POD1UM-303 Ushers in Era of Upfront PD-1 Blockade in SCAC, Revealing Unmet Needs in Later Lines

Data from the pivotal phase 3 POD1UM-303/InterAACT2 trial (NCT04472429) has successfully moved PD-1 blockade into the frontline setting for patients with advanced squamous cell carcinoma of the anal canal (SCAC) with the May 2025 FDA approval of retifanlimab-dlwr (Zynyz) plus carboplatin and paclitaxel.¹ However, this shift in strategy exposes a growing unmet need for effective second-line strategies for patients with platinum-refractory disease after progression on frontline chemoimmunotherapy, according to Marwan G. Fakih, MD.

“The data show that the best outcomes occur in patients who receive retifanlimab upfront,” said Fakih in an interview with OncLive®. “We cannot compensate for missing retifanlimab in the first-line setting by using it as a salvage strategy, as it appears to result in a lower OS. [However], as we use it in the first line, we can no longer make the case for using any other PD-1 agent in the second-line setting, as giving more retifanlimab, nivolumab [Opdivo], or pembrolizumab [Keytruda] upon progression is of unproven efficacy.”

In addition to underscoring the value of chemoimmunotherapies in the first line, Fakih highlighted key efficacy and safety outcomes from POD1UM-303, including a doubling of response duration; detailed the toxicity and quality of life benefits for patients as a result of this prolonged period of disease control; and reiterated the need for continued drug development in the second-line setting and beyond for patients with advanced SCAC.

Fakih serves as 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 in Duarte, California.

OncLive: What are some of the current unmet needs and treatment gaps within the first-line setting for patients with advanced SCAC?

Fakih: Unfortunately, we did not previously have many options for patients with metastatic SCAC, or for patients who had localized disease and received chemoradiation but then had a non-operable locoregional recurrence. Historically, these patients have been treated with carboplatin and paclitaxel. Until recently, our practice was driven by smaller phase 2 trials, and we knew that the combination of carboplatin and paclitaxel appeared as good as, or slightly better than, cisplatin plus fluorouracil regarding efficacy, while being safer.

Thankfully, the landscape has changed because of the randomized, phase 3 POD1UM-303 trial. This is the first well-conducted phase 3 trial to ask whether incorporating an immunotherapy agent—specifically the PD-1 antibody retifanlimab—on top of carboplatin and paclitaxel improves survival. We now know that adding retifanlimab to first-line therapy improves progression-free survival [PFS] in a statistically significant fashion. As we follow these patients further, we note that they also derive a clinically meaningful increase in overall survival [OS].

Since its FDA approval in May 2025, how has retifanlimab plus carboplatin and paclitaxel altered the treatment landscape and patient expectations in frontline SCAC?

There has been an ongoing increase in the use of this combination in patients with advanced or recurrent SCAC. It is important to disseminate the data; many are now aware that the improvement in PFS is notable when retifanlimab is added to carboplatin and paclitaxel. The median PFS improved from 7.4 months [95% CI, 7.1-7.7] with chemotherapy to 9.3 months [95% CI, 7.5-11.3] with the triplet.²

This represents a [reduction in the risk of] progression [or death] of 37% [HR, 0.63; 95% CI, 0.47-0.84; P = .0006], which is very meaningful. We see an early separation in the PFS curves that continues beyond 2 years. We also see that patients receiving the retifanlimab triplet have a higher objective response rate [ORR] at 55.8% [95% CI, 47.6%-63.8%] compared with 44.2% [95% CI, 36%-52.4%] with chemotherapy alone.

What does the prolonged DOR seen with the addition of retifanlimab to chemotherapy signal?

It appears that patients not only have a higher likelihood of achieving a very good response, but those responses also last a lot longer. On the POD1UM-303 trial, systemic chemotherapy was capped at 6 months. The median DOR for those receiving the retifanlimab triplet was 14 months [95% CI, 8.6-22.2] compared with 7.2 months [95% CI, 5.6-9.3] for those receiving chemotherapy alone.²

Adding retifanlimab doubled the DOR. This is very meaningful for patients because it represents a period of disease control without the need for chemotherapy. Patients are able to stay off chemotherapy longer without progression, which is significant not only for an eventual OS advantage, but also because they are not dealing with the major toxicities related to cytotoxics during that time.

What safety and OS outcomes have been seen with this combination?

The toxicities with retifanlimab are similar to what you expect with other PD-1 agents, such as nivolumab and pembrolizumab. Typically, we see some arthralgia, skin rash, or a slight increase in diarrhea, but these were manageable toxicities with a low rate of significant immune-related adverse effects.

Regarding OS, the study was designed as a crossover study, which can sometimes dilute the impact of a new agent. However, despite the fact that approximately half of the patients on the control arm crossed over to receive retifanlimab later, the OS was a lot better in the frontline retifanlimab arm. Numerically, it was 32.8 months [(95% CI, 25.7-44.5) with the retifanlimab combination] vs 22.2 months [(95% CI, 15.7-27.2) with the chemotherapy triplet].² This [approximate] 10-month difference in median OS is quite meaningful, as no large, randomized studies in advanced SCAC have previously reached a 30-month OS threshold.

Based on this level 1 evidence, the National Comprehensive Cancer Network has endorsed the combination as a first-line treatment.

With the frontline and second-line FDA approvals for retifanlimab, how do you view immunotherapy’s ability to continue impacting the treatment paradigm, and where might research go next?

POD1UM-303 is practice-changing and has moved PD-1 therapy into the frontline. [However], evidence for strategies like fluoropyrimidine monotherapy or other combinations in the second line is very thin. This highlights the significant unmet need in the second line.

We must address patients who are platinum-refractory, [defined as] those who [experience disease progression] within the first 6 months, as we cannot simply "recycle" the chemotherapy in those patients. We need clinical trials in the second line and beyond to move past low-level evidence and continue improving outcomes.

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 March 10, 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