Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Department of Oncology and Hematology, University Hospital Modena, Modena, Italy.
J Immunother Cancer. 2024 May 31;12(5):e008689. doi: 10.1136/jitc-2023-008689.
BACKGROUND: Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma. Here, we present the results from patients with MSI-H/dMMR metastatic CRC treated with nivolumab plus relatlimab in the CheckMate 142 study. METHODS: In this open-label, phase II study, previously treated patients with MSI-H/dMMR metastatic CRC received nivolumab 240 mg plus relatlimab 160 mg intravenously every 2 weeks. The primary end point was investigator-assessed objective response rate (ORR). RESULTS: A total of 50 previously treated patients received nivolumab plus relatlimab. With median follow-up of 47.4 (range 43.9-49.2) months, investigator-assessed ORR was 50% (95% CI 36% to 65%) and disease control rate was 70% (95% CI 55% to 82%). The median time to response per investigator was 2.8 (range 1.3-33.1) months, and median duration of response was 42.7 (range 2.8-47.0+) months. The median progression-free survival per investigator was 27.5 (95% CI 5.3 to 43.7) months with a progression-free survival rate at 3 years of 38%, and median overall survival was not reached (95% CI 17.2 months to not estimable), with a 56% overall survival rate at 3 years. The most common any-grade treatment-related adverse events (TRAEs) were diarrhea (24%), asthenia (16%), and hypothyroidism (12%). Grade 3 or 4 TRAEs were reported in 14% of patients, and TRAEs of any grade leading to discontinuation were observed in 8% of patients. No treatment-related deaths were reported. CONCLUSIONS: Nivolumab plus relatlimab provided durable clinical benefit and was well tolerated in previously treated patients with MSI-H/dMMR metastatic CRC. TRIAL REGISTRATION NUMBER: NCT02060188.
背景：程序性死亡受体-1（PD-1）抑制剂，包括纳武利尤单抗，在先前治疗的微卫星不稳定高/错配修复缺陷（MSI-H/dMMR）转移性结直肠癌（CRC）患者中显示出长期生存获益。PD-1 和淋巴细胞激活基因 3（LAG-3）是两个不同的免疫检查点，它们经常在肿瘤浸润淋巴细胞上共表达，并导致肿瘤介导的 T 细胞功能障碍。Relatlimab 是一种 LAG-3 抑制剂，在黑色素瘤患者中与纳武利尤单抗联合使用已显示出疗效。在这里，我们报告了在 CheckMate 142 研究中接受纳武利尤单抗加 relatlimab 治疗的 MSI-H/dMMR 转移性 CRC 患者的结果。
方法：在这项开放标签、二期研究中，先前治疗的 MSI-H/dMMR 转移性 CRC 患者接受纳武利尤单抗 240mg 加 relatlimab 160mg 静脉注射，每 2 周一次。主要终点为研究者评估的客观缓解率（ORR）。
结果：共有 50 名先前接受过治疗的患者接受了纳武利尤单抗加 relatlimab 治疗。中位随访 47.4 个月（范围 43.9-49.2），研究者评估的 ORR 为 50%（95%CI36%-65%），疾病控制率为 70%（95%CI55%-82%）。研究者评估的中位反应时间为 2.8 个月（范围 1.3-33.1），中位缓解持续时间为 42.7 个月（范围 2.8-47.0+）。研究者评估的中位无进展生存期为 27.5 个月（95%CI5.3-43.7），3 年无进展生存率为 38%，中位总生存期未达到（95%CI17.2 个月至无法估计），3 年总生存率为 56%。最常见的任何级别与治疗相关的不良事件（TRAEs）是腹泻（24%）、乏力（16%）和甲状腺功能减退（12%）。14%的患者报告了 3 级或 4 级 TRAEs，8%的患者出现了任何级别导致停药的 TRAEs。无治疗相关死亡报告。
结论：纳武利尤单抗加 relatlimab 为先前治疗的 MSI-H/dMMR 转移性 CRC 患者提供了持久的临床获益，并具有良好的耐受性。
试验注册：NCT02060188。
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