From Sorbonne Université, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Unité Mixte de Recherche Scientifique 938, and SIRIC CURAMUS, Paris (T.A.), Hopital Foch, Suresnes (J.B.), and Institut Paoli-Calmettes (C.F.), and La Timone, Aix Marseille Université (L.D.), Marseille - all in France; Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona (E.E.), Hospital Universitario Virgen del Rocío, Seville (M.L.L.), Institut Català d'Oncologia, Hospital Universitario Germans Trias i Pujol, Badalona (J.L.M.M.), and Hospital Universitario 12 de Octubre, Imas12, Medicine Department-UCM, Madrid (R.G.-C.) - all in Spain; University Hospitals Gasthuisberg and University of Leuven (KU Leuven), Leuven, Belgium (E.V.C.); the University Hospital of Southern Denmark, Vejle Hospital, Vejle (L.H.J.); Hospital Universitario Fundacion Favaloro, Buenos Aires (G.M.); Centrul de Oncologie Sf Nectarie, Craiova, Romania (M.S.); the National Cancer Center Hospital East, Chiba, Japan (T.Y.); Shanghai East Hospital, Shanghai, China (J.L.); the University of Southern California Norris Comprehensive Cancer Center, Los Angeles (H.-J.L.); Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome (G.T.), and Veneto Institute of Oncology IOV-IRCCS, Padua (S.L.) - both in Italy; the Netherlands Cancer Institute, Amsterdam (M.C.); Cancer Research SA, Adelaide, SA, Australia (R.J.); Hematology-Oncology Practice Eppendorf (HOPE) and University Cancer Center Hamburg (UCCH), Hamburg, Germany (E.G.); the Institute of Cancer of São Paulo, São Paulo (M.I.B.); Adana City Education and Research Hospital, Adana, Turkey (T. Cil); and Bristol Myers Squibb, Princeton, NJ (E.C., T. Chen, M.L., M.D., S.A.).
N Engl J Med. 2024 Nov 28;391(21):2014-2026. doi: 10.1056/NEJMoa2402141.
Patients with microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) metastatic colorectal cancer have poor outcomes with standard chemotherapy with or without targeted therapies. Nivolumab plus ipilimumab has shown clinical benefit in nonrandomized studies of MSI-H or dMMR metastatic colorectal cancer.
In this phase 3 open-label trial, we randomly assigned patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR status according to local testing to receive, in a 2:2:1 ratio, nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The dual primary end points, assessed in patients with centrally confirmed MSI-H or dMMR status, were progression-free survival with nivolumab plus ipilimumab as compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab as compared with nivolumab alone in patients regardless of previous systemic treatment for metastatic disease. At this prespecified interim analysis, the first primary end point (involving nivolumab plus ipilimumab vs. chemotherapy) was assessed.
A total of 303 patients who had not previously received systemic treatment for metastatic disease were randomly assigned to receive nivolumab plus ipilimumab or chemotherapy; 255 patients had centrally confirmed MSI-H or dMMR tumors. At a median follow-up of 31.5 months (range, 6.1 to 48.4), progression-free survival outcomes (the primary analysis) were significantly better with nivolumab plus ipilimumab than with chemotherapy (P<0.001 for the between-group difference in progression-free survival, calculated with the use of a two-sided stratified log-rank test); 24-month progression-free survival was 72% (95% confidence interval [CI], 64 to 79) with nivolumab plus ipilimumab as compared with 14% (95% CI, 6 to 25) with chemotherapy. At 24 months, the restricted mean survival time was 10.6 months (95% CI, 8.4 to 12.9) longer with nivolumab plus ipilimumab than with chemotherapy, a finding consistent with the primary analysis of progression-free survival. Grade 3 or 4 treatment-related adverse events occurred in 23% of the patients in the nivolumab-plus-ipilimumab group and in 48% of the patients in the chemotherapy group.
Progression-free survival was longer with nivolumab plus ipilimumab than with chemotherapy among patients who had not previously received systemic treatment for MSI-H or dMMR metastatic colorectal cancer. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 8HW ClinicalTrials.gov number, NCT04008030.).
微卫星不稳定性高（MSI-H）或错配修复缺陷（dMMR）转移性结直肠癌患者在接受标准化疗联合或不联合靶向治疗时预后较差。纳武利尤单抗联合伊匹单抗在 MSI-H 或 dMMR 转移性结直肠癌的非随机研究中显示出临床获益。
在这项 3 期开放标签试验中，我们根据当地检测结果，将无法切除或转移性结直肠癌且 MSI-H 或 dMMR 状态的患者随机分为 2:2:1 的比例，接受纳武利尤单抗联合伊匹单抗、纳武利尤单抗单药或化疗联合或不联合靶向治疗。双重主要终点为：根据中心确认的 MSI-H 或 dMMR 状态评估，纳武利尤单抗联合伊匹单抗作为一线治疗与化疗相比的无进展生存期；以及无论转移性疾病先前接受何种系统治疗，纳武利尤单抗联合伊匹单抗与纳武利尤单抗单药相比的无进展生存期。在此次预先设定的中期分析中，评估了第一个主要终点（涉及纳武利尤单抗联合伊匹单抗与化疗）。
共有 303 名未接受转移性疾病系统治疗的患者被随机分配接受纳武利尤单抗联合伊匹单抗或化疗；255 名患者的肿瘤经中心确认为 MSI-H 或 dMMR。中位随访 31.5 个月（范围，6.1 至 48.4）时，纳武利尤单抗联合伊匹单抗组的无进展生存期（主要分析）显著优于化疗组（使用双侧分层对数秩检验计算的组间无进展生存差异，P<0.001）；24 个月无进展生存率分别为 72%（95%置信区间[CI]，64 至 79）和 14%（95%CI，6 至 25）。24 个月时，纳武利尤单抗联合伊匹单抗组的限制平均生存时间比化疗组延长了 10.6 个月（95%CI，8.4 至 12.9），与无进展生存期的主要分析结果一致。纳武利尤单抗联合伊匹单抗组 23%的患者和化疗组 48%的患者发生 3 级或 4 级治疗相关不良事件。
对于未接受 MSI-H 或 dMMR 转移性结直肠癌系统治疗的患者，与化疗相比，纳武利尤单抗联合伊匹单抗可延长无进展生存期。（由 Bristol Myers Squibb 和小野制药公司资助；CheckMate 8HW ClinicalTrials.gov 编号，NCT04008030）。
