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 Vβ 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 (PM2.5)和乳腺癌发病率 (2/2/2025)
PM2.5 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 PM2.5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 PM2.5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 PM2.5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 PM2.5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 PM2.5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 PM2.5 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 PM2.5 associations (heterogeneity = .046). In a meta-analysis of the Multiethnic Cohort Study and 10 other prospective cohorts, breast cancer incidence was associated with PM2.5 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 PM2.5 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 PM2.5 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
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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