期。在调整潜在混杂因素后，评估抗组胺药对免疫疗效的影响。

结果: 在 896 例一线化疗后出现疾病进展的局部晚期或转移性尿路上皮癌患者中，155 例（17%）在免疫肿瘤治疗期间接受抗组胺药治疗。相对于未使用抗组胺药的人, 抗组胺药治疗延长了总生存期（风险比 [HR]：0.59；95% 置信区间 [CI]：0.47-0.74；P <0.001）, 无进展生存期（HR：0.70；95%CI：0.57-0.87；P=0.001）和癌症特异性生存期 [sHR：0.58；95%CI：0.45-0.75； P<0.001)。在排除了发生不良事件并接受抗组胺药治疗的患者后，进行敏感性分析,  结果显示相似的延长的癌症特异性生存率（sHR 0.78；95%CI：0.59-0.98，P=0.031）和总生存率（HR 0.71；95%CI：0.52-0.94，P=0.021）。

结论: 对于接受阿替利珠单抗作为转移性尿路上皮癌二线治疗的患者，同时服用抗组胺药可改善总生存率, 无进展生存率, 和癌症特异性生存率。需要进一步的临床研究来阐明抗组胺药在免疫肿瘤治疗中的作用。

Preclinical studies have shown that antihistamines can reverse macrophage immunosuppression, reactivate T cell cytotoxicity, and enhance immunotherapy responses.

Methods: Based on individual patient data from the IMvigor210 trial (a phase II single-arm trial comparing second-line atezolizumab in metastatic urothelial carcinoma) and the IMvigor211 trial (a phase III randomized trial comparing second-line atezolizumab versus chemotherapy in metastatic urothelial carcinoma), patients who did and did not receive antihistamines were selected among patients undergoing immuno-oncology therapy. Multivariable Cox or competing risk regression models were used to predict progression-free survival, overall survival, and cancer-specific survival. The effect of antihistamines on immunotherapy efficacy was assessed after adjustment for potential confounders.

Results: Among 896 patients with locally advanced or metastatic urothelial carcinoma who had disease progression after first-line chemotherapy, 155 (17%) received antihistamines during immuno-oncology therapy. Compared with those who did not use antihistamines, those who received antihistamines had prolonged overall survival (hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.47-0.74; P < 0.001), progression-free survival (HR: 0.70; 95%CI: 0.57-0.87; P = 0.001), and cancer-specific survival [sHR: 0.58; 95%CI: 0.45-0.75; P < 0.001]. Sensitivity analysis after excluding patients who experienced adverse events and received antihistamines showed similar prolonged cancer-specific survival (sHR 0.78; 95%CI: 0.59-0.98, P = 0.031) and overall survival (HR 0.71; 95%CI: 0.52-0.94, P = 0.021).

Conclusion: For patients receiving atezolizumab as second-line treatment for metastatic urothelial carcinoma, concomitant administration of antihistamines improved overall survival, progression-free survival, and cancer-specific survival. Further clinical studies are needed to clarify the role of antihistamines in immuno-oncology therapy.

参考文献 Reference

Fallara G et al. Urol Onc: Seminars Original Investigations 2025;43: 188 .e9-188.e17

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美国胰腺癌和结直肠腺癌的发病率 (4/19/2025)

Incidence of pancreas and colorectal adenocarcinoma in the US

这项队列研究发现两种腺癌的年百分比变化率最高的年龄组（15-34岁和35-54岁）。

胰腺癌是全球第七大癌症死亡原因，结直肠癌是第二大癌症死亡原因，两者的发病率均呈上升趋势，尤其是在年轻群体中。

这项回顾性队列研究使用了来自“监测, 流行病学和最终结果”数据库的数据，以考察2000年至2021年的发病率趋势。研究对象包括胰腺腺癌和结直肠腺癌患者。

结果: 2000 年至 2021 年，共确诊胰腺腺癌 275,273 例，其中男性 142,633 例（51.8%）；年龄 ≥ 55 岁 239,840 例（87.1%）。15 至 34 岁组胰腺腺癌的年度百分比变化为 4.35（95% CI，2.03 至 6.73），显著高于 55 岁及以上组的年度百分比变化 1.74（95% CI，1.59 至 1.89）（P = .007）和 35 至 54 岁组的年度百分比变化 1.54（95% CI，1.18 至 1.90）（P = .004）。

共确诊1,215,200例结直肠癌，其中男性641,776例（52.8%），年龄≥55岁976,716例（80.4%）。55岁及以上人群结直肠腺癌的年度百分比变化为 -3.31（95% CI，-3.54至-3.08），显著低于15至34岁人群的年度百分比变化 1.75（95% CI，1.08至2.42）（P = .001）和35至54岁人群的年度百分比变化 0.78（95% CI，0.51至1.06）（P = .002）。  

结论与意义：本队列研究结果提示，胰腺腺癌的发病率在所有年龄组中均呈上升趋势，而结直肠腺癌的发病率在年轻人群中呈上升趋势。

Pancreatic cancer is the seventh leading cause of cancer death worldwide, and colorectal cancer is the second leading cause of cancer death. This cohort study found the highest annual percentage change rates for both adenocarcinomas in the age groups (15-34 years and 35-54 years). The incidence of both is increasing, especially in younger groups. This retrospective cohort study used data from the Surveillance, Epidemiology, and End Results database to examine incidence trends from 2000 to 2021. The study subjects included patients with pancreatic adenocarcinoma and colorectal adenocarcinoma.

Results: From 2000 to 2021, a total of 275,273 cases of pancreatic adenocarcinoma were diagnosed, of which 142,633 (51.8%) were males; 239,840 (87.1%) were aged ≥ 55 years. The annual percentage change for pancreatic adenocarcinoma in the 15- to 34-year-old group was 4.35 (95% CI, 2.03 to 6.73), which was significantly higher than the annual percentage change of 1.74 (95% CI, 1.59 to 1.89) in the 55-year-old group or older (P = .007) and the annual percentage change of 1.54 (95% CI, 1.18 to 1.90) in the 35- to 54-year-old group (P = .004).

A total of 1,215,200 cases of colorectal cancer were diagnosed, of which 641,776 (52.8%) were males and 976,716 (80.4%) were aged ≥55 years. The annual percentage change of colorectal adenocarcinoma in people aged 55 years and older was -3.31 (95% CI, -3.54 to -3.08), which was significantly lower than the annual percentage change of 1.75 (95% CI, 1.08 to 2.42) in people aged 15 to 34 years (P = .001) and the annual percentage change of 0.78 (95% CI, 0.51 to 1.06) in people aged 35 to 54 years (P = .002).

Conclusion: The results of this cohort study suggest that the incidence of pancreatic adenocarcinoma is increasing in all age groups, while the incidence of colorectal adenocarcinoma is increasing in younger people.

参考文献 Reference

Bussetty A e al. JAMA 2025; 8: e254682

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卵巢癌衍生的IL-4促进免疫治疗抵抗,  阻断 IL-4 可能改善免疫治疗反应 (4/13/2025)

Ovarian cancer-derived IL-4 promotes immunotherapy resistance, blocking IL-4 may improve immunotherapy response

卵巢癌对免疫疗法具有耐药性，这受到以巨噬细胞为主导的免疫抑制肿瘤微环境 (TME) 的影响。耐药性也受到肿瘤内异质性的影响，而肿瘤内异质性的形成机制尚不明确。研究者采用了空间功能基因组学筛选 (Perturb-map)，重点研究推测参与肿瘤-巨噬细胞通讯的受体/配体。Perturb-map 重现了肿瘤异质性，并揭示了白细胞介素 4 (IL-4) 促进对抗 PD-1 的耐药性。卵巢癌细胞是 IL-4 的主要来源，IL-4 通过巨噬细胞控制指导免疫抑制性 TME 的形成。附近表达 IL-4 的克隆无法补偿 IL-4 的损失，揭示了 TME 组成的短程调控决定了肿瘤的演化。

研究表明，异质性肿瘤微环境 (TME) 可由癌症衍生的细胞因子/趋化因子的局部表达改变而产生，这些细胞因子/趋化因子会建立免疫富集区和免疫排斥区，从而驱动克隆选择和免疫疗法耐药性。 当IL-4受到抑制时，卵巢肿瘤对PD-1抑制剂（包括派姆单抗和纳武单抗更加敏感。通过将IL-4受体抑制剂（Dupilumab，目前用于治疗湿疹和哮喘的IL-4受体抑制剂）与PD-1免疫疗法相结合，可能是一种克服卵巢癌对免疫疗法耐药性的方法。

Ovarian cancer is resistant to immunotherapy, influenced by an immunosuppressive tumor microenvironment (TME) dominated by macrophages. Resistance is also influenced by intratumor heterogeneity, which is mediated by poorly understood mechanisms. The researchers  employed a spatial functional genomics screen (Perturb-map) focusing on receptors/ligands putatively involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin 4 (IL-4) promotes resistance to anti-PD-1. Ovarian cancer cells are a major source of IL-4, which directs the formation of an immunosuppressive TME through macrophage control. Nearby IL-4-expressing clones were unable to compensate for the loss of IL-4, revealing that short-range regulation of TME composition dictates tumor evolution. Studies have shown that a heterogeneous tumor microenvironment (TME) can be generated by altered local expression of cancer-derived cytokines/chemokines that establish immune-enriched and immune-exclusive zones, driving clonal selection and immunotherapy resistance.

Studies have also shown that targeting IL-4 can promote the development of new cytokine/chemokine-rich and immune-exclusive zones. When IL-4 is inhibited, ovarian tumors are more sensitive to PD-1 inhibitors, including pembrolizumab and nivolumab. Combining IL-4 receptor inhibitors (dupilumab, currently used to treat eczema and asthma) with PD-1 immunotherapy may be a way to overcome ovarian cancer resistance to immunotherapy.

参考文献 Reference

Mollaoğlu G et al. Cell 2024 ; 187 :7492

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大剂量静脉注射维生素C可能增加胰腺癌患者生存期 (4/12/2025)

High-dose intravenous vitamin C may increase pancreatic cancer survival

静脉注射维生素 C 与口服相比可显著提高吸收率。 最近的 I 期试验表明，静脉注射维生素 C 可以安全地与吉西他滨同时使用。

方法: 一项临床试验评估了静脉注射维生素 C 在 36 名 IV 期胰腺癌患者队列中的生存获益。 研究人员将参与者随机分配至标准治疗组，单用吉西他滨和白蛋白结合型紫杉醇，或联合静脉注射维生素C，剂量为每周三次，每次75克。 在34例接受治疗的患者中，16例（中位年龄65岁；年龄范围：56-72岁；50%为女性；93.8%为白人）接受了维生素C治疗，18例（中位年龄58.5岁；年龄范围：54.5-69岁；33.3%为女性；94.4%为白人）接受了单纯化疗。总生存期为主要终点, 无进展生存期和安全性为次要终点。

结果: 添加维生素C可延长无进展生存期（中位数：6.2个月 vs. 3.9个月；HR = 0.43；90% CI，0.2-0.92）和总生存期 (OS)（中位数：16个月 vs. 8.3个月；HR = 0.46；90% CI，0.23-0.92）。

受试者的不良事件与吉西他滨和白蛋白结合型紫杉醇治疗常见。维生素C组的严重不良事件发生率较低（1.2% vs. 1.7%）, 3级或4级血液学事件发生率也较低（1.1% vs. 1.6%）。 研究人员对生活质量进行了探索性分析。服用维生素 C 的人群中，失眠（6.2 个月 vs. 3.8 个月；P = .047）, 和便秘（6.2 个月 vs. 3.8 个月；P = .032）。

研究人员认为这项研究存在局限性，包括样本量小和研究对象缺乏多样性。

Intravenous vitamin C significantly improves absorption compared with oral administration. A recent phase I trial showed that intravenous vitamin C can be safely used with gemcitabine. Methods: A clinical trial evaluated the benefit of intravenous vitamin C in a cohort of 36 patients with stage IV pancreatic cancer. The researchers randomly assigned participants to standard treatment of gemcitabine and nab-paclitaxel alone, or in combination with intravenous vitamin C at a dose of 75 grams three times a week. Of the 34 treated patients, 16 (median age, 65 years; age range, 56-72 years; 50% women; 93.8% white) received vitamin C and 18 (median age, 58.5 years; age range, 54.5-69 years; 33.3% women; 94.4% white) received chemotherapy alone. Overall survival was the primary endpoint, and progression-free survival and safety were secondary endpoints.

Results: Adding vitamin C prolonged progression-free survival (median: 6.2 months vs. 3.9 months; HR = 0.43; 90% CI, 0.2-0.92) and overall survival (OS) (median: 16 months vs. 8.3 months; HR = 0.46; 90% CI, 0.23-0.92). Adverse events were common with gemcitabine and nab-paclitaxel. Serious adverse events were less frequent in the vitamin C group (1.2% vs. 1.7%), as were grade 3 or 4 hematologic events (1.1% vs. 1.6%). The researchers conducted an exploratory analysis of quality of life. Insomnia (6.2 months vs. 3.8 months; P = .047), and constipation (6.2 months vs. 3.8 months; P = .032) were less frequent in the vitamin C group.

The researchers noted limitations of the study, including the small sample size and lack of diversity in the subjects studied.

参考文献 Reference

Bodeker KL et al. Recox Biol doi:10.1016/j.redox.2024.103375

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转移性结直肠癌的新型耦合 CAR T 疗法 GCC19CART 的 1 期研究 (4/6/2025)

A phase 1 study of CAR T cell therapy, GCC19CART, for metastatic colorectal cancer

GCC19CART 是一种多靶点 CAR-T 细胞疗法，旨在通过将靶向 CAR 的实体瘤与额外的靶向 CD19 的 CAR 配对来克服传统 CAR-T 细胞在实体恶性肿瘤中的局限性。这种添加旨在增强 CAR-T 细胞的增殖, 活化和持久性，以克服实体瘤对 CAR-T 细胞的固有抗性。鸟苷酸环化酶-C (GCC) 在 80% 以上的结直肠癌中表达，正常表达主要局限于胃肠道的腔侧。

方法： 美国 1 期研究(NCT05319314)于 2022 年 8 月启动，针对难治性转移性结直肠癌患者。截至 2023 年 12 月 31 日的数据截止日，在对第一位接受剂量水平 2 治疗的患者进行剂量限制毒性的预定分析后，已有 5 名受试者重新输注：剂量水平 1 中有 4 名，剂量水平 2 中有 1 名。受试者接受了 GCC 表达筛查。超过 95% 的参与者筛查结果为阳性，因此取消了这项要求。符合条件的受试者接受了白细胞分离术、单剂量氟达拉滨 30mg/m² 和环磷酰胺 300mg/m² 的淋巴细胞清除化疗以及 GCC19CART 输注。  

结果： 五名受试者接受了治疗，其中 4 名接受剂量水平 1（1×10⁶ 个细胞/公斤），1 名接受剂量水平 2（2×10⁶ 个细胞/公斤），并已完成 30 天的剂量限制毒性期。最常见的 CAR-T 相关不良事件是 5/5 受试者的细胞因子释放综合征（1 级：2/5 (40%) 和 2 级：3/5 (60%), 4/5 受试者的腹泻（1 级：1/5 (20%), 2 级：2/5 (40%) 和 3 级：1/5 (20%)）和 免疫效应细胞相关神经毒性综合征（2 级：1/5 (20%)）。所有不良事件均通过治疗得到解决。独立审查的客观响应率为 40% (2/5)：2 名受试者表现出部分响应，另外 1 名受试者在 PET/CT 上表现出部分代谢反应且病情稳定。2 名参与者的病情进展。  

结论： GCC19CART 在难治性转移性结直肠癌中具有可接受的安全性和有意义的临床活性。这项试验正在进行中，并将提供最新数据，包括接受剂量水平 2（2×10⁶ CAR-T 细胞/kg）治疗的患者的数据。

Background: GCC19CART is a multi-targeted CAR-T cell therapy designed to overcome the limitations of traditional CAR-T cells in solid tumors by pairing a solid tumor targeting CAR with an additional CD19-targeting CAR. This addition is designed to enhance the proliferation, activation and persistence of CAR-T cells to overcome the intrinsic resistance of solid tumors to CAR-T cells. Guanylate cyclase-C (GCC) is expressed in more than 80% of colorectal cancers, and normal expression is primarily confined to the luminal side of the gastrointestinal tract. Methods: The US phase 1 study (NCT05319314) was initiated in August 2022 in patients with refractory metastatic colorectal cancer. As of the data cutoff date of December 31, 2023, after the pre-specified analysis of dose-limiting toxicity in the first patient treated with dose level 2, 5 subjects have been re-infused: 4 in dose level 1 and 1 in dose level 2. Subjects were screened for GCC expression. More than 95% of participants screened positive, so this requirement was removed. Eligible subjects received leukapheresis, lymphodepleting chemotherapy with a single dose of fludarabine 30mg/m² and cyclophosphamide 300mg/m², and GCC19CART infusion. Results: Five subjects were treated, 4 at dose level 1 (1×10⁶ cells/kg) and 1 at dose level 2 (2×10⁶ cells/kg), and completed the 30-day dose-limiting toxicity period. The most common CAR-T-related adverse events were cytokine release syndrome in 5/5 subjects (grade 1: 2/5 (40%) and grade 2: 3/5 (60%), diarrhea in 4/5 subjects (grade 1: 1/5 (20%), grade 2: 2/5 (40%) and grade 3: 1/5 (20%)), and immune effector cell-related neurotoxicity syndrome (grade 2: 1/5 (20%)). All adverse events resolved with treatment. The objective response rate by independent review was 40% (2/5): 2 subjects showed partial response and another subject showed partial metabolic response on PET/CT with stable disease. 2 participants had progressive disease.

Conclusion: GCC19CART has an acceptable safety profile and meaningful clinical activity in refractory metastatic colorectal cancer. This trial is ongoing and will provide updated data, including data from patients treated at dose level 2 (2×10⁶ CAR-T cells/kg).

参考文献 Reference

Keenan BP et al. J Clin Oncol. 2025;43 (suppl 4):175

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帕博利珠单抗联合化疗加上奥拉帕尼维持一线治疗晚期 BRCA 非突变性卵巢癌 (4/5/2025)

Pembrolizumab plus chemotherapy followed by olaparib maintenance therapy as first-line treatment for advanced BRCA-nonmutated ovarian cancer: ENGOT-OV43/GOG-3036/KEYLYNK-001

这是一项III期临床试验（KEYLYNK-001），招募1.367名患者参加, 她们为新诊断的 III 期或 IV 期上皮性卵巢癌, 原发性腹膜癌或输卵管癌且未发生 BRCA 突变的患者。患者被随机分配到以下三个组之一： 1) 派姆单抗/奥拉帕尼组：化疗（紫杉醇/卡铂）加派姆单抗，随后进行派姆单抗加奥拉帕尼维持治疗 (n = 455); 2) 派姆单抗：化疗（紫杉醇/卡铂）加派姆单抗，随后进行派姆单抗维持治疗 (n = 458); 3)  对照组：仅化疗无维持治疗（n = 454）。 帕博利珠单抗每 3 周给药一次，每次 200 毫克，共 35 个周期，化疗（卡铂/紫杉醇）共 6 个周期，维持治疗奥拉帕尼每天两次，每次 300 毫克，共 2 年。贝伐单抗可在化疗和维持治疗期间开具。主要终点是无进展生存期，总生存期是次要终点。

中位随访时间为 30.1 个月，该研究达到了其主要结果，即无论 PD-L1 状态如何，使用派姆单抗和奥拉帕尼均能改善无进展生存期。派姆单抗/奥拉帕尼组的中位无进展生存期为 22.1 个月，而单纯化疗组的中位无进展生存期为 14.6 个月（风险比 [HR] = 0.68；P < .0001）。3 年后，分别有 30.9% 和 19.7% 的患者无进展。

This is a phase III clinical trial (KEYLYNK-001) that enrolled 1,367 patients with newly diagnosed stage III or IV BRCA-nonmutated epithelial ovarian, primary peritoneal, or fallopian tube cancer . Patients were randomly assigned to one of three groups: 1) pembrolizumab/olaparib group: chemotherapy (paclitaxel/carboplatin) plus pembrolizumab, followed by pembrolizumab plus olaparib maintenance therapy (n = 455); 2) pembrolizumab: chemotherapy (paclitaxel/carboplatin) plus pembrolizumab, followed by pembrolizumab maintenance therapy (n = 458); 3) control group: chemotherapy alone without maintenance therapy (n = 454). Pembrolizumab was given at a dose of 200 mg every 3 weeks for 35 cycles, chemotherapy (carboplatin/paclitaxel) for 6 cycles, and maintenance therapy with olaparib at a dose of 300 mg twice daily for 2 years. Bevacizumab could be prescribed during chemotherapy and maintenance therapy. The primary endpoint was progression-free survival, and overall survival was a secondary endpoint.

With a median follow-up of 30.1 months, the study met its primary outcome of improved progression-free survival with pembrolizumab and olaparib, regardless of PD-L1 status. The median progression-free survival was 22.1 months in the pembrolizumab/olaparib group and 14.6 months in the chemotherapy-only group (hazard ratio [HR] = 0.68; P < .0001). After 3 years, 30.9% and 19.7% of patients, respectively, were progression-free.

参考文献 Reference

Powell L et al. 2025 SGO Ann Meeting on Women Cancer abstr LBA7

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低水平砷暴露与肾癌风险之间的关系 (3/30/2025)

Low-level arsenic exposure in drinking water and kidney cancer risk

美国和世界各地的肾癌发病率都在上升。砷是一种已知的人类致癌物，被怀疑是导致这种发病率上升的一个因素，尤其是在地下水砷含量丰富的地区。一些先前的流行病学研究表明，砷暴露与肾癌之间存在正相关关系。然而，这些研究中的大多数都是基于暴露于 100 ppb 高砷水平的人群，因此，关于 10 ppb 以下低浓度砷暴露对肾癌风险的影响的证据有限。因此，本研究旨在调查饮用水中低浓度砷暴露与患肾癌风险之间的关系，

结果: 本研究调查了饮用水中低水平砷暴露与德克萨斯州患肾癌风险之间的关系。结果表明，与砷水平低（<1 ppb）的县相比，砷水平中等（1-5 ppb）和高（>5 ppb）的县患肾癌的风险显著增加，分别为 6% （RR 1.06，95% CI 1.01，1.11）和 22%（RR 1.22，95% CI 1.12，1.34），在调整空间因素和协变量后，呈现出剂量反应关系。饮用水每增加一倍，癌症风险就会增加 4%（RR 1.04，95% CI 1.02，1.07）。

本研究表明，接触低浓度饮用水砷可能与肾癌风险增加有关。

Kidney cancer rates are increasing in the United States and around the world. Arsenic, a known human carcinogen, is suspected to be a contributing factor to this increasing incidence, especially in areas where groundwater is rich in arsenic. Some previous epidemiological studies have shown a positive association between arsenic exposure and kidney cancer. However, most of these studies were based on populations exposed to high arsenic levels of 100 ppb, so there is limited evidence on the effect of low-level arsenic exposure below 10 ppb on kidney cancer risk. Therefore, this study aimed to investigate the association between low-level arsenic exposure in drinking water and the risk of kidney cancer,

Results: This study investigated the association between low-level arsenic exposure in drinking water and the risk of kidney cancer in Texas. Results showed that compared with counties with low arsenic levels (<1 ppb), counties with moderate (1-5 ppb) and high (>5 ppb) arsenic levels had significantly increased risks of kidney cancer, 6% (RR 1.06, 95% CI 1.01, 1.11) and 22% (RR 1.22, 95% CI 1.12, 1.34), respectively, showing a dose-response relationship after adjusting for spatial factors and covariates. For every doubling of drinking water, the risk of cancer increased by 4% (RR 1.04, 95% CI 1.02, 1.07). This study suggests that exposure to low concentrations of drinking water arsenic may be associated with an increased risk of kidney cancer.

参考文献 Reference

Hasan NT et al. Environmental Pollution 2024:363: part 1

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阿替利珠单抗联合卡铂和紫杉醇治疗晚期胸腺癌 (3/29/2025)

Atezolizumab plus carboplatin and paclitaxel in advanced thymic carcinoma: MARBLE trial

方法: 在日本 15 家医院进行的这项多中心, 单组,  II 期试验中，转移性或复发性胸腺癌患者接受了阿替利珠单抗联合卡铂和紫杉醇治疗。符合条件的患者经组织学证实为 Masaoka III 期,  IVA 或 IVB 期胸腺癌，不适合进行确定性治疗或确定性治疗后复发性胸腺癌；并且既往无胸腺癌全身药物治疗。患者每 3 周静脉注射 1200 mg 阿替利珠单抗, 卡铂曲线下面积 6 mg/mL/min 和紫杉醇 200 mg/m²，最多 6 个周期，然后每 3 周静脉注射 1200 mg 阿替利珠单抗，最多 2 年，直至病情进展或出现不可接受的毒性。主要终点是客观响应率。该试验在日本临床试验注册中心注册(jRCT2031220144)，目前已停止接受报名。

结果: 2022 年 6 月 14 日至 2023 年 7 月 6 日期间，共招募了 48 名患者，并纳入疗效和安全性分析。中位随访时间为 15.3 个月（IQR 13.8–16.6）。48 名患者中有 29 名（60%）为男性，19 名（40%）为女性。患者中位年龄为 67.5 岁（IQR 56.5–72.5）。所有患者均为亚洲人。客观响应率为 56%（95% CI 41–71；Fisher 精确检验 p<0.0001）；48 名参与者中有 27 名（56%）有部分响应。最常见的 3 级或更严重的不良反应是中性粒细胞减少症（48 名患者中有 27 名 [56%]）、白细胞减少症（16 名 [33%]）、发热性中性粒细胞减少症（11 名 [23%]）和斑丘疹（6 名 [13%]）。没有与治疗相关的死亡病例，总共有 8 例死亡。

解释: 在先前未接受治疗的晚期胸腺癌中，将阿替利珠单抗添加到卡铂和紫杉醇中可产生具有临床意义的抗肿瘤活性，且安全性可控。阿替利珠单抗加卡铂和紫杉醇可能成为先前未接受治疗的晚期或复发性胸腺癌的可行治疗选择。

Methods: In this multicenter, single-arm, phase II trial conducted at 15 hospitals in Japan, patients with metastatic or recurrent thymic carcinoma received atezolizumab in combination with carboplatin and paclitaxel. Eligible patients had histologically confirmed Masaoka stage III, IVA, or IVB thymic carcinoma who were not suitable for definitive therapy or had recurrent thymic carcinoma after definitive therapy; and had no prior systemic therapy for thymic carcinoma. Patients received 1200 mg of atezolizumab intravenously every 3 weeks, carboplatin AUC of 6 mg/mL/min, and paclitaxel 200 mg/m² for up to 6 cycles, followed by 1200 mg of atezolizumab intravenously every 3 weeks for up to 2 years until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. This trial is registered with the Japan Clinical Trial Registry (jRCT2031220144) and is currently closed for enrollment.

Results: Between June 14, 2022, and July 6, 2023, a total of 48 patients were enrolled and included in the efficacy and safety analyses. The median follow-up was 15.3 months (IQR 13.8–16.6). Twenty-nine (60%) of the 48 patients were male and 19 (40%) were female. The median patient age was 67.5 years (IQR) 56.5–72.5). All patients were Asian. The objective response rate was 56% (95% CI 41–71; Fisher’s exact test p<0.0001); 27 of the 48 participants (56%) had a partial response. The most common grade 3 or higher adverse events were neutropenia (27 of 48 patients [56%]), leukopenia (16 [33%]), febrile neutropenia (11 [23%]), and maculopapular rash (6 [13%]). There were no treatment-related deaths, and there were 8 deaths overall.

Interpretation: In previously untreated advanced thymic carcinoma, the addition of atezolizumab to carboplatin and paclitaxel resulted in clinically meaningful antitumor activity with a manageable safety profile. Atezolizumab plus carboplatin and paclitaxel may be a viable treatment option for previously untreated advanced or recurrent thymic carcinoma. 

参考文献 Reference

Shukuya T et al. Lancet Onc 2025 ; 26 :331

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单周期新辅助帕博利珠单抗治疗 MMR 缺陷结肠癌患 (3/23/2025)

Single-cycle neoadjuvant pembrolizumab in patients with stage MMR-deficient colon cancer

方法： RESET-C (NCT05662527) 是一项由研究者发起的 II 期单组多中心试验，旨在研究单周期新辅助帕博利珠单抗对 85 名可切除 I-III 期 dMMR 结肠癌患者的疗效和安全性。入组后，患者接受一周期帕博利珠单抗 4mg/kg（最大 400mg）治疗，并在三至五周内接受手术。手术前进行了肿瘤响应评估，包括血液样本, 胸部和腹部的CT扫描以及结肠镜检查。主要终点是病理完全响应率。次要终点包括手术并发症, 派姆单抗的安全性, 主要病理反应  (肿瘤消退 1 级或 2 级) 和无病生存期。

结果： 2023 年 2 月至 2024 年 3 月期间，共纳入 85 名患者。中位年龄为 74 岁 (IQR，68-79)，72% 为女性，60% 患有临床 III 期疾病。所有患者均接受了派姆单抗治疗，84 名患者接受了手术。一名患有 I 期疾病的患者决定不接受手术。病理完全响应率为 44% (37/84; 95% CI, 33-55)，主要病理响应率为 57% (48/84; 95% CI, 46-68)。I-II 期 (20/33) 患者的病理完全响应率显著高于 III 期 (17/51) 患者 (61% vs 33%; p=0.02)。31 名患者共出现 41 次手术并发症 (37%; 95% CI, 27-48)。其中 8 次并发症为 Clavien-Dindo 3a 级或以上，包括 3 名患者出现吻合口漏，2 名患者在 30 天内死亡。死亡患者年龄分别为 80 岁和 81 岁 (均未归因于免疫疗法)。 85 名患者中有 7 名（8%；95% CI，3-16）出现 3 级不良事件，其中 3 例与治疗相关。未记录 4 级或 5 级不良事件。

结论： 单周期新辅助 pembrolizumab 对 dMMR 结肠癌患者有效且安全。对于大多数临床 I-II 期疾病患者，单周期治疗足以实现病理完全响应。

Methods: RESET-C (NCT05662527) is an investigator-initiated, phase II, single-arm, multicenter trial designed to investigate the efficacy and safety of a single cycle of neoadjuvant pembrolizumab in 85 patients with resectable stage I-III dMMR colon cancer. After enrollment, patients received one cycle of pembrolizumab 4 mg/kg (maximum 400 mg) and underwent surgery within three to five weeks. Tumor response assessments were performed before surgery, including blood samples, CT scans of the chest and abdomen, and colonoscopy. The primary endpoint was pathological complete response rate. Secondary endpoints included surgical complications, safety of pembrolizumab, major pathological response (tumor regression grade 1 or 2), and disease-free survival.

Results: A total of 85 patients were enrolled between February 2023 and March 2024. The median age was 74 years (IQR, 68-79), 72% were female, and 60% had clinical stage III disease. All patients received pembrolizumab, and 84 patients underwent surgery. One patient with stage I disease decided not to undergo surgery. The pathological complete response rate was 44% (37/84; 95% CI, 33-55), and the major pathological response rate was 57% (48/84; 95% CI, 46-68). The pathological complete response rate was significantly higher in patients with stage I-II (20/33) than in those with stage III (17/51) (61% vs 33%; p=0.02). A total of 41 surgical complications occurred in 31 patients (37%; 95% CI, 27-48). Eight complications were Clavien-Dindo grade 3a or higher, including anastomotic leaks in three patients, and two patients died within 30 days. The patients who died were 80 and 81 years old (neither attributable to immunotherapy). Seven of 85 patients (8%; 95% CI, 3-16) had grade 3 adverse events, three of which were treatment-related. No grade 4 or 5 adverse events were recorded.

Conclusions: A single cycle of neoadjuvant pembrolizumab is effective and safe in patients with dMMR colon cancer. A single cycle of treatment is sufficient to achieve a pathological complete response in most patients with clinical stage I-II disease.

参考文献 Reference

Qvortrup C et al. 2025 ASCO GI Cancers Symp. Abstr 19

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CD47 髓系检查点抑制剂 evorpacept 用于HER2 过度表达的胃癌/胃食管癌患者的的 II/III 期研究 (3/21/2025)

A CD47 myeloid checkpoint inhibitor evorpacept used in patients with HER2-overexpressing gastric/gastroesophageal cancer

在 ASPEN-06 研究的 II 期部分，共有 127 名 HER2 阳性胃癌和胃食管交界处癌患者被随机分配接受 evorpacept 加曲妥珠单抗, ramucirumab和紫杉醇 (TRP) 联合使用或单独接受 TRP 治疗。所有参与者在接受至少一次抗 HER2 治疗时都经历了疾病进展，其中约 60% 接受了二线治疗。 Evorpacept 加 TRP组的客观响应率为41.3% 相对于TRP组的 26.6% 。Evorpacept 加 TRP 的中位响应持续时间更长: 15.7 个月 相对于 9.1 个月。无进展生存期中位数相似，但 evorpacept 加 TRP 显示出有利的风险比 (HR) 0.77，表明在中位时间点之后可能具有无进展生存期益处。 值得注意的是，亚组分析显示，在约 40% 的参与者中进行的新鲜活检中保留 HER2 阳性的患者从 evorpacept 中获得了特别的益处。在这一亚组中，evorpacept 加 TRP 的客观响应率达到 59%，而单独使用 TRP 的客观响应率仅为 23%。 当将新鲜活检 HER2 状态数据与基于循环肿瘤 DNA (ctDNA) 的 HER2 扩增（在约 65% 的患者中检测到）相结合时，也出现了类似的丰富情况，evorpacept 加 TRP 组的响应率高达 49%（HR = 0.62–0.64）。  

两组之间的毒性特征通常相当。Evorpacept 加 TRP 组的中性粒细胞减少症和贫血率略高，但差异仍低于 10%，发热性中性粒细胞减少症的发生率没有增加。每组均报告了一例与治疗相关的死亡。

这些发现显示了 evorpacept 增强曲妥珠单抗治疗 HER2 阳性胃/胃食管交界处肿瘤患者的潜力，尤其是那些通过新鲜活检或 ctDNA 分析确认 HER2 表达强劲的患者。第二阶段数据显示了 evorpacept 的可接受安全性。

In the phase II portion of the ASPEN-06 study, a total of 127 patients with HER2-positive gastric and gastroesophageal junction cancer were randomized to receive either evorpacept plus a combination of trastuzumab, ramucirumab, and paclitaxel (TRP) or TRP alone. All participants had experienced disease progression on at least one anti-HER2 therapy, and approximately 60% received second-line therapy. The objective response rate was 41.3% in the evorpacept plus TRP group versus 26.6% in the TRP group. The median duration of response was longer with evorpacept plus TRP: 15.7 months versus 9.1 months. Median progression-free survival was similar, but evorpacept plus TRP showed a favorable hazard ratio (HR) of 0.77, suggesting a possible progression-free survival benefit after the median time point. Notably, subgroup analyses showed that patients with retained HER2 positivity on fresh biopsy, which occurred in approximately 40% of participants, derived particular benefit from evorpacept. In this subgroup, objective response rates were achieved with evorpacept plus TRP in 59% compared with 23% with TRP alone. A similar enrichment was seen when fresh biopsy HER2 status data were combined with circulating tumor DNA (ctDNA)-based HER2 amplification, which was detected in approximately 65% ​​of patients, with a response rate of 49% in the evorpacept plus TRP group (HR = 0.62–0.64).

The toxicity profile was generally comparable between the two groups. Neutropenia and anemia rates were slightly higher in the evorpacept plus TRP group, but the differences were still less than 10%, and there was no increase in the incidence of febrile neutropenia. One treatment-related death was reported in each group.

These findings demonstrate the potential of evorpacept to augment trastuzumab in patients with HER2-positive gastric/GEJ tumors, particularly those with strong HER2 expression confirmed by fresh biopsy or ctDNA analysis. The phase 2 data demonstrate the acceptable safety profile of evorpacept.

参考文献 Reference

Shitara K et al. 2025 ASCO GI Cancers Symp Abstract 332

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帕博利珠单抗联合放化疗，随后使用帕博利珠单抗一线治疗局部晚期宫颈癌 (3/16/2025)

Pembrolizumab owith chemoradiotherapy followed by pembrolizumab for newly diagnosed locally advanced cervical cancer: KEYNOTE-A18

方法: 在这项随机, 双盲, 安慰剂对照的 III 期临床试验中(ENGOT-cx11/GOG-3047/KEYNOTE-A18, NCT04221945)，来自 30 个国家/地区的 176 家医疗中心的新诊断, 高风险, 局部晚期宫颈癌的成年人,  通过集成网络响应的交互式语音应答系统随机分配（1:1），每 3 周接受 5 个周期的派姆单抗（200 毫克）或安慰剂加放化疗，然后每 6 周接受 15 个周期的派姆单抗（400 毫克）或安慰剂。随机化根据计划外束放射治疗类型, 筛查时的宫颈癌分期（国际妇产科联盟 2014 年 IB2-IIB 期淋巴结阳性 vs III-IVA 期）和计划总放射治疗。主要终点是无进展生存期, 由研究者确定或通过组织病理学确认疑似疾病进展和总生存期。主要分析在意向治疗人群中进行，其中包括所有随机分配的参与者。安全性在按治疗人群中进行评估，其中包括所有随机分配并接受至少一剂研究治疗的患者。

结果: 2020 年 6 月 9 日至 2022 年 12 月 15 日期间，1,060 名参与者被随机分配接受治疗，其中 529 名被分配到派姆单抗-放化疗组，531 名被分配到安慰剂-放化疗组。在数据截止时（2023 年 1 月 9 日），两个治疗组的中位随访时间为 17.9 个月（IQR 11.3–22.3）。两组的中位无进展生存期均未达到；派姆单抗-放化疗组 24 个月的生存率为 68%，而安慰剂-放化疗组为 57%。疾病进展或死亡的风险比 (HR) 为 0.70（95% CI 0.55–0.89，p =0.0020），符合方案规定的主要目标。24 个月时，派姆单抗-放化疗组的总生存率为 87%，安慰剂-放化疗组的总生存率为 81%。死亡的风险比为 0.73（0.49–1.07）；这些数据尚未超过统计学意义的界限。派姆单抗-放化疗组 3 级或更高不良事件发生率为 75%，安慰剂-放化疗组为 69%。

解释: 派姆单抗联合放化疗显著改善了新诊断, 高风险, 局部晚期宫颈癌患者的无进展生存期。

Methods: In this randomized, double-blind  phase III trial (ENGOT-cx11/GOG-3047/KEYNOTE-A18, NCT04221945)., adults with newly diagnosed, high-risk, locally advanced cervical cancer from 176 medical centers in 30 countries were randomly assigned (1:1) by an interactive voice response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomization was based on planned external-beam radiation therapy type, cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node-positive vs stage III-IVA), and planned total radiation therapy. The primary endpoints were progression-free survival, investigator-determined or suspected disease progression confirmed by histopathology, and overall survival. The primary analysis was performed in the intention-to-treat population, which included all randomly assigned participants. Safety was assessed in the as-treated population, which included all patients who were randomly assigned and received at least one dose of study treatment.

Results: Between June 9, 2020, and Dec 15, 2022, 1,060 participants were randomly assigned to treatment, with 529 assigned to pembrolizumab-chemoradiotherapy and 531 to placebo-chemoradiotherapy. At data cutoff (January 9, 2023), the median follow-up was 17.9 months (IQR 11.3–22.3) in both treatment groups. Median progression-free survival was not reached in either group; the 24-month survival rate was 68% in the pembrolizumab-chemoradiotherapy group and 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0.70 (95% CI 0.55–0.89, p = 0.0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group. The hazard ratio for death was 0.73 (0.49–1.07); these data did not cross the statistical significance limit. Grade 3 or higher adverse events occurred in 75% of the pembrolizumab-chemoradiotherapy group and 69% of the placebo-chemoradiotherapy group.

Interpretation: The addition of pembrolizumab to chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer.

参考文献 Reference

Lorruso D. et al. Lancet 2024 ; 403 :1341

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Talazoparib + 恩杂鲁胺一线治疗转移性去势抵抗性前列腺癌改善生存率 (3/15/2025)

Talazoparib  + enzalutamide as first-line treatment in metastatic castration-resistant prostate cancer (mCRPC) improved survival : TALAPRO-2 trial

III期 TALAPRO-2 试验达到了其主要终点:在未选定同源重组修复 (HRR) 基因变异的 mCRPC 患者中 (所有患者；队列 1)，Talazoparib + 恩杂鲁胺 (enzalutamide) 与安慰剂 + 恩杂鲁胺作为一线治疗相比，放射学无进展生存率有所改善。我们在此报告队列 1 中的最终 OS 数据、rPFS 的描述性更新和延长安全性随访。

方法： 在队列 1 中，患者按 1:1 随机分配至恩杂鲁胺 160 mg + Talazoparib 0.5 mg（如果肾功能中度受损则为 0.35 mg）或安慰剂，每日一次，并根据先前的阿比特龙或多西他赛（是/否）对去势敏感前列腺癌和 HRR 基因变异状态进行分层。关键资格标准包括无症状或轻度症状的转移性去势抵抗性前列腺癌, ECOG PS ≤1, 正在进行雄激素剥夺治疗以及没有接受过延长去势抵抗性前列腺癌寿命的治疗。主要终点是通过盲法独立中央审查确定的放射学无进展生存率。总生存率是受 alpha 保护的关键次要终点。

结果： 总体而言，805 名患者被随机分配，其中 402 名接受 Talazoparib +恩杂鲁胺治疗，403 名接受 安慰剂 +恩杂鲁胺治疗。在数据截止时（2024 年 9 月 3 日），Talazoparib + 恩杂鲁胺组有 211 名患者（52%）死亡，安慰剂 + 恩杂鲁胺组有 243 名患者（60%）死亡；中位随访期分别为 52.5 个月和 53.0 个月。Talazoparib + 恩杂鲁胺与 安慰剂 + 恩杂鲁胺相比的总生存率风险比 (HR) 为 0.796（95% CI，0.661–0.958；双侧 P=0.0155）；中位总生存期 (95% CI) 分别为 45.8 个月 (39.4–50.8) vs 37.0 个月 (34.1–40.4) 。在预先指定的亚组分析中，在 HRR 缺陷 (n=169; HR, 0.549; 95% CI, 0.364–0.826; P =0.0035) 或 HRR 非缺陷/未知 (n =636; HR, 0.878; 95% CI, 0.713–1.080; P=0.218) 的患者中，Talazoparib + 恩杂鲁胺比安慰剂 + ENZA 的总生存期更佳。在对具有循环肿瘤 DNA 和肿瘤组织结果的患者进行的探索性分析中，在无 BRCA1/2 变异的患者（n =439；HR，0.749；95% CI，0.582–0.963；P=0.024）和无 HRR 变异的患者（n =314；HR，0.782；95% CI，0.582–1.050；P=0.101）中，Talazoparib + 恩杂鲁胺优于 安慰剂 + ENZA。与主要分析一致，更新的放射学无进展生存率数据有利于 Talazoparib + 恩杂鲁胺优于安慰剂 + 恩杂鲁胺（HR，0.667；95% CI，0.551–0.807；P<0.0001）；中位放射学无进展生存率分别为 33.1 个月和 19.5 个月。与主要结果一致，Talazoparib + 恩杂鲁胺最常见的 ≥3 级治疗相关不良反应是贫血 (49%) 和中性粒细胞减少症 (19%)。治疗相关不良反应通常可控；86 名患者 (22%) 因治疗相关不良反应而停止使用 Talazoparib。  

结论： Talazoparib + 恩杂鲁胺作为一线治疗，在未选择 HRR 基因变异的转移性去势抵抗性前列腺癌患者中，与标准护理恩杂鲁胺相比，在总生存率方面表现出统计学上显著且具有临床意义的改善。放射学无进展生存率继续有利于 Talazoparib + 恩杂鲁胺。在长期随访中未发现新的安全信号。   

The phase III TALAPRO-2 trial met its primary endpoint: Talazoparib plus enzalutamide improved radiographic progression-free survival compared with placebo plus enzalutamide as first-line therapy in patients with mCRPC and unselected homologous recombination repair (HRR) gene alterations (all patients; cohort 1. This report described reported the final overall survival (OS) data, a descriptive update on radiographic progression-free survival (rPF)S, and extended safety follow-up in cohort 1.

Methods: In cohort 1, patients were randomized 1:1 to enzalutamide 160 mg + talazoparib 0.5 mg (0.35 mg if renal function was moderately impaired) or placebo once daily and were stratified by prior abiraterone or docetaxel (yes/no) for castration-sensitive prostate cancer and HRR gene alteration status. Key eligibility criteria included asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer, ECOG PS ≤1, ongoing androgen deprivation therapy, and no prior treatment to prolong life for castration-resistant prostate cancer. The primary endpoint was rPFS as determined by blinded independent central review. Overall survival was an alpha-protected key secondary endpoint.

Results: Overall, 805 patients were randomized, with 402 receiving talazoparib + enzalutamide and 403 receiving placebo + enzalutamide. At data cutoff (September 3, 2024), 211 patients (52%) in the talazoparib + enzalutamide group and 243 patients (60%) in the placebo + enzalutamide group had died; median follow-up was 52.5 months and 53.0 months, respectively. The hazard ratio (HR) for overall survival with talazoparib + enzalutamide versus placebo + enzalutamide was 0.796 (95% CI, 0.661–0.958; two-sided P = .0155); the median overall survival (95% CI) was 45.8 months (39.4–50.8) vs 37.0 months (34.1–40.4), respectively. In prespecified subgroup analyses, talazoparib plus enzalutamide resulted in better overall survival than placebo plus ENZA in patients with HRR deficiency ( n=169; HR, 0.549; 95% CI, 0.364–0.826; P =0.0035) or HRR nondeficient/unknown (n =636; HR, 0.878; 95% CI, 0.713–1.080; P=0.218). In an exploratory analysis of patients with both circulating tumor DNA and tumor tissue results, talazoparib plus enzalutamide was superior to placebo plus ENZA in patients without BRCA1/2 alterations (n ​​= 439; HR, 0.749; 95% CI, 0.582–0.963; P = .024) and those without HRR alterations (n ​​= 314; HR, 0.782; 95% CI, 0.582–1.050; P = .101). Consistent with the primary analysis, updated rPFS data favored talazoparib plus enzalutamide over placebo plus enzalutamide (HR, 0.667; 95% CI, 0.551–0.807; P < .0001); median radiographic progression-free survival was 33.1 months versus 19.5 months, respectively. Consistent with the primary results, the most common grade ≥3 treatment-related adverse reactions with talazoparib + enzalutamide were anemia (49%) and neutropenia (19%). Treatment-related adverse reactions were generally manageable; 86 patients (22%) discontinued talazoparib due to treatment-related adverse reactions.

Conclusions: Talazoparib + enzalutamide demonstrated a statistically significant and clinically meaningful improvement in overall survival compared with standard of care enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer who were not selected for HRR genetic alterations. Radiographic progression-free survival continued to favor talazoparib + enzalutamide. No new safety signals were identified at long-term follow-up.

 参考文献 Reference

Agarwal N et al. 2025 ASCO GU Cancers Symp Abstr LBA18

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Invikafusp Alfa 用于PD-(L)1进展的结直肠癌 (3/9/2025) 

Invikafusp Alfa in PD-(L)1 refractory colorectal cancer

Invikafusp alfa 是一个同类首创选择性双 T 细胞激动剂(选择性 V_β T 细胞活化方法针对富含肿瘤浸润淋巴细胞的特定 T 细胞亚群)。一项I/II期多中心研究临床试验（START-001, NCT05592626）招募了接受过大量治疗且对抗 PD-(L)1 疗法有抗性的患者，涉及 16 种肿瘤类型：肾上腺皮质癌 (n = 1), 壶腹部癌 (n = 1), 肛门癌 (n = 5), 乳腺癌 (n = 1), 宫颈癌 (n = 6), 结肠癌 (n = 4), 食道癌 (n = 1), 鼻咽癌 (n = 2), 胰腺癌 (n = 1), 直肠癌 (n = 1), 皮肤癌 (n = 1) 和外阴癌 (n = 1)，以及黑色素瘤 (n = 1), 默克尔细胞癌 (n = 2), 非小细胞肺癌 (n = 2) 和头颈部鳞状细胞癌 (n = 5)。患者需要患有高肿瘤突变负担 (TMB-H), 微卫星不稳定性高/错配修复缺陷。第 1 阶段的主要目标是确定推荐的第 2 阶段剂量，以及安全性和耐受性。关键的次要目标包括初步的抗肿瘤活性和药代动力学。  

结果: 结直肠癌患者(n = 28) 在接受 invikafusp alfa最佳剂量 0.08 mg/kg 和 0.12 mg/kg 下，疾病控制率为 50%，部分响应。此外，在接受最佳生物剂量范围 (n = 14)治疗的患者中，7 名患者的肿瘤缩小，2 名确认部分响应。在接受 PD-(L)1 疾病进展后，invikafusp alfa 有望成为实体瘤的精准癌症免疫治疗剂。2025 年 1 月 8 日 FDA授予快速通道资格，用于治疗具有高肿瘤突变负担 (TMB-H) 的不可切除, 局部晚期或转移性结直肠癌患者。

最常见的治疗相关不良反应是第一次和第二次给药期间的短暂性低度细胞因子释放综合征。未报告免疫效应细胞相关神经毒性综合征或 4 级细胞因子释放综合征。没有 4 级或 5 级不良反应。以最佳生物剂量治疗的患者出现 1/2 级治疗相关不良反应，包括细胞因子释放综合征 (71.4%), 发热 (64.3%) 和呕吐 (57.1%)。

Invikafusp alfa 的 II 期临床研究正在进行中，这种新颖的治疗方法可能会带来一类新的治疗方法，用于治疗对 PD-1 不敏感或有耐药性的肿瘤类型。

Invikafusp alfa is a first-in-class selective dual T-cell agonist (a selective Vβ T-cell activation approach targets specific T-cell subsets enriched in tumor-infiltrating lymphocytes).

A phase I/II multicenter study (START-001, NCT05592626) enrolled heavily pretreated patients resistant to anti-PD-(L)1 therapy across 16 tumor types: adrenocortical carcinoma (n = 1), ampullary carcinoma (n = 1), anal cancer (n = 5), breast cancer (n = 1), cervical cancer (n = 6), colon cancer (n = 4), esophageal cancer (n = 1), nasopharyngeal cancer (n = 2), pancreatic cancer (n = 1), rectal cancer (n = 1), skin cancer (n = 1), and vulvar cancer (n = 1), as well as melanoma (n = 1), Merkel cell carcinoma (n = 2), non-small cell lung cancer (n = 2), and head and neck squamous cell carcinoma (n = 5). Patients were required to have high tumor mutational burden (TMB-H), microsatellite instability high/mismatch repair deficiency. The primary objectives of the phase 1 trial were to determine the recommended phase 2 dose, as well as safety and tolerability. Key secondary objectives included preliminary antitumor activity and pharmacokinetics. 

Results: Colorectal cancer patients (n = 28) had a disease control rate of 50% and partial responses at the optimal dose of invikafusp alfa of 0.08 mg/kg and 0.12 mg/kg. In addition, among patients treated with the optimal biologic dose range (n = 14), seven patients had tumor shrinkage and two had confirmed partial responses. Invikafusp alfa has the potential to be a precision cancer immunotherapy for solid tumors after PD-(L)1 disease progression. January 8, 2025 FDA granted Fast Track designation for the treatment of patients with unresectable, locally advanced or metastatic colorectal cancer with high tumor mutational burden (TMB-H).

The most common treatment-related adverse reactions were transient low-grade cytokine release syndrome during the first and second doses. No immune effector cell-related neurotoxicity syndrome or grade 4 cytokine release syndrome were reported. There were no grade 4 or 5 adverse reactions. Grade 1/2 treatment-related adverse reactions in patients treated with optimal biologic doses included cytokine release syndrome (71.4%), pyrexia (64.3%), and vomiting (57.1%).

Phase II clinical studies of Invikafusp alfa are ongoing This novel treatment approach may lead to a new class of treatments for tumor types that are insensitive or resistant to PD-1.

参考文献 Reference

Gulley JL et al. 2024 Society for Immunotherapy of Cancer Annual Meeting, Abstr 1470

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纳武单抗+伊匹单抗用于抗 PD-1 治疗进展后的黑色素瘤脑转移 (3/8/2025)

Intracranial outcome of ipilimumab and nivolumab for melanoma brain metastases following progression on anti–PD-1   

方法: 患者为接受过 PD-1 抑制剂治疗且出现进展性的黑色素瘤脑转移，于 2011 年 1 月至 2023 年 12 月期间在斯隆凯特琳癌症中心接受了伊匹单抗/纳武单抗治疗。患者必须有一个或多个黑色素瘤脑转移（≥ 5 毫米）且之前未接受过局部干预（例如放疗）。共有28名患者参加, 18 名患者（64%）接受过抗 PD-1 治疗, 但未接受伊匹单抗，其中 10 名（56%）未接受其他全身治疗，10 名（36%）接受过 PD-1 抑制剂加伊匹单抗治疗。颅内病变中位数为 1.0 cm（interquartile range = 0.6–2.1 cm）, 18 名患者（64%）有超过 5 个颅内病变。主要终点是颅内客观响应率。

结果:中位随访时间为 7 个月（interquartile range = 4–29 个月）。3 名患者（11%，95% 置信区间 [CI] = 2%–28%）出现颅内响应，其中 2 名患者完全响应。2 名完全反应患者属于 4 名有 2 个或 2 个以上病变的患者，且这  2 名患者均未接受过伊匹单抗治疗；截至数据截止时，2 名患者在随访 3 个月和 28 个月时仍然存活且颅内和颅外无进展。5 名病情稳定的患者（18%）病情稳定时间均小于 6 个月。 颅外客观响应率为 14%（95% CI = 4%–33%）。没有颅内响应的患者出现颅外进展。 颅内无进展生存期中位数为 1.6 个月（95% CI = 1.2–4.4 个月）。在 27 名有后续治疗数据的患者中，13 名（48%）接受了局部治疗，8 名（30%）接受了全身治疗。所有患者的中位总生存期为 6.7 个月（95% CI = 3.6–10.0 个月）。

结论 这项研究首次报告了 ipilimumab/nivolumab 对接受抗 PD-1 治疗后出现进展性黑色素瘤脑转移的患者颅内疗效，局部放射治疗，对这些患者至关重要。

Methods: Patients received prior PD-1 inhibitor therapy and experienced progressive melanoma brain metastases. They were treated with ipilimumab/nivolumab at Memorial Sloan Kettering Cancer Center between January 2011 and December 2023. Patients had to have one or more melanoma brain metastases (≥ 5 mm) and had not received prior local intervention (e.g., radiotherapy). A total of 28 patients were enrolled, 18 patients (64%) had received anti-PD-1 therapy but not ipilimumab, 10 (56%) had not received other systemic therapy, and 10 (36%) had received PD-1 inhibitor plus ipilimumab. The median size of intracranial lesions was 1.0 cm (interquartile range = 0.6–2.1 cm), and 18 patients (64%) had more than 5 intracranial lesions. The primary endpoint was intracranial objective response rate.

Results: Median follow-up was 7 months (interquartile range = 4–29 months). Three patients (11%, 95% confidence interval [CI] = 2%–28%) had an intracranial response, including two complete responses. The two complete responders were among four patients with two or more lesions. Neither of the two had received ipilimumab. At data cutoff, both patients were alive and free of intracranial and extracranial progression at 3 and 28 months of follow-up. Five patients (18%) who had stable had stable disease for less than 6 months. The extracranial objective response rate was 14% (95% CI = 4%–33%). No patient with an intracranial response had extracranial progression. The median intracranial progression-free survival was 1.6 months (95% CI = 1.2–4.4 months). Of the 27 patients with subsequent treatment data, 13 (48%) received local therapy and 8 (30%) received systemic therapy. The median overall survival for all patients was 6.7 months (95% CI = 3.6–10.0 months).

Conclusion This study is the first to report the intracranial efficacy of ipilimumab/nivolumab in patients with progressive melanoma brain metastases after anti-PD-1 therapy; local radiation therapy is crucial for these patients.

参考文献 Reference

Lochrin SE et al. JAMA Onc 2025 ; doi:10.1001/jamaoncol.2024.6168

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肛门鳞状细胞癌的放射治疗：ASTRO  实践指南 (3/2/2025)

Radiation therapy for anal squamous cell carcinoma: An ASTRO practice guideline

推荐	强度	质量
局部肛门癌：cT1-4/N0/N+
1. 明确同步放化疗，使用 5-FU + MMC*	强	强高
2. 明确同步放化疗，使用顺铂 + 5-FU	有条件	中等
3. 明确同步放化疗，使用卡培他滨 + MMC	强	低
4. cT1N0, 浅表扩散，无高危特征（3 级、LVI*2、PNI *3）：局部切除（需要密切随访）	有条件	低

辐射剂量

1. cT1-T2：4500-5040 cGy 分25-28 次至原发肿瘤	强	高
2. cT3-4：5320-5940 cGy 分28-33 次至原发肿瘤	强	中等
3. 淋巴结：包括边缘、肛管、直肠、直肠系膜/骶前/髂外/髂内/闭孔/腹股沟淋巴结	强	高
4. 淋巴结阴性，接受连续加强放射治疗，3600 cGy，180 cGy/次 照射至整个选择性（未受累）淋巴结体积，可额外增加 900 cGy，180 cGy/次 照射至包含真骨盆的较小选择性淋巴结体积	强	中等
5. 淋巴结阳性，接受连续加强放射治疗：   • 3600 cGy，180 cGy/次 照射至整个选择性（未受累）淋巴结体积，并且   • 4500 cGy，180 cGy/次 照射至包含真骨盆和阳性淋巴结区域的较小选择性淋巴结体积，并且  • 5040-5400 cGy，180 cGy/次 照射至阳性淋巴结，	强	中等
6. 淋巴结阳性，同时接受综合加强：   • 4000-4200 cGy 分28 次, 或 4500 cGy 分30 次至选择性（未受累）淋巴结体积，并且 • 5040-5400 cGy 分28 -30次至临床阳性淋巴结	强	中等

按 T 和 N 分期的辐射剂量

原发肿瘤
cT1-2	4500-5040 cGy 分25-28 次	顺序或 SIB*5
cT3-4	5320-5940 cGy 分28-33 次	顺序或 SIB
淋巴结
cN0	• 3600 cGy分20 次至选择性淋巴结体积   • 4500 cGy分25 次 至真骨盆（可选）	顺序增强
cN0	• 4000-4200 cGy 分28 次 或  4500 cGy 分30次至选择性淋巴结体积	SIB
cN+	• 3600 cGy 分 20次至选择性淋巴结体积 • 4500 cGy 分25次至真骨盆和受累淋巴结 • 5040-5400 cGy 分28-30次至受累淋巴结	顺序增强
cN+	• 4000-4200 cGy 分28次或 4500 cGy分30次至选择性淋巴结体积 •5040 cGy 分28-30次至阳性淋巴结 <3 cm •5320-5400 cGy 分28-30次至阳性淋巴结 ≥3 cm	SIB

*MMC, mitomycin C

*₂ LVI, lymphovascular invasion

*³ perineural invasion

*⁵ SIB simultaneous integrated boost

监测随访：

在确定性放化疗临床完全缓解后，进行临床腹股沟淋巴结检查和直肠指检（加或不加肛门镜检查）（或内窥镜检查）

 • 第 0-2 年每 3 个月一次；

• 第 2-3 年每 6-12 个月一次；

• 第 4-5 年可选择每年随访一次。

• 建议至少每年进行一次横断面成像，直到第 2 年，通常是胸部、腹部和盆腔 CT

• 如果 CT 上发现可疑结果或治疗前发现异常，则考虑进行盆腔 MRI 和/或 FDG-PET/CT 

Radiation, chemotherapy or surgery Recommendation	strength	Quality
Localized anal cancer: cT1-4/N0/N+
Definite concurrent chemoradiation w/ 5-FU + MMC*	strong	high
Definite concurrent chemoradiation w/ cisplatin + 5-FU	conditional	moderate
Definite concurrent chemoradiation w/ capecitabine + MMC	strong	low
cT1No superficial spreading, no high-risk features (grade 3, LVI*2, PNI *3): lcoal excision (need close follow-up)	conditional	low

Radiation dose

cT1-T2: 4500-5040 cGy in 25-28 fx*4 to primary tumor	strong	high
cT3-4: 5320-5940 cGy in 28-33 fx to primary tumor	strong	moderate
lymph nodes: include margins, anal canal, rectum, mesorectal/presacral/external/internal iliac/obturator/inguinal nodes,	strong	high
node-negative, receiving a sequential RT boost, 3600 cGy in 180 cGy per fx to entire elective (uninvolved) nodal volume, with or without an additional 900 cGy boost in 180 cGy per fx to a smaller elective nodal volume that encompasses the true pelvis	strong	moderate
node-positive, receiving a sequential RT boost: • 3600 cGy in 180 cGy per fx to entire elective (uninvolved) nodal volume, AND • 4500 cGy in 180 cGy per fx to a smaller elective nodal volume that encompasses the true pelvis and positive lymph node regions, AND • 5040-5400 cGy in 180 cGy per fx to positive nodes	Strong	moderate
node-positive, receiving simultaneous integrated boost: • 4000-4200 cGy in 28 fr or 4500 cGy in 30 fx to elective (uninvolved) nodal volume, AND • 5040-5400 cGy in 28-30 fx to clinically positive node	Strong	moderate

Radiation dose by T & N stage

cT1-2	4500-5040 cGy in 25-28 fx	sequential or SIB*5
cT3-4	5320-5940 cGy in 28-33 fx	Sequential or SIB
cN0	• 3600 cGy in 20 fx to elective nodal volume • 4500 cGy in 25 fx to true pelvis (optional) • 4000-4200 cGy in 28 fx OR 4500 cGy in 30 fx to elective nodal volume	sequential boost sequential boost SIB
cN+	• 3600 cGy in 20 fx to elective nodal volume • 4500 cGy in 25 fx to true pelvis and involved node(s) • 5040-5400 cGy in 28-30 fx to involved node • 4000-4200 cGy in 28 fx OR 4500 cGy in 30 fx to elective nodal volume • 5040 cGy in 28-30 fx to positive node(s) <3 cm • 5320-5400 cGy in 28-30 fx to positive node(s) ≥3 cm	Sequential boost Sequential boost Sequential boost SIB SIB SIB

*MMC, mitomycin C

*₂ LVI, lymphovascular invasion

*³ perineural invasion

*⁴ Fx, fraction

*⁵ SIB simultaneous integrated boost

Surveillance:

Following clinical complete response after definitive chemoradiation, clinical inguinal lymph node exam and digital rectal exam with or without anoscopy (endoscopy)

• every 3 months for years 0-2;

• then every 6-12 months for years 2-3; and

• optional annual follow-up for years 4-5.

• Cross-sectional imaging is recommended a minimum of annually until year 2, typically, chest, abdomen, and pelvis CT

• Consider pelvic MRI and/or FDG-PET/CT for equivocal findings on CT or if these were abnormal prior to treatment

参考文献 Reference

Feng M et al. Prac Radiat Onc 2025, Feb. 27.

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伊匹单抗联合纳武单抗与单独使用纳武单抗治疗黑色素瘤脑转移患者：一项随机 II 期研究的 7 年随访  (3/1/2025)

Ipilimumab plus nivolumab versus nivolumab alone in patients with melanoma brain metastases: 7-year follow-up of a randomized, phase II study

方法: 这项开放标签, 随机, II期研究(NCT02374242)在澳大利亚的四个地点进行, 且正在进行中。符合条件的患有活动性黑色素瘤脑转移, 未接受过免疫治疗。将没有接受过脑导向治疗的无症状患者随机分配（5:4）到 A组: 静脉注射 ipilimumab 3 mg/kg 加 nivolumab 1 mg/kg，每 3 周注射一次，共注射四次，然后 nivolumab 3 mg/kg 每 2 周注射一次; B组: 静脉注射 nivolumab 3 mg/kg 每 2 周注射一次。接受过既往脑导向治疗, 有神经系统症状或软脑膜疾病的患者被分配到非随机C组: 静脉注射 nivolumab 3 mg/kg 每 2 周一次。主要终点是从第 12 周开始的最佳颅内响应（完全或部分响应）。次要生存终点包括颅内无进展生存期和总生存期。安全性评估从第一次治疗剂量到停止治疗后至少 100 天。对接受至少一剂研究药物的患者进行了分析。

结果: 主要分析结果已报告，本文是该试验的长期随访。 2014 年 11 月 4 日至 2017 年 4 月 21 日期间，对 89 名患者进行了资格评估，其中 79 名患者入组并分配到队列 A（n=36）、队列 B（n=27）或队列 C（n=16）。三名患者（A组 一名，B组 两名）因不符合资格而被排除在外。在数据截止时（2024 年 3 月 26 日），中位随访时间为 7.6 年（IQR 6.9–8.2）。A组 中有 18 名（51% [95% CI 34–69]）患者出现总体颅内响应，B组 中有 5 名（20% [7–41]）患者出现总体颅内响应，C组 中有 1 名（6% [0–30]）患者出现总体颅内响应。A组 的 7 年颅内无进展生存率为 42%（95% CI 29–63），B组 为 15%（6–39），C组 为 6%（1–42）。A组 的 7 年总生存率为 48%（34–68），B组 为 26%（13–51），C 组为 13%（3–46）。安全性结果与主要分析一致。 50 名患者死亡，其中 A 组 18 名（51%），B 组 18 名（72%），C 组 14 名（88%）。

解释: 研究结果表明，对于活动性无症状脑转移患者，伊匹单抗加纳武单抗至少可维持 7 年疗效。伊匹单抗加纳武单抗应成为黑色素瘤脑转移患者的标准治疗方案；一项研究立体定向手术在这一新模式中的作用的试验正在进行中 。

Methods: This open-label, randomized, phase II study (NCT02374242) was conducted at four sites in Australia and is ongoing. Eligible patients had active melanoma brain metastases and had not received prior immunotherapy. Asymptomatic patients who had not received prior brain-directed therapy were randomized (5:4) to group A: ipilimumab 3 mg/kg plus nivolumab 1 mg/kg IV every 3 weeks for four injections, followed by nivolumab 3 mg/kg every 2 weeks; or group B: nivolumab 3 mg/kg IV every 2 weeks. Patients who had received prior brain-directed therapy and had neurologic symptoms or leptomeningeal disease were assigned to the non-randomized group C: nivolumab 3 mg/kg IV every 2 weeks. The primary endpoint was best intracranial response (complete or partial response) from week 12. Secondary survival endpoints included intracranial progression-free survival and overall survival. Safety was assessed from the first treatment dose to at least 100 days after discontinuation of treatment. Patients who received at least one dose of study drug were analyzed.

Results: The results of the primary analysis have been reported, and this is the long-term follow-up of the trial. Between Nov 4, 2014, and April 21, 2017, 89 patients were assessed for eligibility, of whom 79 were enrolled and assigned to cohort A (n=36), cohort B (n=27), or cohort C (n=16). Three patients (one in cohort A and two in cohort B) were excluded because of ineligibility. At data cutoff (March 26, 2024), the median follow-up was 7.6 years (IQR 6.9–8.2). Overall intracranial response was observed in 18 patients (51% [95% CI 34–69]) in group A, 5 patients (20% [7–41]) in group B, and 1 patient (6% [0–30]) in group C. The 7-year intracranial progression-free survival was 42% (95% CI 29–63) in group A, 15% (6–39) in group B, and 6% (1–42) in group C. The 7-year overall survival was 48% (34–68) in group A, 26% (13–51) in group B, and 13% (3–46) in group C. Safety results were consistent with the primary analysis. Fifty patients died, including 18 (51%) in group A, 18 (72%) in group B, and 14 (88%) in group C.

Interpretation: The findings suggest that ipilimumab plus nivolumab may maintain efficacy for at least 7 years in patients with active asymptomatic brain metastases. Ipilimumab plus nivolumab should become the standard of care for patients with brain metastases from melanoma; a trial investigating the role of stereotactic surgery in this new paradigm is ongoing.

参考文献 Reference

Long GV et al. Lancet Onc 2025 ; Feb 17, 2025

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新型 CD19-1XX 嵌合抗原受体在大 B 细胞淋巴瘤中具有校准信号传导的首次人体 研究 (2/23/2025)

First-in-human study of a novel CD19-1XX chimeric antigen receptor with calibrated signaling in large B-cell lymphoma

一种新型 CD19 靶向嵌合抗原受体 (CAR)包含一个校准信号传导模块，称为 1XX，与传统的 CD28/CD3ζ 和 4-1BB/CD3ζ CAR 不同。临床前数据表明，1XX CAR 产生了强大的效应功能，而不会破坏 T 细胞持久性。

方法: 在这项首次人体 I 期剂量递增和扩展临床试验中，复发或难治性大 B 细胞淋巴瘤患者接受了四种剂量水平的 19(T2)28z-1XX CAR T 细胞治疗，剂量范围从 25 到 200 × 10⁶。

结果: 28 名患者接受了白细胞分离术并接受了 CAR T 细胞治疗。剂量递增组和扩展组分别有 16 名和 12 名患者接受治疗。整个组的总体响应率为 82%，完全响应率为 71%。选择最低剂量 25 × 10⁶ 进行剂量扩展。在接受此剂量水平治疗的 16 名患者中，88% 的患者实现了总体响应率，75% 的患者实现了完全响应率。中位随访期为 24 个月，1 年无事件生存率为 61%（95% CI，45 至 82），14 名患者在 12 个月后仍保持持续完全响应。在所有队列中，≥3 级细胞因子释放综合征和免疫效应细胞相关神经毒性综合征发生率分别为 4% 和 7%。1XX CAR T 细胞产品含有更高比例的具有记忆特征的 CD8 T 细胞，并且在持续完全响应的患者中检测到 CAR T 细胞持续存在超过 1-2 年。  

结论: 1XX CAR 的校准效力在低细胞剂量下具有出色的疗效，具有良好的毒性特征，可能有益于治疗其他血液系统恶性肿瘤, 实体瘤和自身免疫。

A novel CD19-targeting chimeric antigen receptor (CAR) contains a calibrated signaling module, called 1XX, that differs from conventional CD28/CD3ζ and 4-1BB/CD3ζ CARs. Preclinical data suggest that 1XX CARs produce robust effector function without impairing T cell persistence. Methods: In this first-in-human phase I dose-escalation and expansion clinical trial, patients with relapsed or refractory large B-cell lymphoma were treated with 19(T2)28z-1XX CAR T cells at four dose levels ranging from 25 to 200 × 10⁶.

Results: Twenty-eight patients underwent leukapheresis and received CAR T-cell therapy. Sixteen and 12 patients were treated in the dose-escalation and expansion groups, respectively. The overall response rate for the entire group was 82%, with a complete response rate of 71%. The lowest dose of 25 × 10⁶ was selected for dose expansion. Of the 16 patients treated at this dose level, 88% achieved an overall response rate and 75% achieved a complete response rate. With a median follow-up of 24 months, the 1-year event-free survival rate was 61% (95% CI, 45 to 82), and 14 patients maintained a sustained complete response after 12 months. Grade ≥3 cytokine release syndrome and immune effector cell-related neurotoxicity syndrome occurred in 4% and 7%, respectively, across all cohorts. 1XX CAR T-cell products contain a higher proportion of CD8 T cells with memory characteristics, and CAR T-cell persistence was detected for more than 1-2 years in patients with sustained complete responses.

Conclusions: The calibrated potency of 1XX CARs provides excellent efficacy at low cell doses with a favorable toxicity profile and may be beneficial in the treatment of other hematologic malignancies, solid tumors, and autoimmunity.  

参考文献 Reference

Park JH et al. J Clin Onc 2025 ; https://doi.org/10.1200/JCO-24-024

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卡博替尼治疗晚期神经内分泌肿瘤的 III 期试验 (2/22/2025)

Phase III trial of cabozantinib in advanced neuroendocrine tumors

方法: 这是一项III期临床试验（NCT03375320），招募了两组独立的患者——胰腺外神经内分泌肿瘤患者和胰腺神经内分泌肿瘤患者。他们接受过多肽受体放射性核素治疗或靶向治疗或两者兼有。患者按 2:1 的比例随机分配接受卡博替尼（每日 60 毫克）或安慰剂治疗。主要终点是无进展生存期。关键次要终点包括客观响应, 总体生存期和安全性。

结果: 在 203 名胰腺外神经内分泌肿瘤患者队列中，卡博替尼组的中位无进展生存期为 8.4 个月，而安慰剂组的中位无进展生存期为 3.9 个月（分层进展或死亡风险比为 0.38； 95% 置信区间 [CI]，0.25 至 0.59；P <0.001）。在 95 名胰腺神经内分泌肿瘤患者队列中，卡博替尼组的中位无进展生存期为 13.8 个月，而安慰剂组的中位无进展生存期为 4.4 个月（分层风险比为 0.23；95% CI，0.12 至 0.42；P<0.001）。在胰腺外和胰腺神经内分泌肿瘤患者中，卡博替尼证实的客观响应发生率分别为 5% 和 19%，而安慰剂组为 0%。

一共62% 至 65% 的卡博替尼治疗患者出现 3 级或更高级别的不良事件，而接受安慰剂治疗的患者中这一比例为 23% 至 27%。常见的 3 级或更高级别的治疗相关不良事件包括高血压, 疲劳, 腹泻和 血栓栓塞事件。

结论: 与安慰剂相比，卡博替尼显著改善了先前接受过治疗的进展性晚期胰腺外或胰腺神经内分泌肿瘤患者的无进展生存期。不良事件与卡博替尼已知的安全性一致。

Methods: This was a phase III clinical trial (NCT03375320) that enrolled two independent groups of patients—those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors. They had received prior peptide receptor radionuclide therapy or targeted therapy or both. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg daily) or placebo. The primary end point was progression-free survival. Key secondary end points included objective response, overall survival, and safety.

Results: In the cohort of 203 patients with extrapancreatic neuroendocrine tumors, the median progression-free survival was 8.4 months in the cabozantinib group and 3.9 months in the placebo group (stratified hazard ratio for progression or death, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P < .001). In a cohort of 95 patients with pancreatic neuroendocrine tumors, median progression-free survival was 13.8 months with cabozantinib and 4.4 months with placebo (stratified hazard ratio, 0.23; 95% CI, 0.12 to 0.42; P<0.001). Confirmed objective responses occurred in 5% and 19% of patients with extrapancreatic and pancreatic neuroendocrine tumors, respectively, with cabozantinib, as compared with 0% with placebo.

A total of 62% to 65% of patients treated with cabozantinib experienced adverse events of grade 3 or higher, as compared with 23% to 27% of those treated with placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events.

Conclusions: Cabozantinib significantly improved progression-free survival compared with placebo in patients with previously treated advanced extrapancreatic or pancreatic neuroendocrine tumors. Adverse events were consistent with the known safety profile of cabozantinib.

参考文献 Reference

Chan JA et al. N Engl J Med 2025; 392:653

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Zenocutuzumab 对 NRG1 融合阳性肺癌和胰腺癌的疗效 (2/17/2025)

Efficacy of Zenocutuzumab  in NRG1 fusion-positive non-small cell lung cancer and pancreatic cancer

Zenocutuzumab, 一个针对 HER2 和 HER3 的双特异性抗体, 是FDA 批准的首个 NRG1 融合阳性非小细胞肺癌和胰腺腺癌靶向疗法。

方法：这是一项II期临床试验（NCT02912949），患有任何肿瘤类型的晚期 NRG1 融合阳性癌症的患者每 2 周接受一次 750 毫克静脉注射。主要终点是根据研究者评估得出的总体响应。次要终点包括响应持续时间、无进展生存期和安全性。 

结果: 总共有 204 名患有 12 种肿瘤类型的患者入组并接受治疗。在 158 名具有可测量疾病且在数据截止日期前至少 24 周入组的患者中，30%（95% CI，23-37）的患者出现响应。中位响应持续时间为 11.1 个月（95% CI 7.4-12.9）；截至数据截止日期，19% 的响应仍在持续。在 93 名肺癌患者中 27 名（29%）和 36 名胰腺癌患者中 15 名（42%）观察到响应，并且涉及多个 NRG1 融合模式。中位无进展生存期为 6.8 个月（95% CI 5.5-9.1）。最常见的不良反应是腹泻（18%）, 疲劳（12%）和恶心（11%）。14% 的患者出现输液相关反应。一名患者因治疗相关不良反应而停药。

结论：Zenocutuzumab对晚期NRG1融合阳性癌症患者有疗效，尤其是非小细胞肺癌和胰腺癌，且不良反应较低。

Zenocutuzumab, a bispecific antibody targeting HER2 and HER3, is the first FDA-approved targeted therapy for NRG1 fusion-positive non-small cell lung cancer and pancreatic adenocarcinoma.

Methods: This was a phase II clinical trial (NCT02912949) in which patients with advanced NRG1 fusion-positive cancer of any tumor type received 750 mg intravenously every 2 weeks. The primary endpoint was overall response according to investigator assessment. Secondary endpoints included duration of response, progression-free survival, and safety.

Results: A total of 204 patients with 12 tumor types were enrolled and treated. Among the 158 patients with measurable disease who were enrolled at least 24 weeks before the data cutoff date, 30% (95% CI, 23-37) of patients had a response. The median duration of response was 11.1 months (95% CI 7.4-12.9); 19% of responses were ongoing as of the data cutoff date. Responses were observed in 27 of 93 lung cancer patients (29%) and 15 of 36 pancreatic cancer patients (42%), involving multiple NRG1 fusion patterns. Median progression-free survival was 6.8 months (95% CI 5.5-9.1). The most common adverse reactions were diarrhea (18%), fatigue (12%), and nausea (11%). Infusion-related reactions occurred in 14% of patients. One patient discontinued the drug due to treatment-related adverse reactions.

Conclusions: Zenocutuzumab is effective in patients with advanced NRG1 fusion-positive cancers, especially non-small cell lung cancer and pancreatic cancer, with low adverse reactions.

参考文献 Reference

Schram AM et al. New Engl J Medicine 2025; Feb 6

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帕博利珠单抗联合或不联合贝伐单抗治疗铂类耐药性鼻咽癌 (2/9/2025)

Pembrolizumab with or without bevacizumab in platinum-resistant nasopharyngeal carcinoma (NPC)

方法: 在新加坡两家医院进行的这项随机, 开放标签的 II 期试验中(NCT03813394)，铂耐药性复发性或转移性鼻咽癌患者被分配（1:1；使用大小为 4 和 6 的随机置换区组）每 21 天接受一次静脉注射派姆单抗 (200 毫克) 或派姆单抗与静脉注射贝伐单抗 (7.5 毫克/公斤) 的组合，每次给药前 1 周给药，直到放射学疾病进展, 不可接受的毒性, 完成 32 个周期或撤回同意。主要终点是客观响应率，并在意向治疗人群中进行分析。

结果: 2019 年 5 月 13 日至 2023 年 12 月 6 日期间，研究者评估了 60 人是否符合资格，排除了 12 人，将 48 人随机分配到单独使用派姆单抗（n =24）或贝伐单抗和派姆单抗联合治疗（n =24）。中位年龄为 56 岁（IQR 48–65），48 名患者中有 40 名（83%）为男性，8 名（17%）为女性。中位随访时间为 28.3 个月（IQR 15.1–55.9）。贝伐单抗和帕博利珠单抗组的客观响应率（58.3% [95% CI 36.6–77.9]）显著高于帕博利珠单抗组（12.5% [2.7–32.4]。

帕博利珠单抗组 24 例患者中有 2 例（8%）出现 3 级治疗相关不良事件，贝伐单抗和帕博利珠单抗组 24 例患者中有 7 例（29%）出现 3 级治疗相关不良事件；最常见的严重或 3-4 级治疗相关不良事件是血栓形成或出血（贝伐单抗和帕博利珠单抗组 24 例患者中有 4 例 [17%] vs 帕博利珠单抗组 24 例患者中无），其他包括转氨酶升高（无 vs 1 [4%]）、结肠炎（1 [4%] vs 无]）、血细胞减少症（无 vs 1 [4%]）、皮肤毒性（1 [4%] vs 无]）、高血压（1 [4%] vs 无]）和蛋白尿（1 [4%] vs 无]）。两组均未发生 4 级治疗相关不良事件或治疗相关死亡。

解释: 对于铂类耐药性鼻咽癌，派姆单抗联合贝伐单抗比派姆单抗单药治疗更有效，且毒性可控。如果在 III 期试验中得到验证，联合疗法可能成为这类患者新的治疗标准。

Methods: In this randomized, open-label, phase II trial (NCT03813394) conducted at two hospitals in Singapore, patients with platinum-resistant recurrent or metastatic NPC were assigned (1:1; using randomized permuted block sizes of 4 and 6) to receive either intravenous pembrolizumab (200 mg) or a combination of pembrolizumab and intravenous bevacizumab (7.5 mg/kg) every 21 days, 1 week before each dose, until radiographic disease progression, unacceptable toxicity, completion of 32 cycles, or withdrawal of consent. The primary endpoint was objective response rate and was analyzed in the intention-to-treat population.

Results: Between May 13, 2019, and Dec 6, 2023, we assessed 60 people for eligibility, excluded 12, and randomly assigned 48 to pembrolizumab alone (n = 24) or bevacizumab and pembrolizumab (n = 24). The median age was 56 years (IQR 48–65), and 40 of the 48 patients (83%) were men and 8 (17%) were women. The median follow-up was 28.3 months (IQR 15.1–55.9). The objective response rate was significantly higher in the bevacizumab and pembrolizumab group (58.3% [95% CI 36.6–77.9]) than in the pembrolizumab group (12.5% ​​[2.7–32.4].

Grade 3 treatment-related adverse events occurred in 2 of 24 patients (8%) in the pembrolizumab group and in 7 of 24 patients (29%) in the bevacizumab and pembrolizumab group; the most common serious or grade 3-4 treatment-related adverse events were thrombosis or bleeding (4 of 24 patients [17%] in the bevacizumab and pembrolizumab group vs none of 24 patients in the pembrolizumab group), and others included elevated aminotransferases (none vs 1 [4%]), colitis (1 [4%] vs none), cytopenias (none vs 1 [1%]), skin toxicity (1 [4%] vs none]), hypertension (1 [4%] vs none]), and proteinuria (1 [4%] vs none]). There were no grade 4 treatment-related adverse events or treatment-related deaths in either group.

Interpretation: The combination of pembrolizumab and bevacizumab was more effective than pembrolizumab alone in patients with platinum-resistant nasopharyngeal carcinoma with manageable toxicity. If validated in a phase III trial, the combination therapy could become a new standard of care for these patients.

参考文献 Reference

Chong W-Q et al.  Lancet Haemtol 2024; 11: E682

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BRUIN 研究Pirtobrutinib 治疗Richter 转化的亚组分析 (2/8/2025)

Subset analysis in BRUIN trial of Pirtobrutinib treating Richter transformation

本研究旨在报告多中心, 开放标签, 1/2 期 BRUIN 研究中，Pirtobrutinib单药治疗对 Richter 转化患者亚组的安全性和活性。

方法: 这是一项I/II期临床试验（NCT03740529），本分析包括经组织学证实的 Richter 转化、东部肿瘤协作组体能状态评分为 0-2 分且既往治疗无限制的成年患者（年龄≥18 岁）。Pirtobrutinib 200 毫克，每天口服一次，每 28 天为一个周期。之前已报道过，BRUIN 试验第 1 阶段的主要终点是确定Pirtobrutinib单药治疗的推荐第 2 阶段剂量，第 2 阶段的主要终点是总体响应率。在所有接受至少一剂Pirtobrutinib单药治疗的患者中测量了安全性和活性。

结果 2019 年 12 月 26 日至 2022 年 7 月 22 日期间，共招募了 82 名患者，其中 5 名在第 1 阶段招募，77 名在第 2 阶段招募。除一名患者外，所有患者均以推荐的第 2 阶段剂量每天一次接受 200 毫克Pirtobrutinib的起始剂量。其余患者每天接受 150 毫克Pirtobrutinib，未增加至 200 毫克。患者中位年龄为 67 岁 (IQR 59–72)。82 名患者中有 55 名 (67%) 为男性，27 名 (33%) 为女性。大多数患者为白种人 (65/82 [79%])。82 名患者中有 74 名 (90%) 至少接受过一次 Richter 转化-导向疗法。大多数患者 (61/82 [74%]) 曾接受过针对慢性淋巴细胞白血病或 Richter 转化的共价 BTK 抑制剂治疗。总体响应率为 50.0% (95% CI 38.7–61.3)。82 名患者中有 11 名 (13%) 完全响应，30 名 (37%) 部分响应。8 名持续响应的患者选择停用Pirtobrutinib并接受干细胞移植。最常见的 3 级或更严重不良事件是中性粒细胞减少症 (n =19)。没有治疗相关的死亡。

解释: Pirtobrutinib在 Richter 转化患者中显示出良好的安全性和活性，其中大多数患者之前接受过 Richter 转化导向治疗，包括共价 BTK 抑制剂。这些数据表明，有必要进一步研究Pirtobrutinib作为共价 BTK 抑制剂治疗后复发或难治性 Richter 转化患者的治疗选择。

This study reported the safety and activity of pirtobrutinib monotherapy in the subgroup of patients with Richter’s transformation.

Methods: This is a phase I/II clinical trial (NCT03740529). The analysis included adult patients (age ≥18 years) with histologically confirmed Richter’s transformation, EOG performance status of 0-2, and no restrictions on previous treatment. Pirtobrutinib 200 mg was taken orally once daily every 28 days. As previously reported, the primary endpoint of the phase I of the BRUIN trial was to determine the recommended phase II dose of pirtobrutinib monotherapy, and the primary endpoint of phase 2 was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy.

Findings: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, 5 in phase I and 77 in phase II. All but one patient received a starting dose of 200 mg pirtobrutinib once daily at the recommended stage II dose. The remaining patients received 150 mg pirtobrutinib daily without escalation to 200 mg. The median age of the patients was 67 years (IQR 59–72). Fifty-five of the 82 patients (67%) were male and 27 (33%) were female. The majority of patients were white (65/82 [79%]). 74 of the 82 patients (90%) had received at least one prior Richter transformationl-directed therapy. Most patients (61/82 [74%]) had received prior covalent BTK inhibitor therapy for chronic lymphocytic leukemia or Richter’s transformation. The overall response rate was 50.0% (95% CI 38.7–61.3). Eleven of 82 patients (13%) had a complete response and 30 (37%) had a partial response. Eight patients with an ongoing response elected to discontinue pirtobrutinib and undergo stem cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n = 19). There were no treatment-related deaths.

Interpretation: Pirtobrutinib showed a favorable safety profile and activity in patients with Richter’s transformation, most of whom had received prior Richter’s transformation-directed therapy, including a covalent BTK inhibitor. These data suggest that further investigation of pirtobrutinib as a treatment option for patients with Richter’s transformation who have relapsed or are refractory to covalent BTK inhibitor therapy is warranted.

参考文献 Reference

Wierda WG et al. Lancet Hematol 2024;11:e682

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多民族队列研究细颗粒物 (PM_2.5)和乳腺癌发病率 (2/2/2025)

PM_2.5 and Breast Cancer Incidence in the Multiethnic Cohort Study

方法: 在多民族队列研究的 58,358 名加州女性参与者中，平均随访时间为 19.3 年（1993-2018 年），研究者使用 Cox 比例风险回归分析了随时间变化的颗粒物与侵袭性乳腺癌风险之间的关联（n = 3,524 例；70% 为非裔美国人和拉丁裔女性），并根据社会人口统计学和生活方式因素进行了调整。对种族和民族, 激素受体状态和乳腺癌风险因素进行了亚组分析。

结果: 基于卫星的 PM_2.5与乳腺癌发病率显著增加相关（每 10 μg/m³ 的风险比 [HR]，1.28 [95% CI，1.08 至 1.51]）。没有发现种族和民族以及激素受体状态之间存在异质性关联的证据。乳腺癌家族史表明 PM_2.5关联存在异质性（异质性 = .046）。在对多民族队列研究和其他 10 个前瞻性队列的荟萃分析中，乳腺癌发病率与 PM_2.5暴露相关（每增加 10 μg/m³ 的 HR，1.05 [95% CI，1.00 至 1.10]；P = .064）。  

结论: 这个长期接触空气污染物的大型多民族队列和已发表的前瞻性队列研究的结果支持 PM_2.5是乳腺癌的风险因素。由于大约一半的乳腺癌无法用已知的乳腺癌风险因素来解释，而且发病率持续上升，特别是在低收入和中等收入国家，这项研究结果强调，乳腺癌预防不仅应包括以个人行为为中心的方法，还应包括遏制 PM_2.5暴露。

Methods: The researchers used Cox proportional hazards regression to examine the association between time-varying particulate matter and invasive breast cancer risk in 58,358 California women enrolled in the Multiethnic Cohort Study (n = 3,524; 70% African American and Latina women) followed for a mean of 19.3 years (1993-2018), adjusting for sociodemographic and lifestyle factors. Subgroup analyses were performed for race and ethnicity, hormone receptor status, and breast cancer risk factors.

Results: Satellite-based PM_2.5 was associated with a significant increase in breast cancer incidence (hazard ratio [HR] per 10 μg/m³, 1.28 [95% CI, 1.08 to 1.51]). No evidence of heterogeneous associations was found by race and ethnicity and hormone receptor status. Family history of breast cancer showed heterogeneity in PM_2.5 associations (heterogeneity = .046). In a meta-analysis of the Multiethnic Cohort Study and 10 other prospective cohorts, breast cancer incidence was associated with PM_2.5 exposure (HR per 10 μg/m³ increase, 1.05 [95% CI, 1.00 to 1.10]; P = .064).

Conclusions: The results of this large multiethnic cohort with long-term exposure to air pollutants and published prospective cohort studies support PM_2.5 as a risk factor for breast cancer. Because approximately half of breast cancers cannot be explained by known breast cancer risk factors and incidence continues to rise, particularly in low- and middle-income countries, the findings of this study emphasize that breast cancer prevention should include not only approaches centered on individual behavior but also curbing PM_2.5 exposure.

参考文献 Reference

Wu AH et al. J Clin Onc 2025 ; 43 : 273

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帕博利珠单抗联合辅助化疗（联合或不联合放疗）治疗高风险错配修复缺陷型子宫内膜癌 (2/1/2025)

Pembrolizumab plus adjuvant chemotherapy +/- Radiotherapy for high-risk endometrial cancer: results in dMMR Tumors

研究者报告了 III 期 ENGOT-en11/GOG-3053/KEYNOTE-B21 研究（NCT04634877）中新诊断的高风险子宫内膜癌治愈性手术后错配修复缺陷型 (dMMR) 肿瘤患者的方案预设亚组分析。患者被随机分配接受每 3 周一次的 pembrolizumab 200 mg 或安慰剂（六个周期）加卡铂-紫杉醇（四至六个周期）治疗，然后每 6 周一次（六个周期）接受 pembrolizumab 400 mg 或安慰剂治疗。患者由研究者决定是否接受放射治疗。研究者评估的无病生存期是主要终点。没有进行正式的假设检验进行亚组分析。

在意向治疗人群中，pembrolizumab 组有 141 名患者，安慰剂组有 140 名患者患有 dMMR 肿瘤。在此中期分析中，无病生存期的风险比有利于 pembrolizumab（0.31 [95% CI，0.14 至 0.69]）；两组的中位无病生存期均未达到。两年无病生存率分别为 92.4%（95% CI，84.4 至 96.4）和 80.2%（95% CI，70.8 至 86.9）。未出现新的安全信号。最终分析时将评估长期随访结果。

根据研究分层因素进行的预先计划的亚组分析表明，派姆单抗联合 化疗可改善无病生存期，并且对于以治愈为目的的 dMMR 肿瘤患者具有临床意义。

Investigators reported a protocol-prespecified subgroup analysis of patients with newly diagnosed, high-risk endometrial cancer who had mismatch repair-deficient (dMMR) tumors after curative surgery in the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (NCT04634877). Patients were randomly assigned to receive pembrolizumab 200 mg or placebo every 3 weeks (for six cycles) plus carboplatin-paclitaxel (four to six cycles) followed by pembrolizumab 400 mg or placebo every 6 weeks (for six cycles). Patients received radiation therapy at the discretion of the investigator. Investigator-assessed disease-free survival was the primary endpoint. Subgroup analyses were performed without formal hypothesis testing.

In the intention-to-treat population, 141 patients in the pembrolizumab group and 140 patients in the placebo group had dMMR tumors. At this interim analysis, the hazard ratio for disease-free survival favored pembrolizumab (0.31 [95% CI, 0.14 to 0.69]); median disease-free survival was not reached in either group. Two-year disease-free survival rates were 92.4% (95% CI, 84.4 to 96.4) and 80.2% (95% CI, 70.8 to 86.9), respectively. No new safety signals emerged. Long-term follow-up outcomes will be assessed at the final analysis.

Preplanned subgroup analyses according to study stratification factors showed that the improvement in disease-free survival with the addition of pembrolizumab to chemotherapy was clinically meaningful in patients with dMMR tumors who were treated with curative intent.

参考文献 Reference

Slomovitz BM et al. J Clin Onc 2025 ;43 :251

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依维莫司联合lanreotide相比于依维莫司单药治疗不可切除或复发性胃肠胰神经内分泌肿瘤 (1/26/2025)

Everolimus combined with lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumor

方法：将具有不良预后因素（Ki-67 标记指数 5-20% 或弥漫性肝转移）的 1 级或 2 级无功能性胃肠胰神经内分泌肿瘤 (GEP-NET) 患者随机分配（1:1）接受依维莫司（10 毫克/天）或 依维莫司/lanreotide（是合成的激素生长抑素, 120 毫克，每 28 天一次）治疗。主要终点是无进展生存期。关键次要终点是总体生存期，其他次要终点包括客观响应率, 疾病控制率和安全性。该研究基于以下假设：依维莫司的中位无进展生存期为 11.0 个月，预计依维莫司/lanreotide 可改善 4 个月（HR：0.73）。计划样本量为 250，总共需要 195 个事件，随访期为 1.5 年。

结果：2020 年 4 月至 2024 年 6 月期间，共入组 178 名患者，并于 2024 年 6 月对 145 名患者（依维莫司组 72 名，依维莫司/lanreotide组 73 名）进行了计划中的中期分析，数据截止日期为 2023 年 11 月。依维莫司组的中位中位无进展生存期为 11.5 个月，依维莫司/lanreotide 组的中位中位无进展生存期为 29.7 个月（HR 0.38 [99.91% CI 0.15–0.96]，P = 0.00017。总体生存期的 HR 为 0.97（95% CI：0.24-3.90）。 依维莫司组的客观响应率和疾病控制率分别为 8.7% (6/69) 和 87.0% (60/69)，依维莫司/lanreotide组的客观响应率和疾病控制率分别为 26.8% (19/71) 和 91.5% (65/71)。

依维莫司/lanreotide组的血液学和非血液学毒性都比依维莫司 组更常见。两组均未观察到与治疗相关的死亡。根据疗效结果，数据和安全监测委员会建议提前终止研究。

结论：与依维莫司单药治疗相比，依维莫司/lanreotide可显著延长无进展生存期，且依维莫司/lanreotide的安全性是可控的。对于具有不良预后因素的高分化 1/2 级 GEP-NET，依维莫司/lanreotide可能成为一线治疗的新标准。

Methods: Patients with grade 1 or 2 nonfunctional gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with adverse prognostic factors (Ki-67 labeling index  5-20% or diffuse liver metastases) were randomized (1:1) to everolimus (10 mg/day) or everolimus/lanreotide (synthetic version of somatostatin, 120 mg every 28 days). The primary endpoint was progression-free survival. The key secondary endpoint was overall survival, and other secondary endpoints included objective response rate, disease control rate, and safety. The study was based on the following assumptions: the median progression-free survival with everolimus was 11.0 months, and everolimus/lanreotide was expected to improve by 4 months (HR: 0.73). The planned sample size was 250, with a total of 195 events required and a follow-up period of 1.5 years.

Results: Between April 2020 and June 2024, 178 patients were enrolled, and a planned interim analysis was performed in June 2024 on 145 patients (72 in the everolimus group and 73 in the everolimus/lanreotide group), with a data cutoff of November 2023. The median progression-free survival was 11.5 months in the everolimus group and 29.7 months in the everolimus/lanreotide group (HR 0.38 [99.91% CI 0.15–0.96], P = 0.00017. The HR for overall survival was 0.97 (95% CI: 0.24-3.90). The objective response rate and disease control rate were 8.7% (6/69) and 87.0% (60/69) in the everolimus group and 26.8% (19/71) and 91.5% (65/71) in the everolimus/lanreotide group, respectively.

The hematological and non-hematological toxicities of the everolimus/lanreotide group were lower than those of the everolimus group. group. No treatment-related deaths were observed in either group. Based on the efficacy results, the Data and Safety Monitoring Board recommended early termination of the study.

Conclusion: Everolimus/lanreotide significantly prolonged progression-free survival compared with everolimus monotherapy, and the safety of everolimus/lanreotide was manageable. For well-differentiated grade 1/2 GEP-NET with adverse prognostic factors, everolimus/lanreotide may become a new standard for first-line treatment.

参考文献 Reference

Hijioka S et al. 225 ASCO GICancer Symp Abstr 625

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Siremadlin 和 ribociclib 用于晚期脂肪肉瘤 (1/26/2025)

Siremadlin and ribociclib used in advanced liposarcoma

这是一项II期临床试验（MEGAMOST），旨在评估与晚期实体瘤的分子改变相匹配的分子驱动治疗的安全性和疗效。研究显示了ribociclib（CDK4/6 抑制剂） 和Siremadlin  (p53-MDM2 抑制剂）队列的结果。  

方法: 参加试验的晚期实体瘤患者存在 CDK6 和/或 CDK4 扩增和/或 CDKN2A 纯合缺失，和/或 CCND1 和/或 CCND3 扩增，且不存在 RB1 拷贝数缺失/丢失超过一个且 P53 野生型(包括 WD/DD-生存脂肪肉瘤, well-differentiated/de-differentiated）。 主要终点是 3 个月后的无进展率。次要终点是 3 个月后的客观响应率, 最佳总体响应, 无进展生存期 , 总生存期 , 长期响应者百分比 (> 6 个月) 和安全性概况。

结果: 纳入的 50 名患者中，49 名可评估（中位年龄 63 岁 [27-79]；42.9% 为女性），包括 17 名 WD/DD-脂肪肉瘤（15 名 DD 和 2 名 WD）和 32 名其他组织型。所有脂肪肉瘤均含有 MDM2/CDK4 扩增，而其他脂肪肉瘤的分子改变则不均一。先前的治疗线中位数为 2 [0-5]。21 名患者（42%）报告了 ≥3 级相关不良事件，主要是贫血 (8%) 和恶心 (6%)。暴露时间中位数为 2.8 个月 [0.7; 32.4]。3 个月后的无进展生存率为 41.2% [95% CI：28.2； 54.8]，估计3 个月后的无进展生存率 ≥ 40%（有效率边界）的预测概率为 56%，3 个月后的客观响应率为 0，有 2 例晚期部分响应（均为脂肪肉瘤患者）。中位 无进展生存期为 2.8 个月 [95%CI：2.4；5.1]，中位总生存期为 10.7 个月 [95%CI：7.6；13.8]。在分析时，一名患者被认为是长期应答者（21 个月）。在脂肪肉瘤组中，3 个月后的无进展生存率为 78.9% [95% CI：58.6；93.6]，中位无进展生存期为  8.3 个月 [95%CI：5.2； 19.5]，6 个月无进展生存率为 52.9% [95%CI：27.6-73]，中位总生存期为 23.0 个月 [95%CI：10.9；NE]。   

结论: Siremadlin 和 ribociclib在晚期 MDM2-CDK4 扩增的脂肪肉瘤患者中表现出可控的安全性和一定的疗效，而在其他以不同分子改变为特征的癌症中，结果则不理想。

This is a phase II clinical trial (MEGAMOST) designed to evaluate the safety and efficacy of molecularly driven therapies matched to molecular alterations in advanced solid tumors. The study presented results from the ribociclib (CDK4/6 inhibitor) and siremadlin (p53-MDM2 inhibitor) cohorts.

Methods: Patients with advanced solid tumors with CDK6 and/or CDK4 amplification and/or CDKN2A homozygous deletion, and/or CCND1 and/or CCND3 amplification, without more than one RB1 copy number deletion/loss and P53 wild-type (including WD/DD-liposarcoma, well-differentiated/de-differentiated) were enrolled in the trial. The primary endpoint was progression-free survival rate after 3 months. Secondary endpoints were objective response rate after 3 months, best overall response, progression-free survival, overall survival, percentage of long-term responders (> 6 months) and safety profile.

Results: Of the 50 patients enrolled, 49 were evaluable (median age 63 years [27-79]; 42.9% female), including 17 WD/DD-liposarcoma (15 DD and 2 WD) and 32 other histotypes. All liposarcoma harbored MDM2/CDK4 amplification, whereas other liposarcoma molecular alterations were heterogeneous. The median number of prior lines of therapy was 2 [0-5]. Twenty-one patients (42%) reported grade ≥3 related adverse events, primarily anemia (8%) and nausea (6%). The median duration of exposure was 2.8 months [0.7; 32.4]. Twenty patients were in succcess, with a progression-free survival rate of 41.2% [95% CI: 28.2; 54.8] after 3 months, an estimated predicted probability of a progression-free survival rate ≥ 40% (response margin) after 3 months of 56%, an objective response rate of 0 after 3 months, and 2 late partial responses (both in patients with liposarcoma). The median progression-free survival was 2.8 months [95% CI: 2.4; 5.1], and the median overall survival was 10.7 months [95% CI: 7.6; 13.8]. At the time of analysis, one patient was considered a long-term responder (21 months). In the liposarcoma group, the progression-free survival rate after 3 months was 78.9% [95%CI: 58.6; 93.6], the median progression-free survival was 8.3 months [95%CI: 5.2; 19.5], the progression-free survival rate at 6 months was 52.9% [95%CI: 27.6-73], and the median overall survival was 23.0 months [95%CI: 10.9; NE].

Conclusions: Siremadlin and ribociclib showed manageable safety and moderate efficacy in patients with advanced MDM2-CDK4-amplified liposarcoma, while the results were less favorable in other cancers characterized by different molecular alterations.

参考文献 Reference

Brahmi M et al. Ann Onc 2024 ; 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623

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¹⁷⁷Lu-Dotatate 对手术和放射治疗无效的脑膜瘤患者的前瞻性 II 期研究 (1/19/2025)

A prospective, phase II study of ¹⁷⁷Lu-dotatate in Patients with surgery- and radiation-Refractory meningioma

脑膜瘤通常通过手术和/或放射治疗进行治疗。然而，WHO II 级和 III 级脑膜瘤的复发率分别高达 40-80%。每次复发，安全有效的挽救方案很快就会耗尽。由于几乎所有脑膜瘤都表达生长抑素受体，研究者评估了镥¹⁷⁷ (¹⁷⁷Lu)-Dotatate 对难治性脑膜瘤的疗效。

方法: 这是一项在Mayo Clinic   (Rochester) 进行的单组 II 期临床试验。符合条件的患者包括那些手术和放射治疗难治性脑膜瘤且疾病可测量且 6 个月内生长率≥ 15% 的患者。进行了 ⁶⁸Ga-DOTATATE PET/MRI 检查，177Lu-Dotatate 的剂量为 7.4 GBq (200 mCi)，每 8 周一次，共给药 4 次。每次给药前进行脑部 MRI 检查。主要终点是 6 个月无进展生存期 (PFS-6)。 PFS-6 超过既定的 RANO 历史基准 26%，表明这是一种有希望的治疗方法。次要终点包括 PFS, 总生存期和至少可能与研究药物相关的不良事件发生率。单独的 WHO I 级队列继续招募。

结果: 从 2020 年 4 月到 2023 年 4 月，筛选了 26 名患者，其中 20 名符合所有资格要求并被纳入 WHO II/III 级队列。中位年龄为 66.8 岁（范围 = 38.9-85.0），95% 患有 WHO II 级脑膜瘤。总共有 40% 的患者有癫痫病史，65% 的患者有与难治性肿瘤相关的神经系统缺陷病史，尽管只有 15% 的患者在入组时正在接受皮质类固醇治疗。45%、45% 和 10% 的患者分别观察到 Krenning 评分为 2、3 和 4。PFS-6 和中位 PFS 分别为 77.8% (95% CI = 52-94) 和 10.7 个月。未达到中位生存期。1 年总生存期为 88.5% (95% CI = 47-96)。没有可归因于治疗的 4 级或 5 级不良事件发生率。共有 10 名患者出现 3 级血液学不良事件发生率，其中两名患者出现 3  级肝炎 (n = 1) 和 3 级癫痫 (n = 1)，至少可能归因于治疗。 5 名患者由于可能与治疗相关的不良反应 (n = 2)、肿瘤进展 (n = 2) 和其他合并症 (n = 1) 而未完成全部 4 次给药。

结论: 这项 II 期临床试验达到了 PFS-6 的主要终点，该药物产生了显著的临床疗效，超越了既定的临床基准，具有合理的安全性。

Meningiomas are usually treated with surgery and/or radiation therapy. However, recurrence rates for WHO grade II and grade III meningiomas are as high as 40-80%, respectively. With each recurrence, avilable safe and effective salvage options are quickly exhausted. Since almost all meningiomas express somatostatin receptors, the researchers evaluated the efficacy of lutetium-177 (177Lu)-Dotatate in refractory meningiomas.

Methods: This was a single-arm, phase II clinical trial conducted at Mayo Clinic (Rochester). Eligible patients included those with meningiomas refractory to surgery and radiation therapy with measurable disease and a growth rate of ≥ 15% within 6 months. ⁶⁸Ga-DOTATATE PET/MRI was performed, and ¹⁷⁷Lu-Dotatate was administered at a dose of 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses. Brain MRI was performed before each dose. The primary endpoint was progression-free survival at 6 months (PFS-6). PFS-6 exceeded the established historical RANO benchmark by 26%, indicating that this is a promising treatment approach. Secondary endpoints included PFS, overall survival, and the incidence of adverse events that were at least possibly related to the study drug. Enrollment in the separate WHO grade I cohort continues.

Results: From April 2020 to April 2023, 26 patients were screened, of whom 20 met all eligibility requirements and were included in the WHO grade II/III cohort. The median age was 66.8 years (range = 38.9-85.0), and 95% had WHO grade II meningiomas. In total, 40% of patients had a history of epilepsy and 65% had a history of neurologic deficits related to refractory tumors, although only 15% were receiving corticosteroids at enrollment. Krenning scores of 2, 3, and 4 were observed in 45%, 45%, and 10% of patients, respectively. PFS-6 and median PFS were 77.8% (95% CI = 52-94) and 10.7 months, respectively. Median survival was not reached. One-year overall survival was 88.5% (95% CI = 47-96). There were no grade 4 or 5 adverse events attributable to treatment. A total of 10 patients experienced grade 3 hematologic adverse events, including two patients with grade 3 hepatitis (n = 1) and grade 3 seizures (n = 1) that were at least possibly attributable to treatment. Five patients did not complete all 4 doses due to adverse reactions that were possibly related to treatment (n = 2), tumor progression (n = 2), and other comorbidities (n = 1).

Conclusion: This phase II clinical trial achieved the primary endpoint of PFS-6, and the drug produced significant clinical efficacy, surpassing the established clinical benchmark, with a reasonable safety profile.

参考文献 Reference

Merrell KW et al. Int J Radia Onc  Biol Physics 2024:120 (2 Suppl_S11)

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FDA 批准 datopotamab deruxtecan-dlnk 用于治疗不可切除或转移性, HR 阳性、HER2 阴性乳腺癌 (1/18/2025)

FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer

2025 年 1 月 17 日，FDA批准 datopotamab deruxtecan-dlnk，一种 Trop-2 定向抗体和拓扑异构酶抑制剂偶联物，用于治疗不可切除或转移性, 激素受体 (HR) 阳性, HER2 阴性 (IHC 0、IHC1+ 或 IHC2+/ISH-) 乳腺癌患者，这些患者之前曾接受过内分泌治疗和化疗。 在一项多中心, 开放标签, 随机试验 TROPION-Breast01 (NCT05104866) 中评估了疗效。患者必须经历疾病进展，被认为不适合进一步内分泌治疗，并且已经接受过一到两种无法切除或转移性疾病的化疗。对需要使用类固醇的间质性肺病/肺炎病史, 持续的间质性肺病/肺炎, 临床活动性脑转移或临床显著的角膜疾病的患者被排除在外。 随机分组按之前的化疗方案, 之前的 CDK4/6 抑制剂治疗和地理区域分层。共有 732 名患者被随机分配（1:1）接受 datopotamab deruxtecan-dlnk（n=365）或研究者选择的化疗（n=367）；eribulin（60%）, 卡培他滨（21%）, 长春瑞滨（10%）或吉西他滨（9%）。 主要疗效结果指标为无进展生存期, 以及总生存期。其他疗效结果包括客观响应率和响应持续时间。

Datopotamab deruxtecan-dlnk 组的中位无进展生存期为 6.9 个月 (95% CI: 5.7, 7.4)，化疗组的中位无进展生存期为 4.9 个月 (95% CI: 4.2, 5.5)（风险比 0.63 [95% CI: 0.52, 0.76] 双侧 p 值 <0.0001）。 Datopotamab deruxtecan-dlnk 组的中位总生存期为 18.6 个月（95% CI：17.3, 20.1），化疗组的中位总生存期为 18.3 个月（95% CI：17.3, 20.5）（风险比 1.01 [95% CI：0.83, 1.22]；双侧 p 值无统计学意义）。Datopotamab deruxtecan-dlnk 和化疗组的确认客观响应率分别为 36%（95% CI：31, 42）和 23%（95% CI：19, 28），中位响应持续时间分别为 6.7 个月（95% CI：5.6, 9.8）和 5.7 个月（95% CI：4.9, 6.8）。

最常见的不良反应（≥20%）包括实验室异常，包括口腔炎, 恶心, 疲劳, 白细胞减少, 钙减少, 脱发, 淋巴细胞减少, 血红蛋白减少, 便秘, 中性粒细胞减少, 干眼症, 呕吐, ALT 升高, 角膜炎, AST 升高和碱性磷酸酶升高。

Datopotamab deruxtecan-dlnk 的推荐剂量为 6 mg/kg（≥90 kg 患者最大剂量为 540 mg），以静脉输注方式给药，每 3 周一次（21 天为一个周期），直至病情进展或出现不可接受的毒性。

On January 17, 2025, the FDA approved datopotamab deruxtecan-dlnk, a Trop-2 directed antibody and topoisomerase inhibitor conjugate, for the treatment of patients with unresectable or metastatic, hormone receptor (HR)-positive, HER2-negative (IHC 0, IHC1+, or IHC2+/ISH-) breast cancer who have previously received endocrine therapy and chemotherapy. Efficacy was evaluated in a multicenter, open-label, randomized trial, TROPION-Breast01 (NCT05104866). Patients must have experienced disease progression. They were considered ineligible for further endocrine therapy, and have received one to two prior lines of chemotherapy for unresectable or metastatic disease. Patients with a history of interstitial lung disease/pneumonitis requiring steroids, persistent interstitial lung disease/pneumonitis, clinically active brain metastases, or clinically significant corneal disease were excluded. Randomization was stratified by prior chemotherapy regimen, prior CDK4/6 inhibitor treatment, and geographic region. A total of 732 patients were randomized (1:1) to receive datopotamab deruxtecan-dlnk (n=365) or investigator’s choice of chemotherapy (n=367); eribulin (60%), capecitabine (21%), vinorelbine (10%), or gemcitabine (9%). The primary efficacy outcome measures were progression-free survival, and overall survival. Other efficacy outcomes included objective response rate and duration of response.

The median progression-free survival was 6.9 months (95% CI: 5.7, 7.4) in the datopotamab deruxtecan-dlnk group and 4.9 months (95% CI: 4.2, 5.5) in the chemotherapy group (hazard ratio 0.63 [95% CI: 0.52, 0.76]; two-sided p-value <0.0001). The median overall survival was 18.6 months (95% CI: 17.3, 20.1) in the datopotamab deruxtecan-dlnk group and 18.3 months (95% CI: 17.3, 20.5) in the chemotherapy group (hazard ratio 1.01 [95% CI: 0.83, 1.22]; two-sided p-value not statistically significant). The confirmed objective response rates were 36% (95% CI: 31, 42) and 23% (95% CI: 19, 28) in the datopotamab deruxtecan-dlnk and chemotherapy groups, respectively, and the median duration of response was 6.7 months (95% CI: 5.6, 9.8) and 5.7 months (95% CI: 4.9, 6.8), respectively.

The most common adverse reactions (≥20%) included laboratory abnormalities, including stomatitis, nausea, fatigue, leukopenia, calcium decrease, alopecia, lymphopenia, hemoglobin decrease, constipation, neutropenia, dry eyes, vomiting, ALT increase, keratitis, AST increase, and alkaline phosphatase increase.

The recommended dose of datopotamab deruxtecan-dlnk is 6 mg/kg (maximum dose 540 mg for patients ≥90 kg) administered as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast

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Metformin (二甲双胍)对肥胖症和肺癌预后和免疫治疗效果的改善(1/12/2025)

Obesity-specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin

方法: 研究者回顾性分析了 2 个临床队列，并使用互补的小鼠模型来检验我们的假设。一组包括体重超重（≥ 25 kg/m2，n = 511）和非体重超重（< 25 kg/m2，n = 232）的接受肺叶切除术的非小细胞肺癌病人，评估二甲双胍对临床结果的影响。另一组研究了二甲双胍对超重（n = 284）和非超重（n = 184）非小细胞肺癌患者免疫检查点抑制剂治疗后无进展生存期的影响。使用肺癌模型评估了二甲双胍对肥胖和正常体重小鼠的肿瘤进展, 抗肿瘤免疫和免疫检查点抑制剂反应的影响。

结果: 二甲双胍与肺叶切除术后超重病人的无复发生存期增加有关（风险比 [HR] = 0.47，95% 置信区间 [CI] = 0.24 至 0.94；P = .035）。它还以淋巴细胞特异性方式纠正了饮食诱导的肥胖小鼠模型中加速的肿瘤生长，同时逆转了肥胖增强的几种免疫抑制机制。程序性细胞死亡阻断与二甲双胍联合使用在限制肥胖小鼠的肿瘤负担方面更有效，并且仅在接受免疫治疗的超重患者中与无进展生存期相关（HR = 0.60，95% CI = 0.39 至 0.93；P = .024）。  

结论: 二甲双胍可以改善肥胖和超重肺癌病人的肺癌特异性临床结果，并增强这一不断增长的人群的免疫治疗效果。这项研究将肥胖确定为二甲双胍在肺癌中抗癌和免疫治疗增强特性的潜在预测生物标志物，同时揭示了潜在的免疫现象。

Methods: The researchers retrospectively analyzed 2 clinical cohorts and used complementary mouse models to test our hypotheses. One cohort included overweight (≥ 25 kg/m2, n = 511) and nonoverweight (< 25 kg/m2, n = 232) patients with NSCLC undergoing lobectomy to evaluate the effect of metformin on clinical outcomes. The other cohort investigated the effect of metformin on progression-free survival after immune checkpoint inhibitor treatment in overweight (n = 284) and nonoverweight (n = 184) patients with NSCLC. The effects of metformin on tumor progression, antitumor immunity, and immune checkpoint inhibitor response were evaluated in obese and normal-weight mice using lung cancer models.

Results: Metformin was associated with increased recurrence-free survival in overweight patients after lobectomy (hazard ratio [HR] = 0.47, 95% confidence interval [CI] = 0.24 to 0.94; P = .035). It also corrected accelerated tumor growth in a diet-induced obese mouse model in a lymphocyte-specific manner, while reversing several obesity-enhanced immunosuppressive mechanisms. Programmed cell death blockade combined with metformin was more effective in limiting tumor burden in obese mice and was associated with improved progression-free survival in overweight patients receiving immunotherapy (HR = 0.60, 95% CI = 0.39 to 0.93; P = .024).

Conclusions: Metformin may improve lung cancer-specific clinical outcomes in obese and overweight lung cancer patients and enhance the efficacy of immunotherapy in this growing population. This study identifies obesity as a potential predictive biomarker for the anticancer and immunotherapy-enhancing properties of metformin in lung cancer, while shedding light on underlying immune phenomena.

参考文献 Reference

Smith RJ Jr. J Natl Cancer Inst. 2024; https://doi.org/10.1093/jnci/djae295

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年轻人与老年人的结肠直肠癌发病率趋势：癌症登记数据分析 (1/11/2025)

Colorectal cancer incidence trends in younger versus older adults: population-based cancer registry data

先前的研究表明，在多个高收入西方国家，年轻人（年龄 <50 岁）的结肠直肠癌发病率正在增加，而老年人（年龄 ≥50 岁）的发病率则保持稳定或下降趋势。本研究旨在调查年轻人与老年人的当代结肠直肠癌发病率趋势。

方法: 从世卫组织-国际癌症研究机构五大洲癌症发病率数据库中提取了 50 个国家和地区的结肠直肠癌发病率数据，包括诊断年份, 性别和 5 岁年龄组。2022 年人类发展指数来自联合国发展计划署，分为非常高 (>0.80), 高 (0.70–0.79), 中等 (0.55–0.69) 和低 (<0.55) 类。早发性为25 至 49 岁之间诊断, 晚发性为50 至 74 岁之间诊断。研究每 100 ,000 人年的年龄标准化发病率 (ASR)。主要研究目标是研究当代年轻人与老年人的结肠直肠癌发病率趋势。按诊断年龄分层（25-49 岁或 50-74 岁）, 估计年均百分比变化 (AAPC)。   

结果: 最近 5 年,早发性结直肠癌发病率最高的国家为澳大利亚（ASR 16.5 [95% CI 16.1-16.9]）, 美国（波多黎各；15.2 [14.2-16.2]）, 新西兰（14.8 [14.0-15.6]）, 美国（14.8 [14.7-14.9]）和韩国（14.3 [14.0-14.5]），最低的是乌干达（4.4 [3.6-5.2]）和印度（3.5 [3.3-3.7]）。老年人群发病率最高的国家是荷兰（168.4 [166.9–170.0]）和丹麦（158.3 [155.8–160.9]），最低的国家是乌干达（45.9 [38.5–51.4]）和印度（23.5 [22.8–24.3]）。就年均百分比变化而言，最近10年，23个国家早发性结直肠癌发病率保持稳定，但27个国家的发病率有所上升，年增幅最大的国家是新西兰（AAPC 3.97% [95% CI 2.44–5.52]）, 智利（3.96% [1.26–6.74]）, 波多黎各（3.81% [2.68–4.96]）和英格兰（3.59% [3.12–4.06]）。 27 个国家和地区中，有 14 个国家和地区的老年人口趋势稳定（阿根廷、法国、爱尔兰、挪威和波多黎各）或下降（澳大利亚, 加拿大, 德国, 以色列, 新西兰, 斯洛文尼亚, 英格兰, 苏格兰和美国）。

解释: 在接受调查的 50 个国家和地区中，有 27 个国家和地区的早发性结直肠癌发病率正在上升，其中 20 个国家的发病率上升速度要么是早发性疾病独有的，要么比老年人发病率的上升速度更快。研究结果强调，需要加大力度找出推动这些趋势的因素，并提高认识，以促进早期发现。

Previous studies have shown that the incidence of colorectal cancer is increasing in young adults (age <50 years) in several high-income Western countries, whereas the incidence in older adults showed a stabilizing or decreasing trends in incidence in older adults (age ≥50 years). This study aimed to investigate contemporary trends in colorectal cancer incidence in younger versus older adults. Methods: Data on colorectal cancer incidence for 50 countries and territories were extracted from the WHO-IARC Five Continents Cancer Incidence Database, including year of diagnosis, sex, and 5-year age groups. The 2022 Human Development Index was obtained from the United Nations Development Program and was categorized into very high (>0.80), high (0.70–0.79), moderate (0.55–0.69), and low (<0.55). Early onset was diagnosed between 25 and 49 years of age, and late onset was diagnosed between 50 and 74 years of age. Age-standardized incidence rates (ASRs) per 100 ,000 person-years were studied. The primary study objective was to investigate contemporary trends in colorectal cancer incidence in younger versus older adults and estimated average annual percentage change (AAPC) by age at diagnosis (25-49 years or 50-74 years).

Results: In the most recent 5 years (most countryies from 2013 to 2017), the countries with the highest incidence of early-onset colorectal cancer were Australia (ASR 16.5 [95% CI 16.1-16.9]), the United States (Puerto Rico; 15.2 [14.2-16.2]), New Zealand (14.8 [14.0-15.6]), the United States (14.8 [14.7-14.9]), and South Korea (14.3 [14.0-14.5]). The lowest were Uganda (4.4 [3.6-5.2]) and India (3.5 [3.3-3.7]). The highest incidence rates among the elderly were in the Netherlands (168.4 [166.9–170.0]) and Denmark (158.3 [155.8–160.9]), and the lowest rates were in Uganda (45.9 [38.5–51.4]) and India (23.5 [22.8–24.3]). In terms of average annual percentage change, the incidence of early-onset colorectal cancer remained stable in 23 countries over the past 10 years, but increased in 27 countries, with the largest annual increases in New Zealand (AAPC 3.97% [95% CI 2.44–5.52]), Chile (3.96% [1.26–6.74]), Puerto Rico (3.81% [2.68–4.96]), and England (3.59% [3.12–4.06]). In 14 of the 27 countries and territories, trends in the older population were stable (Argentina, France, Ireland, Norway, and Puerto Rico) or declining (Australia, Canada, Germany, Israel, New Zealand, Slovenia, England, Scotland, and the United States).

Interpretation: Early-onset colorectal cancer rates are increasing in 27 of the 50 countries and territories surveyed, and in 20 of these countries the rate of increase is either unique to early-onset disease or faster than the rate of increase in older adults. The findings highlight the need for greater efforts to identify the factors driving these trends and to increase awareness to promote early detection.

参考文献 Reference

Sung H  et al. Lancet Onc 2025;26:51

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蒽环类药物对复发评分>31淋巴结阴性 HR+/HER2- 乳腺癌的影响 (1/5/2025)

Impact of anthracyclines in RS >31 node-negative HR+/HER2- breast cancer

背景：对于激素受体阳性乳腺癌患者，在含紫杉烷的化疗中添加蒽环类药物并不能明显改善无侵袭性疾病生存率,  但尚未研究蒽环类药物对高 Oncotype DX 复发评分 (RS) 患者的益处。

方法：研究者分析了 TAILORx 试验 (NCT00310180) 中接受紫杉烷 + 蒽环类/环磷酰胺和类似方案 (T-AC) 或紫杉烷 + 环磷酰胺 (TC) 化疗的患者的数据，该试验招募了 I/II 期, 淋巴结阴性, HR+/HER2 阴性乳腺癌患者。RS 在 11 至 25 之间的患者随机接受内分泌治疗或内分泌治疗加医生选择的化疗，而 RS > 26 的患者接受医生选择的化疗。使用调整后的风险比 (aHR) 比较了远处无复发间隔, 无复发间隔, 远处无复发生存期, 无复发生存期和总生存期。结果按 RS > 31 和 < 31 分层。  

结果：在符合条件的 2,528 例病例中，437 例接受 T-AC 治疗，2,091 例接受 TC 治疗。 T-AC 组的治疗方案包括1) 蒽环类 + 环磷酰胺（剂量密集或 标准），然后接受紫杉烷（n = 298, 68%），2) 同时接受蒽环类, 环磷酰胺和 多西他赛（n = 59, 14%），3) 其他蒽环类 + 紫杉烷组合（n = 80, 18%）。 TC 组所有患者均接受紫杉烷和环磷酰胺治疗。32% 的患者 RS > 26（n = 816），20% 的患者 RS > 31（n = 501）。平均年龄为 55 岁，中位随访时间为 7.3 年。

与接受 TC 治疗的患者相比，接受 T-AC 治疗的患者 RS 更高（平均 30 vs 23），肿瘤更大（平均 20 毫米 vs 18 毫米），并且高级别的可能性更大（38% 高级别 vs 25%）。在调整协变量后 RS > 31 的患者中，接受 T-AC 与 5 年结果改善相关，T-AC 组的远处无复发间隔调整率为 97.5%, TC 组为 89.4%（aHR 0.27，p = 0.01），TAC 组的远处无复发间隔调整率为 96.5%，TC 组为 88.3%（aHR 0.45，p = 0.03），T-AC 组的无复发生存期调整 5 年率为 94.6%，TC 组为 86.6%； aHR 0.45，p = 0.02)，且 5 年总生存期有改善趋势 （T-AC 组调整后比率为 97.7%，TC 组为 92.5%；aHR 0.58，p = 0.22）。

在 RS < 31 的病例中，接受 T-AC 与远处无复发间隔改善 (aHR 1.12，p = 0.73), 远处无复发生存期 (aHR 1.09，p = 0.75) 或其他结果改善无关。样条回归估计表明随着 RS 的增加，蒽环类药物的益处增加。   

结论：早期, HR+/HER2 阴性乳腺癌和高 RS 值（> 31）患者可能从辅助紫杉烷和含蒽环类药物的治疗中获益多于从 TC 中获益。

Background: For patients with hormone receptor (HR)-positive breast cancer, the addition of anthracyclines to taxane-containing chemotherapy does not significantly improve invasive disease-free survival, but the benefit of anthracyclines in patients with high Oncotype DX recurrence scores (RS) has not been studied.

Methods: The researchers analyzed data from patients who received either taxane + anthracycline/cyclophosphamide and similar regime (T-AC) or taxane + cyclophosphamide (TC) chemotherapy in the TAILORx trial (NCT00310180), which enrolled patients with stage I/II, node-negative, HR+/HER2-negative breast cancer. Patients with RS between 11 and 25 were randomized to endocrine therapy or endocrine therapy plus physician’s choice of chemotherapy, whereas patients with RS > 26 received physician’s choice of chemotherapy. Distant recurrence-free interval (DRFI), recurrence-free interval (RFI), distant recurrence-free survival, recurrence-free survival (RFS), and overall survival (OS) were compared using adjusted hazard ratios (aHRs). Results were stratified by RS > 31 and < 31.

Results: Of the 2,528 eligible cases, 437 were treated with T-AC and 2,091 with TC. Treatment regimens in the T-AC group included 1) anthracycline + cyclophosphamide (dose-dense or standard) followed by taxane (n = 298, 68%), 2) concurrent anthracycline, cyclophosphamide, and docetaxel (n = 59, 14%), and 3) other anthracycline + taxane combinations (n ​​= 80, 18%). All patients in the TC group received taxane and cyclophosphamide. Among them, 32% of patients had RS > 26 (n = 816), and 20% had RS > 31 (n = 501). The mean age was 55 years, and the median follow-up was 7.3 years. Patients treated with T-AC had higher RS ​​(mean 30 vs 23), larger tumors (mean 20 vs 18 mm), and were more likely to be high grade (38% high grade vs 25%) compared with those treated with TC. Among patients with RS > 31 after adjustment for covariates, receiving T-AC was associated with improved 5-year outcomes, with adjusted rates of DRFI of 97.5% in the T-AC group and 89.4% in the TC group (aHR 0.27, p = 0.01), adjusted rates of distant recurrence-free interval of 96.5% in the TAC group and 88.3% in the TC group (aHR 0.45, p = 0.03), and adjusted 5-year rates of recurrence-free survival of 94.6% in the T-AC group and 86.6% in the TC group; aHR 0.45, p = 0.02), and a trend towards improved 5-year overall survival (adjusted rates 97.7% in the T-AC group and 92.5% in the TC group; aHR 0.58, p = 0.22).

In cases with RS < 31, receiving T-AC was not associated with improved distant recurrence-free interval (aHR 1.12, p = 0.73), distant recurrence-free survival (aHR 1.09, p = 0.75), or other outcomes. Spline regression estimates indicated that the benefit of anthracyclines increased with increasing RS.

Conclusions: Patients with early-stage, HR+/HER2-negative breast cancer and high RS values ​​(> 31) may benefit more from adjuvant taxane- and anthracycline-containing therapy than from TC.

参考文献 Reference

Chen N  2024 San Antonio Breast Cancer Symposium (SABCS; Abstract GS3-03)

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新一代雌激素受体降解剂 Imlunestrant+/-阿贝西尼治疗晚期乳腺癌 (1/4/2025)

Next-generation ER degrader Imlunestrant with or without abemaciclib for advanced breast cancer

Imlunestrant 是一种新一代脑渗透性口服选择性雌激素受体 (ER) 降解剂，即使对于 ERα 编码基因 (ESR1) 发生突变的癌症，也能持续抑制 ER。

方法: 在一项 III 期开放标签试验中 (NCT04975308)，研究者招募了 ER 阳性, HER2 阴性的晚期乳腺癌患者，这些患者在芳香化酶抑制剂单独使用或与细胞周期依赖性激酶 4 和 6 (CDK4/6) 抑制剂一起使用期间或之后复发或进展。患者按 1:1:1 的比例分配接受 Imlunestrant、标准内分泌单药治疗或 Imlunestrant-阿贝西尼治疗。主要终点是研究者评估的在所有 ESR1 突变患者中，使用Imlunestrant与标准疗法相比的无进展生存期，以及在所有同时接受随机分组的患者中，使用Imlunestrant -阿贝西利与Imlunestrant相比的无进展生存期。

结果: 总体而言，874 名患者接受了随机分组，其中 331 名患者接受Imlunestrant治疗，330 名患者接受标准疗法治疗，213 名患者接受Imlunestrant -阿贝西利治疗。在 256 名 ESR1 突变患者中，使用Imlunestrant的中位无进展生存期为 5.5 个月，使用标准疗法的中位无进展生存期为 3.8 个月。在19.4 个月时, 估计的平均限制生存时间在使用Imlunestrant患者中为 7.9 个月（95% 置信区间 [CI]，6.8 至 9.1），使用标准疗法的患者为 5.4 个月（95% CI，4.6 至 6.2）（差异为 2.6 个月；95% CI，1.2 至 3.9；P<0.001）。在总体人群中，使用Imlunestrant的患者中位无进展生存期为 5.6 个月，使用标准疗法的患者中位无进展生存期为 5.5 个月（进展或死亡风险比为 0.87；95% CI，0.72 至 1.04；P=0.12）。在 426 名接受Imlunestrant -阿贝马西利相比于Imlunestrant治疗的患者中，中位无进展生存期分别为 9.4 个月和 5.5 个月（风险比为 0.57；95% CI，0.44 至 0.73；P<0.001）。Imlunestrant治疗组 3 级或以上不良事件发生率为 17.1%，标准治疗组为 20.7%，Imlunestrant -阿贝马西利治疗组为 48.6%。

结论: 在 ER 阳性、HER2 阴性晚期乳腺癌患者中，接受Imlunestrant治疗的患者（ESR1 突变患者）的无进展生存期明显长于标准治疗，但总体人群并非如此。与Imlunestrant相比，Imlunestrant -阿贝马西利显著改善了无进展生存期，无论 ESR1 突变状态如何。

Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen receptor (ER) degrader that provides sustained ER inhibition even in cancers with mutations in the gene encoding ERα (ESR1).

Methods: In a phase III, open-label trial (NCT04975308), investigators enrolled patients with ER-positive, HER2-negative advanced breast cancer who had relapsed or progressed during or after an aromatase inhibitor alone or in combination with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib. The primary endpoints were investigator-assessed progression-free survival with imlunestrant compared with standard therapy in all patients with ESR1 mutations and with imlunestrant- abemaciclib compared with imlunestrant in all patients who underwent concurrent randomization.

Results: Overall, 874 patients underwent randomization, with 331 receiving imatinib, 330 receiving standard therapy, and 213 receiving imatinib- abemaciclib. Among the 256 patients with ESR1 mutations, median progression-free survival was 5.5 months with Imlunestrant and 3.8 months with standard therapy. At 19.4 months, the estimated mean restricted survival was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) in patients who received Imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) in those who received standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001). In the overall population, median progression-free survival was 5.6 months with Imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P=0.12). Among the 426 patients who received Imlunestrant-abemaciclib versus Imlunestrant, median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001).

Adverse events of grade 3 or higher occurred in 17.1% of  patients treated with Imlunestrant, 20.7% with standard therapy, and 48.6% with Imlunestrant-abemaciclib.

Conclusions: Among patients with ER-positive, HER2-negative advanced breast cancer, progression-free survival was significantly longer in patients treated with Imlunestrant (those with ESR1 mutations) than in the standard of care, but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival compared with Imlunestrant, regardless of ESR1 mutation status.

参考文献 Reference

Jhaveri KL et al. N Engl J Med Dec 11 2024. DOI: 10.1056/NEJMoa2410858