Advanced Anal Squamous Cell Carcinoma in the Chemoimmunotherapy Era: Retifanlimab, Nivolumab, and a Practical Framework for Treatment Selection

Advanced anal squamous cell carcinoma (ASCC) is a rare human papillomavirus-associated malignancy with historically limited prospective evidence for systemic therapy. InterAAct established carboplatin-paclitaxel as a clinically favorable chemotherapy backbone compared with cisplatin-fluorouracil. POD1UM-303/InterAACT-2 subsequently showed that adding retifanlimab significantly improved progression-free survival in patients with no prior systemic therapy for advanced disease. At the final overall-survival analysis, median overall survival was 32.8 versus 22.2 months (HR 0.75, 95% CI 0.55-1.01); the regimen has received regulatory authorization in the United States, the European Union, and Japan. EA2176 is evaluating carboplatin-paclitaxel with or without nivolumab and will clarify whether first-line PD-1-based chemoimmunotherapy represents a reproducible class effect. This focused narrative review critically summarizes the evidence for retifanlimab- and nivolumab-based strategies and proposes a practical framework for treatment selection. Key considerations include performance status, immune-checkpoint-inhibitor eligibility, HIV infection, autoimmune risk, neuropathy, organ function, tumor burden, local symptom control, and post-chemoimmunotherapy sequencing. Retifanlimab plus carboplatin-paclitaxel currently has the most mature phase III evidence, whereas nivolumab-based chemoimmunotherapy remains investigational pending EA2176. Treatment decisions should distinguish phase III-validated options from class-effect extrapolation and integrate multidisciplinary local therapy when appropriate.