Dr Fakih on Addressing the Growing Unmet Need in Second-Line Metastatic Anal Cancer

"We still have to address the patients who are refractory to carboplatin and paclitaxel. Those are the [patients with the] highest unmet need, in my opinion, because you can't recycle the chemotherapy."

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 evolving role of immunotherapy for advanced squamous cell carcinoma of the anal canal (SCAC).

In May 2025, the FDA approved retifanlimab-dlwr (Zynyz) in combination with carboplatin and paclitaxel for the first-line treatment of adult patients with inoperable locally recurrent or metastatic SCAC; and as monotherapy for the treatment of adult patients with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy. This approval was supported by data from the pivotal phase 3 POD1UM-303/InterAACT2 trial (NCT04472429).

Although this regulatory decision marked a significant advancement in SCAC by enabling the integration of PD-1 blockade into the frontline treatment arsenal, it has simultaneously exposed a critical lack of effective second-line strategies for patients with platinum-refractory disease, Fakih stated. He noted that patients who progress on frontline immunochemotherapy face a major dilemma: if a patient progresses on retifanlimab, there is no conclusive evidence showing that switching to other PD-1–targeted agents such as nivolumab (Opdivo) or pembrolizumab (Keytruda) is effective, he stated.

Fakih noted that the most significant unmet need exists for patients who are refractory to the carboplatin and paclitaxel backbone, specifically those who progress within the first 6 months of therapy. For these individuals, standard chemotherapy regimens—such as 5-fluorouracil plus cisplatin, FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or DCF (docetaxel, cisplatin, and fluorouracil)—cannot be recycled effectively, he explained.

As the frontline chemoimmunotherapy combination becomes further integrated into standard practice, it is imperative to conduct robust clinical trials in the second-line setting, Fakih emphasized. Future research must look beyond PD-1 inhibitors and more appropriately study novel agents and cytotoxic agents to address the high-risk, platinum-refractory population, he concluded.