From Sorbonne Université and Hôpital Saint Antoine, Paris (T.A.), Bordeaux University Hospital, Bordeaux (D.S.), and Léon Bérard Center, Lyon (C.F.) - all in France; University College Hospital, NHS Foundation Trust, London (K.-K.S.); Asan Medical Center, University of Ulsan, Seoul, South Korea (T.W.K.); Herlev and Gentofte Hospital, Herlev (B.V.J.), and University Hospital of Southern Denmark, Vejle (L.H.J.) - both in Denmark; Amsterdam University Medical Center, University of Amsterdam, Amsterdam (C.P.); Hospital Universitario 12 de Octubre, Imas12, Madrid (R.G.-C.), Hospital Regional Universitario, Malaga (M.B.), Hospital Universitario Marques de Valdecilla, Santander (F.R.), and Vall d'Hebron Institute of Oncology, Barcelona (E.E.) - all in Spain; Western Health, St. Albans, VIC, Australia (P.G.); Sarah Cannon Research Institute-Tennessee Oncology, Nashville (J.B.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (D.T.L.); National Cancer Center Hospital East, Kashiwa, Japan (T.Y.); University Hospital Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.); MSD China, Beijing (P.Y.); Merck, Kenilworth, NJ (M.Z.H.F., P.M.); and Memorial Sloan Kettering Cancer Center, New York (L.A.D.).
N Engl J Med. 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699.
BACKGROUND: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown. METHODS: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival. RESULTS: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group. CONCLUSIONS: Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).
背景：程序性死亡受体 1（PD-1）阻断在先前治疗后具有微卫星不稳定性高（MSI-H）或错配修复缺陷（dMMR）肿瘤的临床获益。PD-1 阻断作为 MSI-H-dMMR 晚期或转移性结直肠癌的一线治疗与化疗相比的疗效尚不清楚。
方法：在这项 3 期、开放标签试验中，307 例先前未接受治疗的转移性 MSI-H-dMMR 结直肠癌患者以 1:1 的比例随机分配，接受派姆单抗（200mg，每 3 周一次）或化疗（基于氟尿嘧啶的治疗，联合或不联合贝伐珠单抗或西妥昔单抗），每 2 周一次。接受化疗的患者在疾病进展后可以交叉接受派姆单抗治疗。两个主要终点是无进展生存期和总生存期。
结果：在第二次中期分析时，中位随访（从随机分组到数据截止）时间为 32.4 个月（范围 24.0 至 48.3），与化疗相比，派姆单抗在无进展生存期方面具有优势（中位无进展生存期 16.5 个月 vs. 8.2 个月；风险比 0.60；95%置信区间 [CI] 0.45 至 0.80；P=0.0002）。24 个月随访后估计的限制性平均生存时间为 13.7 个月（范围 12.0 至 15.4），而 10.8 个月（范围 9.4 至 12.2）。截至数据截止日期，派姆单抗组有 56 例患者和化疗组有 69 例患者死亡。总生存数据仍在演变中（所需事件的 66%已经发生），并且在最终分析之前仍然保持盲法。根据实体瘤反应评价标准（RECIST）1.1 评估的总缓解（完全或部分缓解），派姆单抗组为 43.8%，化疗组为 33.1%。在总缓解的患者中，派姆单抗组 83%的患者，与化疗组 35%的患者相比，在 24 个月时有持续缓解。派姆单抗组发生 3 级或更高级别的治疗相关不良事件的比例为 22%，而化疗组为 66%（包括 1 例死亡患者）。
结论：与化疗相比，派姆单抗作为 MSI-H-dMMR 转移性结直肠癌的一线治疗可显著延长无进展生存期，且治疗相关不良事件较少。（由默克公司和 Stand Up to Cancer 资助；KEYNOTE-177 ClinicalTrials.gov 编号，NCT02563002）。
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