Amiot Mathilde, Mortier Laurent, Dalle Stéphane, Dereure Olivier, Dalac Sophie, Dutriaux Caroline, Leccia Marie-Thérèse, Maubec Eve, Arnault Jean-Philippe, Brunet-Possenti Florence, De Quatrebarbes Julie, Granel-Brocard Florence, Gaudy-Marqueste Caroline, Pages Cecile, Stoebner Pierre-Emmanuel, Saiag Philippe, Lesimple Thierry, Dupuy Alain, Legoupil Delphine, Montaudié Henri, Oriano Bastien, Lebbe Celeste, Porcher Raphael
AP-HP Dermato-oncology, Cancer Institute APHP Nord Paris Cité, Saint Louis Hospital, Paris, France.
Dermatology Department, University of Lille, ONCO-THAI INSERM, Lille U1189, France.
EClinicalMedicine. 2024 Dec 4;78:102960. doi: 10.1016/j.eclinm.2024.102960. eCollection 2024 Dec.
Immune checkpoint inhibitors (ICIs) have demonstrated their efficacy with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials provides for treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after treatment cessation shows sustained response and a low risk of relapse in the months following cessation. To date, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI administration.
We emulated target trials using the cloning, weighting and censoring approach. Each emulation trial aimed to compare the effect of discontinuing versus continuing ICIs at a specific timepoint, among patients still under treatment and with disease control at that time. Patients were from MelBase between 2015 and 2021.
435 participants in the MelBase cohort were eligible and were included in the 6-month discontinuation emulated trial. The results showed significantly lower OS when treatment was discontinued, than when treatment was prolonged for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8-60.5), and the corresponding restricted mean survival time difference was 8.3 months (95% CI: 4.1-12.7). Neither the 12-month nor the 18-month discontinuation emulated trials showed evidence of benefit of either discontinuing or continuing ICIs at either of these timepoints. The 24-month discontinuation emulated trial results were more in favor of discontinuing than continuing treatment at that time point, with an absolute 48-month survival rate that was 10.5% higher (95% CI 4.4-18.1).
These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental.
This work was supported by a grant from Bristol Myers Squibb, Merck Sharp Dhome, Pierre Fabre, Novartis, Sun Pharm, Regeneron, Sanofi, Nektar, Therapeutics and Oncyte.
免疫检查点抑制剂（ICIs）已显示出其疗效，晚期患者的7.5年总生存期（OS）接近50%。临床试验设计规定治疗持续至疾病进展或出现毒性反应，或最长持续两年。对治疗停止后缓解者的长期随访显示，缓解持续存在，且停止治疗后的数月内复发风险较低。迄今为止，转移性黑色素瘤抗PD-1治疗的最佳持续时间仍未确定。这项研究的目的是评估ICI给药的最佳持续时间。
我们使用克隆、加权和删失方法模拟目标试验。每项模拟试验旨在比较在特定时间点停止与继续使用ICIs的效果，这些患者当时仍在接受治疗且疾病得到控制。患者来自2015年至2021年的MelBase数据库。
MelBase队列中的435名参与者符合条件，并被纳入6个月停药模拟试验。结果显示，与至少延长治疗三个月相比，停止治疗时的OS显著降低。48个月的生存差异为37.8%（95%置信区间[CI]19.8 - 60.5），相应的受限平均生存时间差异为8.3个月（95%CI：4.1 - 12.7）。12个月和18个月停药模拟试验均未显示在这两个时间点停止或继续使用ICIs有获益的证据。24个月停药模拟试验结果更倾向于在该时间点停止治疗而非继续治疗，48个月的绝对生存率高出10.5%（95%CI 4.4 - 18.1）。
这些结果表明，对于晚期黑色素瘤患者，一年的免疫治疗疗程既必要又足够。超过2年的延长治疗在生存方面似乎并无益处，甚至可能有害。
这项研究得到了百时美施贵宝、默克雪兰诺、皮尔法伯、诺华、太阳药业、再生元、赛诺菲、奈科明、治疗公司和Oncyte的资助。
