Background
Phase III double-blind RCT (POD1UM-303/InterAACT-2), N=308 patients with previously untreated inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCCA). Stratified by disease extent (locally recurrent vs metastatic), geographic region, and ECOG PS. Enrolled 2020–2023 across multiple international sites.
Interventions and follow up
Arm A: Retifanlimab 500 mg IV q4wk + carboplatin AUC5 day 1 + paclitaxel 80 mg/m² days 1, 8, 15 q4wk for up to 6 cycles, then retifanlimab 500 mg q4wk maintenance for up to 2 years
Arm B: Placebo + carboplatin AUC5 + paclitaxel 80 mg/m² × up to 6 cycles, then placebo maintenance
Primary endpoint: Progression-free survival (PFS)
Median follow-up: 20.1 months
Arm B: Placebo + carboplatin AUC5 + paclitaxel 80 mg/m² × up to 6 cycles, then placebo maintenance
Primary endpoint: Progression-free survival (PFS)
Median follow-up: 20.1 months
Results
PFS: 9.3 vs 7.4 months, HR 0.63 (95% CI 0.48–0.82), P=.0006
OS: 32.8 vs 22.2 months, HR 0.68 (95% CI 0.51–0.90), P=.006
ORR: 63% vs 49%
OS: 32.8 vs 22.2 months, HR 0.68 (95% CI 0.51–0.90), P=.006
ORR: 63% vs 49%
Adverse events
Overall: Grade ≥3 AEs 57% vs 49% (Arm A vs B); treatment discontinuation due to AE 14% vs 5%.
Immune-mediated: Any grade 32% vs 8%; grade ≥3: 7% vs 1%. Most common: hypothyroidism, rash, hepatitis.
Immune-mediated: Any grade 32% vs 8%; grade ≥3: 7% vs 1%. Most common: hypothyroidism, rash, hepatitis.
Conclusions
Retifanlimab plus carboplatin+paclitaxel significantly improved both PFS (HR 0.63, P=.0006) and OS (HR 0.68, P=.006) compared to carboplatin+paclitaxel alone in previously untreated advanced anal carcinoma, establishing immunotherapy+chemotherapy as the new first-line standard. The OS benefit of 10.6 months (32.8 vs 22.2 months) is clinically substantial for this population.
Key Limitations
Retifanlimab is a less established anti-PD-1 agent compared to pembrolizumab or nivolumab — no head-to-head comparison with other checkpoint inhibitors in this setting exists. PD-L1 and TMB were analyzed as exploratory biomarkers without prospective validation; HPV status was not formally evaluated as a predictive biomarker despite near-universal HPV association with anal SCCA. The OS benefit is striking but follow-up remains relatively short (median 20.1 months) and mature OS data are needed. The trial does not address patients who received prior immunotherapy (e.g., pembrolizumab for MSI-high). Whether IO maintenance alone (vs. IO+chemo followed by IO maintenance) contributes equally to outcome is unknown.
Clinical Context
FDA approved retifanlimab-dlwr (Zynyz) + carboplatin+paclitaxel for previously untreated locally recurrent or metastatic anal squamous cell carcinoma in 2025 — the first immunotherapy approval for anal cancer. This represents a major practice shift: the new first-line standard for advanced anal SCCA is retifanlimab+carbo+pac, superseding carbo+pac alone (InterAACT). Anal canal SCCA is an HPV-driven malignancy (~90% HPV-positive), and the high immunogenicity may partly explain the robust IO benefit. ESMO-MCBS: not yet scored at time of entry. This is the first phase III-positive trial for first-line metastatic anal cancer.
References