FDA Approves Retifanlimab for Squamous Cell Carcinoma of the Anal Canal
The U.S. Food and Drug Administration (FDA) has approved retifanlimab, a PD-1 inhibitor, for inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC). The drug can be used both in the first line together with chemotherapy and as a single agent after platinum-based therapy.
May 15, 2025. The FDA took an important step in anal canal cancer, a rare disease with limited options in the advanced setting, approving Zynyz (retifanlimab-dlwr) for two separate indications.
The first indication covers the use of retifanlimab 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 (SCAC). The second indication covers the use of the drug as a single agent (monotherapy) in patients with locally recurrent or metastatic SCAC whose disease progressed on or after platinum-based chemotherapy, or who could not tolerate that therapy.
Anal canal cancer accounts for a relatively small share of gastrointestinal tumors, yet once standard chemotherapy is exhausted in the advanced setting, the number of remaining options is limited. For that reason, immunotherapy moving into the first line alongside chemotherapy and also becoming available on its own in a later line fills a gap at two separate points of the patient journey.
Combination With Chemotherapy: POD1UM-303/InterAACT 2
The combination approval is based on POD1UM-303/InterAACT 2, a multicenter, randomized, double-blind trial in 308 chemotherapy-naïve patients. Patients were randomized 1:1 to receive either retifanlimab or placebo in addition to carboplatin and paclitaxel.
- Progression-free survival (PFS): median 9.3 months in the retifanlimab arm versus 7.4 months in the placebo arm (HR 0.63; p=0.0006).
- Overall response rate (ORR): 56% in the retifanlimab arm versus 44% in the placebo arm.
- Overall survival (OS): 29.2 months versus 23.0 months. This difference did not reach statistical significance; about 45% of patients in the placebo arm received retifanlimab after disease progression.
The chemotherapy regimen in the trial was planned for six cycles: carboplatin AUC 5 on day 1, and paclitaxel 80 mg/m² on days 1, 8 and 15. Retifanlimab was given intravenously at 500 mg every four weeks.
Single Agent After Platinum: POD1UM-202
The monotherapy approval is based on data from POD1UM-202, an open-label, single-arm trial in 94 patients whose disease progressed on or after platinum-based chemotherapy, or who were intolerant to it.
- Overall response rate (ORR): 14% (95% confidence interval: 8% to 23%).
- Median duration of response (DOR): 9.5 months.
Although the response rate is relatively low, the median duration of response of 9.5 months among responders is notable. In a group with no standard option after platinum, durability represents a meaningful gain for patients who do respond.
💬 Clinical Significance
Squamous cell carcinoma of the anal canal is an immunogenic tumor type strongly associated with human papillomavirus (HPV). The 1.9-month median PFS gain and the 56% response rate achieved by adding a PD-1 inhibitor to chemotherapy in POD1UM-303 show that this biology translates into the clinic. The lack of statistical significance in overall survival should be interpreted together with the fact that roughly half of the placebo-arm patients received retifanlimab after progression. In practice, the critical point is that immunotherapy can now be used from the very start of treatment while remaining an option after platinum as well.
What Will the Dose and Administration Be?
According to the prescribing information approved by the FDA, the recommended dosing is as follows:
| Drug / Setting | Recommended Dose | Route and Duration |
|---|---|---|
| Retifanlimab (Zynyz), combination | 500 mg every 4 weeks | Intravenous (IV) Up to 12 months. |
| Retifanlimab (Zynyz), single agent | 500 mg every 4 weeks | Intravenous (IV) Up to 24 months. |
| Carboplatin | AUC 5 on day 1 | Intravenous (IV) Up to six cycles. |
| Paclitaxel | 80 mg/m² on days 1, 8 and 15 | Intravenous (IV) Up to six cycles. |
Safety and Side-Effect Profile
Side effects reported in at least 20% of patients on combination therapy include:
- Fatigue and weakness
- Peripheral neuropathy (numbness and tingling in the hands and feet)
- Nausea, vomiting and decreased appetite
- Alopecia (hair loss)
- Diarrhea and constipation
- Musculoskeletal pain and abdominal pain
- Hemorrhage, rash and pruritus
Retifanlimab also carries the warnings typical of the PD-1 inhibitor class: immune-mediated adverse reactions (pneumonitis, colitis, hepatitis, endocrine disorders, severe skin reactions), infusion-related reactions, complications of allogeneic stem cell transplantation and embryo-fetal toxicity. Close monitoring of respiratory, gastrointestinal, liver, thyroid and skin findings is therefore recommended during treatment.
Conclusion
With the approval of retifanlimab, immunotherapy in squamous cell carcinoma of the anal canal is now positioned both alongside chemotherapy in the first line and on its own after platinum. In rare tumors, a wider set of treatment options is decisive for directing patients to the right therapy at the right time, and this development further clarifies the place of immunotherapy in HPV-related tumors.