Retifanlimab Displaces Chemo Alone as the Frontline Standard of Care in SCAC

With definitive, level 1 evidence showing that the addition of retifanlimab-dlwr (Zynyz) to systemic chemotherapy with carboplatin and paclitaxel improves progression-free survival (PFS) vs chemotherapy alone in patients with squamous cell carcinoma of the anal canal (SCAC), the regimen is expected to be swiftly adopted as a frontline standard of care (SOC) in this population, according to Marwan G. Fakih, MD.

Following the readout of the pivotal phase 3 POD1UM-303/InterAACT 2 trial (NCT04472429), the FDA approved the chemoimmunotherapy regimen on May 15, 2025, for the first-line treatment of adults with inoperable locally recurrent or metastatic SCAC.1,2 The FDA also approved retifanlimab, as a single agent, for adults with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy based on single-arm data from the phase 2 POD1UM-202 trial (NCT03597295).

“[POD1UM-303] is the first randomized trial with an immunotherapy agent in advanced SCAC that was positive. From that perspective, there’s no question that this should be implemented in the management of patients with anal cancer that is unresectable or recurrent after chemoradiation,” Fakih said in an interview with OncLive®.

In the interview, Fakih discussed the implications of the approval on patient care, the key efficacy and safety data behind the approval, and what to watch for when it comes to administration and dosing.

Fakih is a professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Research Infrastructure within the Comprehensive Cancer Center, medical director of the Briskin Center for Clinical Research, chief of the Division of GI Medical Oncology, and codirector of the Gastrointestinal Cancer Program at City of Hope in Duarte, California.

OncLive: What is the significance of the FDA approval of retifanlimab for patients with SCAC?

Fakih: The FDA approved retifanlimab in combination with carboplatin and paclitaxel for the first-line treatment of patients with advanced or metastatic SCAC. In addition, retifanlimab was approved as monotherapy in patients who had received prior systemic chemotherapy for patients with unresectable, locally advanced or metastatic SCAC. [Its importance lies in the fact that] the agency approved an immunotherapy drug for the first time in an area where there is significant unmet need.

The POD1UM-303 trial was a randomized, phase 3 clinical trial in patients with advanced squamous cell cancer. The study had a control arm of carboplatin and paclitaxel, which has been the SOC for the management of patients with advanced, unresectable SCAC. Of note, carboplatin and paclitaxel were considered the go-to regimen, not based on phase 3 trials, but based on a phase 2 trial. Now we have an approval based on a randomized phase 3 trial that shows that if you add immunotherapy, specifically retifanlimab, to systemic chemotherapy, you delay [disease] progression [or death] by 37%; the hazard ratio was 0.63 for the primary end point of the study.

This is very important for our patients, because now you can tell a patient that by adding an immunotherapy drug to systemic chemotherapy, carboplatin and paclitaxel, you will delay the progression of the disease by a notable percentage. The improvement in median progression-free survival was 1.9 months, which was statistically significant, and it met the primary end point of the study. As important as this is, we can also say that there has been a very strong trend towards improvement in overall survival, even though that was not the primary end point, in the setting of a phase 3 trial that had a crossover design where patients who progressed on systemic chemotherapy were able to receive immunotherapy. This is good for our patients and is supported by level 1 evidence. This is the first phase 3 trial conducted in this setting, and it was positive.

What is important to know about the safety profile of this agent?

Retifanlimab is a PD-1-targeting antibody. It’s an immunoglobulin IgG4 antibody, and like any other PD-1-targeted agent, it can be associated with some immune-related adverse effects [AEs]. What we’ve seen from the POD1UM-303 and POD1UM-202 trials is that the expected AEs are in line with what we’ve seen with other agents such as nivolumab [Opdivo] and pembrolizumab [Keytruda]. You may expect to see hypothyroidism in patients receiving this combination. You can see immune-related skin rashes, but usually these are low-grade and not associated with discontinuation. The rate of discontinuation secondary to toxicity is expected to be very low. One has to remain vigilant, however, about the potential for colitis and hepatitis, even though the incidence of those grade 3 events was very low. The compliance with the treatment was very high, and we did not see a significant drop off secondary to toxicity, which was reassuring. Most of us nowadays are very experienced in managing AEs of PD-1-targeting agents, and this one is no different.

What is the breakdown of the dosing schedule of this regimen?

Retifanlimab has a relatively long half-life, and it is given every 4 weeks, intravenously. Carboplatin and paclitaxel in POD1UM-303 were also given in an every 4-week cycle, with carboplatin being given on week 1 at an area under the curve of 5, and paclitaxel given at 80 mg/m2 on weeks 1, 2, and 3. The addition of retifanlimab does not really add any additional complexity to the dosing regimen. It’s given on the first day of the treatment, and with that, it affords patients some reasonable leeway. On this study, the chemotherapy was stopped after 6 months of therapy, so the [continued] every 4-week infusion of retifanlimab in the maintenance setting after the 6 months of therapy is very desirable and patient friendly in that they only have to come in once every 4 weeks to the clinic.

References

1. FDA approves retifanlimab-dlwr with carboplatin and paclitaxel and as a single agent for squamous cell carcinoma of the anal canal. FDA. May 15, 2025. Accessed September 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-retifanlimab-dlwr-carboplatin-and-paclitaxel-and-single-agent-squamous-cell-carcinoma
2. Zynyz. Prescribing information. Incyte Corporation; 2025. Accessed September 15, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761334s004lbl.pdf