美国纽约斯隆凯特琳癌症纪念中心Robert J Motzer团队研究了辅助纳武单抗+伊匹单抗治疗肾切除术后局部肾细胞癌患者对预后的影响。相关论文于2023年2月9日发表在《柳叶刀》杂志上。

对于切除的局部肾细胞癌患者，有效的辅助治疗是一个未满足的需求，监测是护理的标准。研究组报告了一项3期随机试验的A部分结果，旨在评估辅助药物纳武单抗+伊匹单抗与安慰剂的疗效和安全性。

这项双盲、随机、3期CheckMate 914试验在随机分配前4-12周招募局部透明细胞肾细胞癌患者，这些患者在根治性或部分肾切除术后复发风险较高。A部分是在20个国家的145家医院和癌症中心完成的。通过互动反应技术系统，患者被随机（1:1）分配到纳武单抗（240 mg）静脉注射每2周一次共12次，伊匹单抗（1 mg/kg）静脉注射每6周一次共4次，或匹配的安慰剂。

预期治疗期为24周，治疗可以持续到第36周，允许治疗延迟。根据TNM分期和肾切除术（部分与根治）对随机分组进行分层。主要终点为无病生存期（根据双盲独立中心评价）；安全性是次要终点。分析所有随机分配的患者（意向治疗人群）的无病生存期；对所有接受至少一剂研究药物的患者（全部治疗人群）进行暴露、安全性和耐受性分析。

2017年8月28日至2021年3月16日，816名患者被随机分配接受辅助药物纳武单抗+伊匹单抗（405名患者）或安慰剂（411名患者）治疗。816例患者中男性580例（71%），女性236例（29%）。中位随访时间为37.0个月，纳武单抗+伊匹单抗组中位无病生存期未达到，安慰剂组中位无病生存期为507个月，风险比为0.92。

在数据截止时，未达到计划总生存期中分析所需的事件数，仅发生了61起事件（纳武单抗+伊匹单抗组为33起，安慰剂组为28起）。接受纳武单抗+伊匹单抗治疗的404例患者中有155例（38%）、接受安慰剂治疗的407例患者中有42例（10%）发生了3-5级不良事件。任何级别的全因不良事件导致404例治疗患者中有129例（32%）停用纳武单抗+伊匹单抗，407例治疗患者中9例（2%）停用安慰剂。4例死亡归因于纳武单抗+伊匹单抗治疗，无一例死亡归因于安慰剂治疗。

研究结果表明，在肾切除术后复发高风险的局部肾细胞癌患者中，纳武单抗+伊匹单抗辅助治疗与安慰剂相比，不能提高无病生存期。该研究结果不支持这种方案作为肾细胞癌的辅助治疗。

附：英文原文

Title: Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial

Author: Robert J Motzer, Paul Russo, Viktor Grünwald, Yoshihiko Tomita, Bogdan Zurawski, Omi Parikh, Sebastiano Buti, Philippe Barthélémy, Jeffrey C Goh, Dingwei Ye, Alejo Lingua, Jean-Baptiste Lattouf, Laurence Albigès, Saby George, Brian Shuch, Jeffrey Sosman, Michael Staehler, Sergio Vázquez Estévez, Burcin Simsek, Julia Spiridigliozzi, Aleksander Chudnovsky, Axel Bex

Issue&Volume: 2023-02-09

Abstract:

Background

Effective adjuvant therapy for patients with resected localised renal cell carcinoma represents an unmet need, with surveillance being the standard of care. We report results from part A of a phase 3, randomised trial that aimed to assess the efficacy and safety of adjuvant nivolumab plus ipilimumab versus placebo.

Methods

The double-blind, randomised, phase 3 CheckMate 914 trial enrolled patients with localised clear cell renal cell carcinoma who were at high risk of relapse after radical or partial nephrectomy between 4–12 weeks before random assignment. Part A, reported herein, was done in 145 hospitals and cancer centres across 20 countries. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks for 12 doses plus ipilimumab (1 mg/kg) intravenously every 6 weeks for four doses, or matching placebo, via an interactive response technology system. The expected treatment period was 24 weeks, and treatment could be continued until week 36, allowing for treatment delays. Randomisation was stratified by TNM stage and nephrectomy (partial vs radical). The primary endpoint was disease-free survival according to masked independent central review; safety was a secondary endpoint. Disease-free survival was analysed in all randomly assigned patients (intention-to-treat population); exposure, safety, and tolerability were analysed in all patients who received at least one dose of study drug (all-treated population). This study is registered with ClinicalTrials.gov, NCT03138512.

Findings

Between Aug 28, 2017, and March 16, 2021, 816 patients were randomly assigned to receive either adjuvant nivolumab plus ipilimumab (405 patients) or placebo (411 patients). 580 (71%) of 816 patients were male and 236 (29%) patients were female. With a median follow-up of 37·0 months (IQR 31·3–43·7), median disease-free survival was not reached in the nivolumab plus ipilimumab group and was 50·7 months (95% CI 48·1 to not estimable) in the placebo group (hazard ratio 0·92, 95% CI 0·71–1·19; p=0·53). The number of events required for the planned overall survival interim analysis was not reached at the time of the data cutoff, and only 61 events occurred (33 in the nivolumab plus ipilimumab group and 28 in the placebo group). 155 (38%) of 404 patients who received nivolumab plus ipilimumab and 42 (10%) of 407 patients who received placebo had grade 3–5 adverse events. All-cause adverse events of any grade led to discontinuation of nivolumab plus ipilimumab in 129 (32%) of 404 treated patients and of placebo in nine (2%) of 407 treated patients. Four deaths were attributed to treatment with nivolumab plus ipilimumab and no deaths were attributed to treatment with placebo.

Interpretation

Adjuvant therapy with nivolumab plus ipilimumab did not improve disease-free survival versus placebo in patients with localised renal cell carcinoma at high risk of recurrence after nephrectomy. Our study results do not support this regimen for the adjuvant treatment of renal cell carcinoma.

DOI: 10.1016/S0140-6736(22)02574-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02574-0/fulltext