Background: 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.
Methods: 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.
Findings: 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.
Interpretation: 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.
Funding: Incyte.
Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
