Retifanlimab Presents a New Treatment Option for Locally Recurrent or Metastatic SCAC

Retifanlimab for Locally Recurrent

or Metastatic SCAC | Image Credit:

© Image by Ashling Wahner & MJH

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The May 2025 FDA approval of retifanlimab-dlwr (Zynyz) plus carboplatin/paclitaxel for the first-line treatment of patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) has provided a significant treatment option for this patient population, whose cancer is no longer considered rare, as incidence rates have increased within the past 20 years, according to Cathy Eng, MD, FACP, FASCO.1

The regulatory decision was supported by data from the phase 3 POD1UM-303/InterAACT2 trial (NCT04472429), which evaluated retifanlimab plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel in patients with locally recurrent or metastatic SCAC. Of note, the study met its primary end point of progression-free survival (PFS), in which the median PFS was 9.3 months (95% CI, 7.5-11.3) vs 7.4 months (95% CI, 7.1-7.7) in the retifanlimab (n = 154) and placebo (n = 154) arms, respectively (HR, 0.63; 95% CI, 0.47-0.84; P = .0006).2 At the data cutoff date of April 15, 2024, a strong trend of improved overall survival (OS) was demonstrated, although the data were immature.

“[Retifanlimab plus carboplatin/paclitaxel] provides another great opportunity for patients. However, the problem is that we don’t have any other options [after that],” Eng explained during an interview with OncLive®. “If you move immuno-oncology [IO] therapy from the second line to the frontline, we have no standard of care left in the second-, third-, or fourth-line settings.”

In the interview, Eng discussed the FDA approval of retifanlimab for patients with SCAC, considerations while dissecting data from the 2 respective trials, and how ongoing research is addressing IO drugs moving into the frontline setting.

Eng is the David H. Johnson Endowed Chair in Surgical and Medical Oncology, a professor of medicine in the Department of Hematology and Oncology, and the director for Strategic Relations at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

OncLive: In May, the FDA approved retifanlimab for patients with SCAC. What are the implications of having retifanlimab available for these 2 indications?

Eng: [POD1UM-303] was the first trial to be presented to demonstrate a PFS benefit of a little over 2 months for [patients with] newly diagnosed metastatic SCAC. [Retifanlimab] is a new option [that allows us] to move IO therapy to the frontline setting. Other trials are ongoing. The POD1UM-303 trial was largely conducted overseas, with a very small component of patients [from the United States (US)]. It’s a huge opportunity for pharmaceutical companies to pursue for metastatic SCAC, and there is an ongoing trial, EA2165 [NCT03233711], that we don’t have the results for in regards to IO therapy in the locally advanced, high-risk setting. Everybody’s anxiously awaiting those results because it’s [looking at 6 months of IO therapy in the adjuvant setting in] patients who have completed their chemoradiation therapy but are at high risk of recurrence due to tumors greater than 4 cm or positive nodes.

There’s another trial looking at IO therapy in the earlier stage, chemoradiation therapy setting, from our European colleagues, that is also currently pending. The IO space is moving towards the frontline, and hopefully, we’ll be moving [IO] into the locally advanced setting. We hope the findings from the phase 3 EA2176 trial (NCT04444921) will validate the findings from the POD1UM-303 study because that would demonstrate that we’re [able to] duplicate those [results] in the US patient population.

In the US, the difference between the [POD1UM-303 and EA2176] studies is that the POD1UM-303 study allowed crossover if patients were in the control arm. EA2176, which is the US study, doesn’t allow crossover, because patients already have nivolumab [Opdivo] plus carboplatin available to them, and it was already [added to] the National Comprehensive Cancer Network guidelines. Our primary end point is purely PFS. OS is a secondary end point, [and therefore] crossover wasn’t needed in the US trial.

How does ongoing research address IO moving into the frontline setting and potentially bringing other agents in to help with treatment sequencing decisions?

We are encouraging pharmaceutical companies to continue to support other efforts in either human papillomavirus [HPV]–associated malignancies or metastatic squamous cell carcinoma malignancies in general. Any breakthroughs that are noted in SCAC can be applied to other HPV-associated malignancies, such as cervical cancer, [among others], because [more than 90% of] anal carcinomas are HPV-associated. It’s an unmet need that pharmaceutical companies should consider. They need to recognize this is not just a rare cancer anymore. This has been rising in incidence as long as my career, by a little less than 3% per year. For over 23 years now, we’ve gone from approximately a little over 2000 cases per year to about 11,000 cases per year in the US. Globally, it’s estimated to be between 40,000 and 50,000 cases per year. That’s important to keep in mind; this is an opportunity for drug development, and pharmaceutical companies need to think broader.

Based on this FDA approval, what takeaways would you offer colleagues about the SCAC treatment paradigm and future research directions in this space?

It’s important [to recognize] that, even within the cooperative group ECOG, we conducted 3 phase 3 trials within the past decade for this patient population. What it demonstrates is that this [research] can be done. The issue is that most of these patients have diffuse metastatic disease. They’re not necessarily cured. We need new treatment options for patients. If we’re prolonging their OS, we will be able to provide them other treatment options down the road. There are so many more unique pathways we need to consider for this patient population. IO resistance is always an issue—it’s very important to keep in mind that these trials only provide systemic chemotherapy. The [POD1UM-303 and EA2176 ]trials only provide systemic chemotherapy for 6 months at a maximum, with the IO therapy, but then the IO therapy is continued for a duration of up to 2 years in both trials.

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 June 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-retifanlimab-dlwr-carboplatin-and-paclitaxel-and-single-agent-squamous-cell-carcinoma
2. Rao S, Samalin-Scalzi E, Evesque L, et al. POD1UM-303/InterAACT 2: phase III study of retifanlimab with carboplatin-paclitaxel (c-p) in patients (pts) with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) not previously treated with systemic chemotherapy (chemo). Ann Oncol. 2024;35(suppl 2):S1217. doi:10.1016/j.annonc.2024.08.2262