Background
Phase II randomized trial (InterAACT), N=91 patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCCA). No prior systemic chemotherapy for advanced disease; prior chemoradiation allowed. Stratified by ECOG PS and disease extent. Conducted across Europe, Israel, and Australia. Enrolled 2013–2017.
Interventions and follow up
Arm A: Carboplatin AUC5 day 1 + paclitaxel 80 mg/m² days 1, 8, 15 q4wk (carbo+pac)
Arm B: Cisplatin 60 mg/m² day 1 + 5-FU 1000 mg/m²/day CI days 1–4 q4wk (cis+5-FU)
Primary endpoint: 12-week disease control rate (DCR)
Median follow-up: 32 months
Arm B: Cisplatin 60 mg/m² day 1 + 5-FU 1000 mg/m²/day CI days 1–4 q4wk (cis+5-FU)
Primary endpoint: 12-week disease control rate (DCR)
Median follow-up: 32 months
Results
12-week DCR: 71% vs 63% (Arm A vs B), P=.33 — not significantly different
mOS: 20.0 vs 12.3 months (Arm A vs B), P=.014
mPFS: 8.1 vs 5.7 months (Arm A vs B), P=.31 — not significant
ORR: 59% vs 57%, P=.91
mOS: 20.0 vs 12.3 months (Arm A vs B), P=.014
mPFS: 8.1 vs 5.7 months (Arm A vs B), P=.31 — not significant
ORR: 59% vs 57%, P=.91
Adverse events
Gastrointestinal: Grade ≥3 nausea 0% vs 22%, mucositis 0% vs 11% (carbo+pac vs cis+5-FU).
Hematologic: Grade ≥3 neutropenia 20% vs 11%.
Overall: Grade ≥3 AEs 36% vs 62%; carbo+pac had fewer dose reductions and hospitalizations.
Hematologic: Grade ≥3 neutropenia 20% vs 11%.
Overall: Grade ≥3 AEs 36% vs 62%; carbo+pac had fewer dose reductions and hospitalizations.
Conclusions
Carboplatin+paclitaxel and cisplatin+5-FU produced similar 12-week disease control rates (primary endpoint not met) but carbo+pac was associated with significantly improved mOS (20.0 vs 12.3 months, P=.014) and substantially less toxicity, establishing carboplatin+paclitaxel as the preferred first-line regimen for advanced anal carcinoma.
Key Limitations
Phase II trial (N=91) — underpowered for definitive conclusions; OS difference is striking but based on a small sample. Primary endpoint (12-week DCR) was not met — statistically significant OS benefit without a significant primary endpoint creates interpretive tension. The OS improvement may reflect crossover or subsequent treatment differences not fully characterized. Both regimens are active but differ substantially in toxicity — the OS advantage may partly reflect tolerability-driven adherence differences rather than intrinsic activity. Trial does not include immunotherapy or biomarker-selected subgroups. Enrolled patients in pre-IO era; current standard for advanced anal cancer now includes retifanlimab (POD1UM-303).
Clinical Context
InterAACT established carboplatin+paclitaxel (carbo+pac) as the preferred first-line chemotherapy backbone for advanced anal squamous cell carcinoma, replacing the traditional cisplatin+5-FU regimen used in the metastatic setting. The OS advantage (20.0 vs 12.3 months) and favorable toxicity profile made carbo+pac the de facto standard. This informed the design of POD1UM-303/InterAACT-2, which used carbo+pac as the backbone for retifanlimab (anti-PD-1) addition. With the positive POD1UM-303 data, retifanlimab+carbo+pac is now the FDA-approved first-line standard for advanced anal carcinoma.
References