Advanced squamous cell carcinoma of the anal canal remains a rare but difficult-to-treat disease, especially when it becomes inoperable, locally recurrent, or metastatic. Although carboplatin–paclitaxel has been an important first-line chemotherapy option, long-term outcomes remain limited, creating a need for treatment strategies that can improve survival without adding unexpected safety concerns.
This new analysis reports the final overall survival results from the phase 3 POD1UM-303/InterAACT-2 trial, evaluating retifanlimab plus carboplatin–paclitaxel versus placebo plus carboplatin–paclitaxel in systemic treatment-naïve patients with advanced squamous cell carcinoma of the anal canal.
The article was published in Annals of Oncology as an Articles in Press original article on May 5, 2026.
Title: Survival outcomes in POD1UM-303/InterAACT-2: a phase 3 study of retifanlimab plus carboplatin–paclitaxel in first-line advanced squamous anal cancer
Authors: S. Rao, E. Samalin-Scalzi, L. Evesque, M. Ben Abdelghani, F. Morano, A. Roy, L. Dahan, S. Tamberi, A.S. Dhadda, M.G. Zampino, N. Casanova, R. Guimbaud, A. Lievre, J. Maurel, P. Zhang, M.C. Munteanu, M. Jones, C. de la Fouchardiere, A. Takashima, M. Fakih, and J. Spano.
Key Statistics for Anal Cancer in 2026
According to the American Cancer Society, anal cancer remains relatively rare and is much less common than colon or rectal cancer. In the United States, an estimated 11,270 new cases of anal cancer are expected in 2026, including 3,570 cases in men and 7,700 cases in women. The disease is also expected to cause approximately 1,700 deaths, including 570 deaths in men and 1,130 deaths in women.
The number of new anal cancer cases has been rising for many years. Anal cancer is uncommon in people younger than 35 and is diagnosed mainly in older adults, with an average age in the early 60s. It is more common in White women and Black men, and in people with certain risk factors, including HIV, autoimmune disease, and immunosuppressive therapy.
How Does Retifanlimab-dlwr Work?
Retifanlimab-dlwr, marketed as Zynyz, is an immunotherapy designed to help the immune system recognize and attack cancer cells. It is a humanized IgG4 monoclonal antibody that targets programmed death receptor-1 (PD-1), a checkpoint protein found on T cells.
Normally, PD-1 helps regulate immune activity by binding to its ligands, PD-L1 and PD-L2. However, some tumor cells can use this pathway to suppress T-cell activity and avoid immune destruction. By binding to PD-1, retifanlimab-dlwr blocks its interaction with PD-L1 and PD-L2.
This blockade helps restore T-cell activation, allowing the immune system to respond more effectively against cancer cells. In simple terms, retifanlimab-dlwr helps “release the brakes” on the immune response, supporting antitumor activity.
Read more about Retifanlimab-dlwr (Zynyz) on OncoDaily.
FDA Approval of Retifanlimab-dlwr
On May 15, 2025, the U.S. Food and Drug Administration approved retifanlimab-dlwr (Zynyz) in combination with carboplatin and paclitaxel for the first-line treatment of adults with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal. The FDA also approved retifanlimab-dlwr as monotherapy for adults with locally recurrent or metastatic disease who progressed on, or were intolerant to, platinum-based chemotherapy.
The approval was supported by two studies: POD1UM-303/InterAACT-2, which evaluated retifanlimab plus chemotherapy in the first-line setting, and POD1UM-202, which assessed retifanlimab monotherapy in previously treated patients.
Study Design
POD1UM-303/InterAACT-2 was a phase 3, randomized, double-blind, controlled, multicenter trial conducted across Europe, Australia, Japan, the United Kingdom, and the United States.
Eligible patients were adults with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal who had not received previous systemic therapy. Patients had an ECOG performance status of 0 or 1, and patients with well-controlled HIV were eligible.
A total of 308 patients were randomized equally into two groups:
- 154 patients received retifanlimab 500 mg every 4 weeks plus carboplatin–paclitaxel.
- 154 patients received placebo plus carboplatin–paclitaxel.
Patients in the placebo arm who had confirmed disease progression by blinded independent central review could cross over to receive retifanlimab monotherapy. In total, 77 patients, representing 50.0% of the placebo group, crossed over to retifanlimab.
The primary endpoint was progression-free survival by blinded independent central review. Overall survival was the key secondary endpoint. Other endpoints included response, disease control, duration of response, safety, and exploratory subgroup analyses.
Key Findings
At the data cutoff of August 1, 2025, the updated efficacy analysis continued to show a progression-free survival benefit with retifanlimab plus carboplatin–paclitaxel compared with placebo plus carboplatin–paclitaxel.
The hazard ratio for progression-free survival was 0.62 with a 95% confidence interval of 0.47 to 0.81 and a nominal P value of 0.0002. Progression-free survival rates were consistently higher with retifanlimab plus chemotherapy at 12, 24, and 36 months.
The final overall survival analysis included 172 observed events. Retifanlimab plus carboplatin–paclitaxel showed a clinically meaningful improvement in overall survival compared with placebo plus chemotherapy. Median overall survival was 32.8 months with retifanlimab plus chemotherapy versus 22.2 months with placebo plus chemotherapy.
The overall survival hazard ratio was 0.75, with a 95% confidence interval of 0.55 to 1.01 and a P value of 0.0305. The survival curves separated from approximately 6 months and remained separated through follow-up.
Overall survival rates were also higher with retifanlimab plus chemotherapy:
- 12 months: 79.4% versus 66.4%
- 24 months: 60.3% versus 47.1%
- 36 months: 47.5% versus 34.3%
Response outcomes also favored the retifanlimab arm. The overall response rate was 56.5% with retifanlimab plus carboplatin–paclitaxel compared with 44.8% with placebo plus chemotherapy. Complete responses occurred in 24.7% versus 13.6% of patients, respectively. Disease control rates were 87.7% versus 80.5%.
Median duration of response was longer with retifanlimab plus chemotherapy, at 14.7 months, compared with 7.2 months in the placebo plus chemotherapy group.
Because half of the patients in the placebo arm crossed over to retifanlimab after progression, the investigators also performed crossover-adjusted analyses. These supported the overall survival benefit seen in the main analysis. Using the rank-preserving structural failure time model, the hazard ratio was 0.63. Using the inverse probability of censoring weights method, the hazard ratio was 0.53.
Exploratory subgroup analyses showed an overall survival benefit favoring retifanlimab plus chemotherapy across analyzed subgroups with sufficient patient numbers. An ad hoc analysis using centrally assessed p16 status as a surrogate for HPV showed that the OS and PFS benefits were maintained regardless of p16 status.
Subsequent anticancer therapy was administered to 48.4% of patients overall and was well-balanced between the two study arms. Sensitivity analyses adjusting for subsequent treatment supported the robustness of the overall survival findings.
Read more about Anal Cancer: Symptoms, Causes, Stages, Diagnosis and Treatment on OncoDaily.
Safety
The safety profile of retifanlimab plus carboplatin–paclitaxel remained consistent with the primary analysis, and no new safety signals or trends were reported with longer follow-up.
The most common treatment-emergent adverse events in the retifanlimab plus chemotherapy arm included anemia, nausea, alopecia, diarrhea, asthenia, and neutropenia. Adverse events leading to treatment discontinuation occurred in 11.7% of patients receiving retifanlimab plus carboplatin–paclitaxel and 2.6% of patients receiving placebo plus chemotherapy.
The most common immune-related treatment-emergent adverse events were hypothyroidism and peripheral sensory neuropathy.
Conclusion
The final analysis of POD1UM-303/InterAACT-2 confirms the benefit of adding retifanlimab to carboplatin–paclitaxel in the first-line treatment of inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal. While the overall survival analysis was prespecified as a secondary endpoint and powered at approximately 70%, the magnitude of benefit and consistency across crossover-adjusted analyses and subgroups support the clinical relevance of the finding.
The trial showed sustained improvement in progression-free survival, a clinically meaningful overall survival benefit, higher response rates, longer duration of response, and no new safety concerns with longer follow-up.
Based on these findings, retifanlimab plus carboplatin–paclitaxel supports a new reference treatment approach and standard of care for patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal.