Immunotherapy Advances in Upfront SCAC Expose Need for Better Second-Line Strategies

With landmark studies such as the phase 3 POD1UM-303/InterAACT 2 trial (NCT04472429) refuting concerns about both the feasibility and clinical value of immunotherapy research in a rare malignancy like squamous cell carcinoma of the anal canal (SCAC), building a stronger second-line treatment arsenal is the next major challenge, according to Aparna R. Parikh, MD.

Primary results from PODIUM-303 demonstrated a clinically meaningful and statistically significant reduction in the risk of progression or death with retifanlimab-dlwr (Zynyz) plus chemotherapy vs placebo plus chemotherapy.¹ These data supported the May 2025 FDA approval of retifanlimab in combination with carboplatin and paclitaxel for the first-line treatment of patients with inoperable, locally recurrent or metastatic SCAC.Of note, the FDA concurrently approved retifanlimab as monotherapy for patients with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy based on findings from the phase 2 POD1UM-202 trial (NCT03597295).

“Previously, immunotherapy was in the National Comprehensive Cancer Network [NCCN] guidelines as an option for the second line but was not preferred because we knew the data were underwhelming,” Parikh shared in an interview with OncLive®. “Having this positive trial leading to FDA approval and a NCCN recommendation is significant. [However,] now we have to understand what to do after this combination. We really need better second-line options.”

In addition to breaking down key data from PODIUM-303, Parikh explained how the study's results have changed the standard of care for first-line treatment in SCAC, emphasized the importance of using the combination of retifanlimab plus chemotherapy up front, and spotlighted ongoing research and potential future strategies in the SCAC space.

Parikh is an assistant in medicine, Hematology and Oncology, and an attending oncologist for the Tucker Gosnell Center for Gastrointestinal Cancers and Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital; as well as an associate professor of medicine at Harvard Medical School in Boston.

OncLive: What treatment gaps and challenges persist in the frontline setting for patients with SCAC?

Parikh: This is a really exciting time [in SCAC]. For the longest time, the historical standard for metastatic or unresectable patients with SCAC was carboplatin and paclitaxel. This was based on an older study, the phase 2 InterAAct trial [NCT02051868], which looked at this regimen vs cisplatin and [5-Fluorouracil (5-FU)]; ultimately, carboplatin plus paclitaxel was the gold standard and the backbone for therapy for years.

Over the last 2 years or so, we have seen many trials looking at the addition of immuno-oncology agents, initially in the second line with pretty unremarkable activity. That led us toward the most recent data from the PODIUM-303 study, which looked at an immunotherapy-chemotherapy combination. This is the combination of a PD-1 inhibitor with the gold standard backbone of carboplatin and paclitaxel.

What was the design of PODIUM-303?

PODIUM-303 was a large, global, double-blinded phase 3 study. Patients could not have had prior systemic therapy for advanced disease.² Patients in this study were randomly assigned to retifanlimab plus carboplatin and paclitaxel vs placebo plus carboplatin and paclitaxel. Patients received induction chemotherapy and then continued to receive the immunotherapy for a set period.

What key findings were reported from this trial?

The primary end point was progression-free survival [PFS], and the study met that end point.^1,2 We saw a median PFS of 9.3 months [(95% CI, 7.5, 11.3) with retifanlimab] vs 7.4 months [(95% CI, 7.1-7.7) with placebo], with a HR of 0.63 [95% CI, 0.47-0.8 P = .0006]. [The retifanlimab combination] was well tolerated, with some immune-related adverse effects, as expected from PD-1 monotherapy.

The published overall survival [OS] data are still immature. There is always a caveat when looking at survival data regarding crossover at the time of progression. However, the median OS was 29.2 months [95% CI, 24.2-not estimable] vs 23 months [(95% CI, 15.1-27.9) with placebo, which is suggestive of benefit even with crossover [HR, 0.70; 95% CI, 0.49-1.01].

These data have truly changed the landscape of treatment. The nice thing is that it does not require any biomarker testing; it is independent of PD-L1 status, and these are microsatellite stable patients, not tumor mutational burden–high patients.

How has this regimen been integrated into clinical practice since its approval, and what has it meant to have this combination in the front line?

There has been some variability regarding which PD-1 inhibitor to use. As we were waiting for the approval, many institutions did not have retifanlimab on their formulary, so some were substituting it with their other PD-1 inhibitor of choice. At our own institution, we felt it was important to reward the company that did the trial in this space. Anal cancer is not a common cancer and is unfortunately understudied; we don't see as much development as we would like. Given that we had the data for retifanlimab, we made sure it was our preferred option. Unless a patient has a severe autoimmune contraindication or a very poor performance status, this combination is now the first-line standard of care.

Why should this immunotherapy regimen be leveraged upfront instead of saved for the second line?

It is very important to give this therapy upfront. If we have a patient who did not receive it initially, there are phase 2 signals for second-line use, but they are much less impressive. I strongly encourage using this as a preferred first-line regimen. For whatever reason, if a patient has been on carboplatin and paclitaxel historically and we are seeing them now or just put them on [treatment with carboplatin and paclitaxel], I would encourage the addition of immunotherapy [to their treatment regimen]. There are many nuances to that, and I hate to make generalizations, but the approval has been out for nearly a year, and we are still lagging a little bit in our [adoption of it]. Hopefully, no new patients are in a position where they are missing out; anyone new now should be going on this combination.

Is there anything else you are watching in this space as a potential next wave of treatment strategies?

There are a few things coming through the pipeline that could be interesting. Outside of this [immunotherapy combination], we don't really have many options; there is some single-agent activity with chemotherapies like FOLFOX, for example, but we really need better second-line options. One thing to discuss with practitioners is that there was a period of induction with carboplatin and paclitaxel in the trial. If a patient derived benefit or if the chemotherapy was stopped even earlier for toxicity rather than frank progression, revisiting that chemotherapy component is an important tool to have in the toolbox.

If you have a patient right now who has some mild progression while on the maintenance immunotherapy phase, you can reintroduce the carboplatin and paclitaxel while keeping the immunotherapy. I had another patient recently who seemed to have good control everywhere but had one site progressing. In those cases, can you do something local like radiation to one lesion while still maintaining the durability of the systemic treatment? It is about trying to think about how to optimize this regimen, not only in the first line, but also figuring out when and where progression happens. They could still be chemoresponsive to carboplatin and paclitaxel, but once they are no longer responding to the combination, there is a tremendous unmet need.

The other space is earlier-stage anal cancer, where concurrent chemoradiation is still the standard of care. There are trials looking at the concurrent use or consolidation of PD-1 inhibitors with chemoradiation or perhaps using circulating tumor DNA in the earlier-stage setting to risk-adapt care and potentially de-escalate treatment for low-risk patients. While 5-FU and mitomycin, or cisplatin, have been the gold standard for decades in the local setting, how the PD-1 inhibitors might come into that earlier-stage setting is something that is being explored.

Why is continuing to drive research in this rare tumor type important?

If we look at trials like PODIUM-303 or SWOG [cooperative group studies], anal cancer is rare despite the incidence. It represents only a few percentage points of large bowel malignancies—1% to 6% of anorectal tumors—with [approximately] 50,000 patients a year globally. There is often skepticism and reluctance to do clinical trials, but PODIUM-303 and others have shown us that we can. To me, those were tremendous efforts to bring trials to this space.

Even outside of the cooperative groups asking these questions, the pharmaceutical industry is seeing that these are feasible trials for a tremendously unmet need. This was also a tumor type with a human papillomavirus [HPV] link, and it will be interesting to see how this shifts over time with HPV vaccination. We also see this cancer in patients living with HIV. We have seen shifts in drug development to now include these patients in trials, allowing those with controlled viral loads to be in studies. Not excluding those patient populations anymore is important. So yes, it is still a relatively rare cancer, but it presents a feasible unmet need that tracks with other HPV malignancies, and the HIV link is important as well.

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 May 13, 2026.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