Retifanlimab Emerges as Potential New SOC in Advanced SCAC

Sheela Rao, MBBS, MD, FRCP

Following encouraging efficacy seen in patients with locally advanced Merkel cell carcinoma (MCC), investigators initiated the phase 3 POD1UM-303/InterAACT 2 trial (NCT04472429) evaluating retifanlimab-dlwr (Zynyz) in patients with squamous cell anal carcinoma (SCAC), and the agent represents a potential treatment option in this patient population, according to Sheela Rao, MBBS, MD, FRCP.

In March 2023, retifanlimab was granted accelerated approval by the FDA for the treatment of adult patients with metastatic or recurrent locally advanced MCC.¹ The regulatory decision was supported by findings from the phase 2 POD1UM-201 trial (NCT03599713), which demonstrated that patients with metastatic or recurrent locally advanced MCC who had not received prior systemic therapy for advanced disease who received the agent (n = 65) achieved an overall response rate (ORR) of 52% (95% CI, 40%-65%).

“SCAC is an HPV-driven cancer which means it [can] happen quite early on,” Rao explained. “It’s part of the etiology of the cancer and thus leads to exhausted T cells from HPV infection. This provides a strong rationale for immunotherapy [use] in this cancer, as well as other HPV-driven cancers, and this was the impetus to study this [agent in this patient population].”

During the 2024 ESMO Congress, Rao presented data from POD1UM-303 showing that the study met its primary end point of PFS.² Patients with locally recurrent SCAC who received retifanlimab in combination with chemotherapy (n = 154) achieved a median PFS of 9.3 months (95% CI, 7.5-11.3) compared with 7.4 months (95% CI, 7.1-7.7) among patients who received placebo plus chemotherapy (n = 154; HR, 0.63; 95% CI, 0.47-0.84; P = .0006).

In an interview with OncLive®, Rao discussed the rationale for POD1UM-303, the significance of the data she presented during the 2024 ESMO Congress, and future research directions for retifanlimab in SCAC. Rao is a consultant medical oncologist specializing in gastrointestinal cancers and cancers of unknown primary within the Gastrointestinal Unit at the Royal Marsden Hospital in London, England.

OncLive: What are some of the key data that support the use of checkpoint inhibitors in SCAC?

Rao: There have been a number of single-arm, phase 2 studies evaluating retifanlimab, but also pembrolizumab [Keytruda] as well as nivolumab [Opdivo], in patients with advanced anal cancer who have disease refractory to chemotherapy. In these trials, we saw [that] when we gave single-agent immunotherapy, ORRs ranged from approximately 13% to 30% and the [median] progression free survival [PFS] was [approximately] 2 to 4 months.

More interestingly, although these [findings] were not outstanding in terms of response rate and PFS, we saw patients who seemed to have a long duration of response. This was really encouraging and something that made us want to study this [agent] further.

How does retifanlimab distinguish itself from other checkpoint inhibitors?

Retifanlimab is an anti–PD-1 antibody [and] it is similar to other immunotherapies. It’s given intravenously [IV] every 4 weeks and is well tolerated. If anything, rather than it being distinguished from others, it has [shown] very consistent safety and efficacy data to other immunotherapy checkpoint inhibitors.

[One difference is] there are some other checkpoint inhibitors [which] are given every 3 weeks and others are given twice weekly. Retifanlimab [is administered] every 4 weeks, which is convenient because patients are not coming in too often [for treatment].

What was the design of POD1UM-303?

POD1UM-303 was a phase 3 trial of patients who had not previously received chemotherapy in the advanced setting. These were patients who had metastatic or locally advanced recurrent SCAC. We randomly assigned these patients 1:1 to receive chemotherapy with carboplatin and paclitaxel—which is the current standard of care and they received that for 6 months in both arms—[in combination with] IV retifanlimab every 4 weeks for up to a year or placebo [for up to a year]. Patients in the placebo arm were able to crossover on confirmed blinded independent central review of progression to receive single-agent retifanlimab had they not received it previously.

What were the key data that you shared from the study during the 2024 ESMO Congress and their potential significance?

The primary end point of this study was PFS, and data demonstrated a significant improvement in the median PFS from 7.4 months in the placebo arm to 9.3 months with the addition of retifanlimab. [Additionally], we saw an improvement in ORR, with [a rate of] 56% [95% CI, 48%-64%] in the retifanlimab arm vs 44% [95% CI, 36%-52%] in the control group. We also saw an improvement in overall survival [OS] at the interim analysis from 23.0 months [95% CI, 15.1-27.9] in the control arm to 29.2 months [95% CI, 24.2-not estimable] in the retifanlimab arm; the 95% CI has not been reached there. These data are still immature, but there is a suggestion based on the curve that there is a trend towards improved OS.

The addition of retifanlimab [to chemotherapy] was well tolerated. We did see an increase in immune adverse effects as one would expect, but these were manageable. The immunotherapy did not compromise the delivery of the chemotherapy, and overall did not lead to significant dose reductions or delays in treatment.

Overall, this study was successful in that we’ve seen an improvement in our efficacy outcomes, including PFS, ORR, and OS, but with manageable toxicity that one would expect when combining chemotherapy with immunotherapy. This is the first phase 3 trial [of a checkpoint inhibitor] conducted in this setting [and] the largest trial in this setting, and it met its primary end point. Therefore, it represents a new standard of care [with] this drug.

Does there appear to be a biomarker of response to retifanlimab in this patient population?

We know from the demographics that [approximately] 90% of patients in both arms had a PD-L1 [expression] of [at least] 1% by combined positive score. However, we are now trying to understand further biomarkers to identify exceptionally good responders or patients who may progress. Currently, we don’t have those data, but this is something that we are exploring further. PD-L1 expression, not just greater than 1%, but greater than 5% and greater than 10%, are all being explored, and we will have those data.

We know that over a third of patients in both arms, but [notably] in particular the patients that received retifanlimab, had metastatic liver disease. This does not seem to be a negative, as in other studies, but there’s further work to be done. We’re also looking at HPV ctDNA and whether changes in that can correlate with response. These are all further data that we will be exploring and then presenting once we have the results.

What is your overall message to your colleagues regarding the investigational landscape of SCAC and immunotherapy in solid tumors in general?

For SCAC, the good news is that compared with even 5 and definitely 10 years ago, if one looks at the number of trials, there are now far more, and this is something that is opening up to investigation. We have pharmaceutical companies interested in reviewing this cancer, and this means that hopefully we will be able to provide better long term treatment.

Immunotherapy in the advanced setting in this cancer seems to have the most efficacy when it’s combined with chemotherapy. The data from POD1UM-303 show that when combined with chemotherapy, the effects of immunotherapy seem to be enhanced much more than when given as a single agent in the refractory setting.

In terms of where we go from here, we need to understand biomarkers and what helps drive this response and the durability of the response, as well as which patients may not benefit from this [treatment approach]. The next tranche of research needs to understand what we give after this, if we give first-line immunotherapy and chemotherapy, what the resistance mechanisms are, and what other targeted or novel agents may be useful. That’s where further clinical trials come into play.

In terms of immunotherapy in solid tumors, those are the broad topics that we need to understand. There are a lot of questions at the moment. In this study, we gave retifanlimab for 1 year. One of the questions that’s [emerging with] immunotherapy in solid tumors is, ‘What is the optimal duration of immunotherapy?’ In many trials in other cancers as well as in some of gastrointestinal cancers, they’re being given for 2 years. In this trial, we gave it for 1 year, and we’re seeing that the curves separate early on and they remain separated. I believe this is going to be an important question going forward.

References

1. FDA grants accelerated approval to retifanlimab-dlwr for metastatic or recurrent locally advanced Merkel cell carcinoma. FDA. March 22, 2023. Accessed January 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-retifanlimab-dlwr-metastatic-or-recurrent-locally-advanced-merkel
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