Why This Study Matters
Anal canal cancer is uncommon but rising: an estimated 10,930 new cases and 2,030 deaths occurred in the U.S. in 2025, with age-adjusted mortality climbing 3.9% each year from 2015-2024. While the overall 5-year relative survival for anal cancer is 71.3%, that figure is driven by potentially curable localized disease. For the roughly 14% of patients who present with distant metastatic disease — most commonly to the liver — the estimated 5-year survival rate falls to 36%.
Prior to this approval, the standard first-line systemic regimen for metastatic or unresectable recurrent squamous cell carcinoma of the anal canal (SCAC) was carboplatin plus paclitaxel, based on the InterAAct trial, and there were no FDA-approved treatments for patients who progressed on first-line systemic therapy. On May 15, 2025, the FDA approved retifanlimab — a PD-1-targeting immune checkpoint inhibitor — in combination with carboplatin and paclitaxel for first-line treatment, and as a single agent for second-line treatment, marking the first checkpoint inhibitor approval in this disease.
Study Design
POD1UM-303 (NCT04472429) was a randomized, multiregional, double-blind trial in chemotherapy-naive patients with inoperable locally recurrent or metastatic SCAC. Patients were randomized 1:1 to receive retifanlimab or placebo, 500 mg IV on Day 1 of each 4-week cycle, combined with carboplatin (AUC 5 mg/mL, Day 1) and paclitaxel (80 mg/m², Days 1, 8, 15) for 6 cycles, with retifanlimab or placebo continuing for up to 1 year. Randomization was stratified by PD-L1 expression, geographic region, and extent of disease. The major efficacy outcome was blinded independent central review (BICR)-assessed progression-free survival (PFS) per RECIST v1.1, with overall survival (OS) as the key secondary endpoint.
| Element | Detail |
|---|---|
| POD1UM-303 design | Randomized, multiregional, double-blind, chemotherapy-naive; retifanlimab or placebo + carboplatin/paclitaxel |
| POD1UM-303 enrollment | 308 patients randomized 1:1; stratified by PD-L1 expression, region, and extent of disease |
| POD1UM-303 primary endpoint | BICR-assessed progression-free survival (RECIST v1.1); key secondary endpoint overall survival |
| POD1UM-202 design | Open-label, multicenter, single-arm; retifanlimab monotherapy after platinum-chemotherapy progression |
| POD1UM-202 enrollment | 94 treated patients; retifanlimab 500 mg IV every 4 weeks for up to 2 years |
| POD1UM-202 primary endpoint | Overall response rate (RECIST 1.1) by independent central review |
POD1UM-202 (NCT03597295) was an open-label, multicenter, single-arm trial in patients with locally advanced or metastatic SCAC who had progressed on or were intolerant to platinum-based chemotherapy, with no prior anti-PD-1/PD-L1 therapy. Patients received retifanlimab 500 mg IV every 4 weeks for up to 2 years. The primary endpoint was overall response rate (ORR) per RECIST 1.1 by independent central review.
Patient Population
In POD1UM-303, baseline demographics were generally balanced across arms: 83% of patients were enrolled in Western Europe and 6% in the U.S.; 90% had PD-L1-positive tumors; 83% had metastatic (versus locally recurrent) disease. HIV-positive status was documented in 3.5% of patients. In POD1UM-202, 81% of the 94 treated patients had metastatic disease; among patients with known PD-L1 status, 47% were PD-L1-positive, and 10% of patients with documented HIV status were HIV-positive. The article notes as a limitation that HPV status was unknown in 79% of POD1UM-303 patients and that central p16 testing was missing in 40% of patients — despite SCAC being a predominantly HPV-driven malignancy.
Primary Endpoint & Efficacy Results
In POD1UM-303, PFS events occurred in 60% of the retifanlimab arm versus 71% of the placebo arm, with median PFS of 9.3 months (95% CI: 7.5, 11.3) versus 7.4 months (95% CI: 7.1, 7.7) — a hazard ratio of 0.63 (95% CI: 0.47, 0.84; p=0.0006). Overall response rate was 56% (95% CI: 48, 64) with retifanlimab versus 44% (95% CI: 36, 52) with placebo, including complete response in 22% versus 14% of patients, and median duration of response was 14.0 months versus 7.2 months. OS events occurred in 34% of the retifanlimab arm versus 47% of the placebo arm, with median OS of 29.2 months versus 23.0 months (HR 0.70, 95% CI: 0.49, 1.01). In the single-arm POD1UM-202 population (n=94), second-line single-agent retifanlimab produced an ORR of 14% (95% CI: 8, 23), with 1 complete response and 12 partial responses, and a median duration of response of 9.5 months.
| Outcome | Retifanlimab + Chemo (n=154) | Placebo + Chemo (n=154) |
|---|---|---|
| PFS events, n (%) | 92 (60%) | 110 (71%) |
| Median PFS, months (95% CI) | 9.3 (7.5, 11.3) | 7.4 (7.1, 7.7) |
| PFS HR (95% CI), p-value | 0.63 (0.47, 0.84), p=0.0006 | (vs. placebo) |
| OS events, n (%) | 53 (34%) | 73 (47%) |
| Median OS, months (95% CI) | 29.2 (24.2, NE) | 23.0 (15.1, 27.9) |
| OS HR (95% CI) | 0.70 (0.49, 1.01) | (vs. placebo) |
| ORR, % (95% CI) | 56 (48, 64) | 44 (36, 52) |
| Complete response, n (%) | 34 (22%) | 21 (14%) |
| Median duration of response, months (95% CI) | 14.0 (8.6, 22.2) | 7.2 (5.6, 9.3) |
Although the median PFS improvement in POD1UM-303 was modest, the effect appears to be consistent over time, with Kaplan-Meier PFS curves showing a separation of the arms, including after the medians were reached.
— Discussion/Regulatory Insights, FDA Approval Summary
Subgroup Analyses
The source article reports a PFS subgroup (forest plot) analysis only in qualitative terms: the overall treatment effect was described as generally consistent across most exploratory subgroups, with the authors noting that subgroups with hazard ratios above one had few patients. No subgroup-specific hazard ratios, confidence intervals, or p-values were reported in the source text, so none are presented here.
Safety Profile
The POD1UM-303 safety analysis was based on 306 treated patients (retifanlimab n=154, placebo n=152). Treatment-emergent adverse events (TEAEs) of any grade occurred in 100% of patients in both arms; Grade 3-4 TEAEs occurred in 81% (retifanlimab) versus 78% (placebo).
| Adverse Event (≥10% incidence) | Retifanlimab + Chemo, All Grade / Gr 3-4 | Placebo + Chemo, All Grade / Gr 3-4 |
|---|---|---|
| Fatigue | 75% / 6% | 73% / 9% |
| Nausea | 56% / 1.9% | 57% / 3.9% |
| Peripheral neuropathy | 56% / 5% | 54% / 2.6% |
| Alopecia | 51% / 2.6% | 50% / 2.6% |
| Diarrhea | 49% / 5% | 43% / 7% |
| Musculoskeletal pain | 40% / 2.6% | 37% / 0.7% |
| Constipation | 36% / 0.6% | 43% / 0.7% |
| Hemorrhage | 29% / 3.2% | 23% / 1.3% |
| Rash | 29% / 1.3% | 18% / 0.7% |
| Pruritus | 24% / 0.6% | 9% / 0% |
| Hypothyroidism | 14% / 0.6% | 9% / 0% |
Grade 3-4 neutropenia was more common with retifanlimab (52%) than placebo (39%). Immune-related adverse events (irAEs) occurred in 49% of retifanlimab-treated patients versus 33% of placebo-treated patients, most commonly hypothyroidism (14%), dermatitis, and colitis (mostly Grade 1-2). In POD1UM-202 (n=94), TEAEs occurring in 20% or more of patients included fatigue, anemia, leukopenia, hypoalbuminemia, AST increase, hyponatremia, musculoskeletal pain, diarrhea, and non-urinary-tract infections; one death occurred due to interstitial lung disease.
Interpretation and Broader Context
This is the first FDA approval of an immune checkpoint inhibitor for squamous cell carcinoma of the anal canal, spanning both first-line combination and second-line single-agent use. The FDA authors describe the OS analysis in POD1UM-303 as not reaching statistical significance at the interim analysis (HR 0.70, 95% CI: 0.49, 1.01), and note that 45% of placebo-arm patients crossed over to receive retifanlimab as a single agent upon disease progression — along with an unknown number who may have received other checkpoint inhibitors — potentially confounding the observed survival effect.
For POD1UM-202, an Oncologic Drugs Advisory Committee (ODAC) originally voted 13-to-4 in 2021 to defer a regulatory decision pending POD1UM-303 data, given questions about whether a 14% ORR was clinically meaningful on its own. With POD1UM-303's subsequent randomized-controlled-trial evidence in hand, the FDA authors write that the POD1UM-202 single-arm data then supported a favorable risk-benefit profile in the second-line setting.
It is expected that most eligible patients with advanced SCAC will receive retifanlimab in the first-line advanced setting where data are available from a randomized controlled trial. This regimen may serve as a basis to build upon in the first-line setting in future trials, either as a regimen to build upon or as a control arm to compare head-to-head.
— Conclusions, FDA Approval Summary
The FDA approved retifanlimab in combination with carboplatin and paclitaxel for first-line treatment, and as a single agent for second-line treatment, of squamous cell carcinoma of the anal canal — the first checkpoint inhibitor approval in this disease. The randomized POD1UM-303 trial showed a statistically significant PFS benefit (HR 0.63) and higher response rate with the addition of retifanlimab to chemotherapy, though the interim OS benefit (HR 0.70) did not cross the prespecified significance threshold and was potentially confounded by substantial crossover. Toxicity was manageable overall, though immune-related adverse events were more frequent with retifanlimab. Together with the single-arm POD1UM-202 data supporting second-line use, these results establish retifanlimab-based therapy as a new standard across both treatment lines for advanced SCAC.