Rao Sheela, Samalin-Scalzi Emmanuelle, Evesque Ludovic, Ben Abdelghani Meher, Morano Federica, Roy Amitesh, Dahan Laetitia, Tamberi Stefano, Dhadda Amandeep Singh, Saunders Mark P, Casanova Nathalie, Guimbaud Rosine, Lievre Astrid, Maurel Joan, Fakih Marwan, Tian Chuan, Harrison Jill, Jones Mark M, Cornfeld Mark, Spano Jean-Philippe, Rochefort Pauline
Royal Marsden Hospital NHS Foundation Trust, Sutton, Surrey, UK.
Institut Régional du Cancer de Montpellier, Montpellier, France.
Lancet. 2025 Jun 14;405(10495):2144-2152. doi: 10.1016/S0140-6736(25)00631-2.
Retifanlimab has activity in programmed death ligand 1-positive advanced squamous cell anal carcinoma (SCAC) that has progressed on platinum chemotherapy. We aimed to prospectively assess the benefit of adding retifanlimab to initial carboplatin-paclitaxel for this disease.
This global, multicentre, double-blind, randomised, controlled, phase 3 trial was done at 70 centres in 12 countries across the EU, Australia, Japan, the UK, and the USA. Patients aged ≥18 years with inoperable locally recurrent or metastatic SCAC, an Eastern Cooperative Oncology Group performance status of 0 or 1, no previous systemic therapy, and well controlled HIV (ie, CD4+ count >200/μL and undetectable viral load) were eligible. Patients were randomly assigned (1:1) to retifanlimab (500 mg intravenous) or placebo every 4 weeks with standard carboplatin-paclitaxel for up to 1 year. Patients in the placebo group could cross over to retifanlimab monotherapy on confirmed disease progression. The primary endpoint was independently assessed progression-free survival (ie, time from date of randomisation to date of first documented progressive disease or death due to any cause) per Response Evaluation Criteria in Solid Tumours version 1.1. Efficacy was assessed by intention to treat. This trial is registered with ClinicalTrials.gov (NCT04472429) and EUDRA-CT (2020-000826-24) and is active but closed to enrolment.
Between Nov 12, 2020, and July 3, 2023, 376 patients were assessed for eligibility and 308 were randomly assigned to retifanlimab plus carboplatin-paclitaxel (n=154) or placebo plus carboplatin-paclitaxel (n=154). 222 (72%) of 308 patients were female and 86 (28%) were male. Median progression-free survival was 9·3 months (95% CI 7·5-11·3) in the retifanlimab group and 7·4 months (7·1-7·7) in the placebo group (hazard ratio 0·63 [95% CI 0·47-0·84]; one-sided p=0·0006). Serious and grade 3 or worse adverse events were more frequent in the retifanlimab plus carboplatin-paclitaxel group compared with the placebo plus carboplatin-paclitaxel group (47·4% vs 38·8% and 83·1% vs 75·0%, respectively). The most common grade ≥3 adverse events were neutropenia (35·1% for retifanlimab plus carboplatin-paclitaxel vs 29·6% for placebo plus carboplatin-paclitaxel) and anaemia (19·5% vs 20·4%). Four fatal adverse events occurred in the retifanlimab plus carboplatin-paclitaxel group, only one (pancytopenia) of which was treatment related. One fatal adverse event occurred in the placebo plus carboplatin-paclitaxel group and was not treatment related.
Retifanlimab provides clinical benefit, with a manageable safety profile, when added to first-line chemotherapy in advanced squamous cell carcinoma of the anal canal. These results suggest retifanlimab with carboplatin plus paclitaxel should be considered as the new standard of care for patients with advanced squamous cell anal carcinoma.
Incyte.
瑞替凡利单抗对铂类化疗进展的程序性死亡配体1阳性晚期肛门鳞状细胞癌（SCAC）有活性。我们旨在前瞻性评估在初始卡铂-紫杉醇方案中加入瑞替凡利单抗对该疾病的益处。
这项全球、多中心、双盲、随机、对照、3期试验在欧盟、澳大利亚、日本、英国和美国的12个国家的70个中心进行。年龄≥18岁、患有无法手术的局部复发或转移性SCAC、东部肿瘤协作组体能状态为0或1、既往未接受过全身治疗且HIV得到良好控制（即CD4 + 细胞计数>200/μL且病毒载量检测不到）的患者符合条件。患者被随机分配（1:1）接受瑞替凡利单抗（500 mg静脉注射）或安慰剂，每4周一次，联合标准卡铂-紫杉醇治疗长达1年。安慰剂组患者在确认疾病进展后可交叉接受瑞替凡利单抗单药治疗。主要终点是根据实体瘤疗效评价标准1.1版独立评估的无进展生存期（即从随机分组日期到首次记录的疾病进展日期或因任何原因死亡的时间）。疗效按意向性分析进行评估。该试验已在ClinicalTrials.gov（NCT04472429）和EUDRA-CT（2020-000826-24）注册，处于活跃状态但已停止入组。
在2020年11月12日至2023年7月3日期间，376例患者接受了资格评估，308例患者被随机分配接受瑞替凡利单抗联合卡铂-紫杉醇（n = 154）或安慰剂联合卡铂-紫杉醇（n = 154）。308例患者中222例（72%）为女性，86例（28%）为男性。瑞替凡利单抗组的中位无进展生存期为9.3个月（95%CI 7.5 - 11.3），安慰剂组为7.4个月（7.1 - 7.7）（风险比0.63 [95%CI 0.47 - 0.84]；单侧p = 0.0006）。与安慰剂联合卡铂-紫杉醇组相比，瑞替凡利单抗联合卡铂-紫杉醇组的严重及3级或更严重不良事件更常见（分别为47.4%对38.8%和83.1%对75.0%）。最常见的≥3级不良事件是中性粒细胞减少（瑞替凡利单抗联合卡铂-紫杉醇组为35.1%，安慰剂联合卡铂-紫杉醇组为29.6%）和贫血（19.5%对20.4%）。瑞替凡利单抗联合卡铂-紫杉醇组发生了4例致命不良事件，其中只有1例（全血细胞减少）与治疗相关。安慰剂联合卡铂-紫杉醇组发生了1例致命不良事件，与治疗无关。
在晚期肛管鳞状细胞癌一线化疗中加入瑞替凡利单抗可提供临床益处，且安全性可控。这些结果表明，瑞替凡利单抗联合卡铂和紫杉醇应被视为晚期肛门鳞状细胞癌患者的新治疗标准。
因赛特公司。
