Dr Fakih on the Advantages of Frontline Retifanlimab Use in SCAC

"I think we lose something by keeping PD-1 targeting for the second line. The big question is what happens if [a patient] progresses on retifanlimab maintenance, and I think [that depends on] how far from [the cessation of] systemic therapy [progression] occurred. It opens doors for additional questions in the future.”

Marwan G Fakih, MD, a professor in the Department of Medical Oncology & Therapeutics Research; associate director of Clinical Sciences; medical director of the Briskin Center for Clinical Research; division chief of GI Medical Oncology; and co-director of the Gastrointestinal Cancer Program at City of Hope, discussed the shifting treatment paradigm for squamous cell anal carcinoma (SCAC) following results from the phase 3 POD1UM-303/InterAACT 2 (NCT04472429) trial.

PODIUM-303 demonstrated a statistically significant improvement in median progression-free survival with retifanlimab-dlwr (Zynyz) plus carboplatin and paclitaxel vs placebo plus carboplatin and paclitaxel (9.3 months [95% CI, 7.5-11.3] vs 7.4 months [95% CI, 7.1-7.7]; HR, 0.63; 95% CI, 0.47-0.84; P = .0006). Moreover, a 10-month improvement in median overall survival (OS) was observed with the retifanlimab-containing triplet vs chemotherapy alone (32.8 months vs 22.2 months). These data supported the FDA approval of retifanlimab plus carboplatin and paclitaxel for patients with inoperable locally recurrent or metastatic SCAC not previously treated with systemic chemotherapy in May 2025.

Data from PODIUM-303 provide a strong clinical rationale for moving immune checkpoint inhibitors into the first-line setting rather than reserving them for later lines of therapy, suggesting a potential synergy when combined with chemotherapy upfront, Fakih explained. He highlighted that the trend for OS continues to favor frontline treatment with carboplatin, paclitaxel, and retifanlimab compared with the crossover group that received the chemotherapy doublet followed by the PD-1 inhibitor only upon progression. Crucially, the crossover population did not achieve outcomes as strong as those who received retifanlimab upfront, Fakih noted. Furthermore, the activity of retifanlimab as a second-line treatment in the crossover group was notably limited, with an overall response rate (ORR) in the single digits.

Although SCAC is a rare disease, Fakih noted that the success of PODIUM-303 demonstrates that clinical trials in this population are feasible and essential for addressing a major unmet need. However, the shift toward frontline immunotherapy has created a new therapeutic challenge: managing patients who progress while on retifanlimab maintenance. Once a patient progresses, they are generally considered resistant to PD-1 therapy, and there is currently no data to support continuing the agent, Fakih said.

For these patients, the appropriate next step depends on the timing of progression, Fakih asserted. If a patient achieved a partial response but experienced disease progression 8 months after their last dose of chemotherapy, a rechallenge with carboplatin-based treatment may be appropriate, he explained. Ultimately, Fakih emphasized that sequencing PD-1 inhibitors earlier in the disease course optimizes response magnitude and survival, marking a significant advancement for patients with this underserved malignancy.

This video was supported in part by Incyte. Content independently developed and published by OncLive