Retifanlimab Combination Signals a New Era of Chemoimmunotherapy in Frontline Advanced Anal Cancer

The frontline treatment of advanced squamous cell carcinoma of the anal canal (SCAC) is increasingly shifting toward chemoimmunotherapy to maximize durability and response rates, as evidenced by the introduction of retifanlimab-dlwr (Zynyz) plus carboplatin/paclitaxel into the treatment paradigm as a new gold standard, according to Richard D. Kim, MD.

The May 2025 FDA approval of retifanlimab plus carboplatin/paclitaxel for the first-line treatment of adult patients with inoperable locally recurrent or metastatic SCAC was supported by data from the phase 3 POD1UM-303/InterAACT2 trial (NCT04472429).¹ This study met its primary progression-free survival (PFS) end point with the chemoimmunotherapy combination reducing the risk of disese progression or death by 37% compared with placebo plus carboplatin/paclitaxel (HR, 0.63; 95% CI, 0.47-0.84; P = .0006).^1,2

“Based on this positive phase 3 study, if I see a patient in my clinic with advanced anal cancer, irrespective of any biomarkers currently out there—because we don't have many—I would choose carboplatin and paclitaxel plus retifanlimab in the first-line setting,” Kim shared in an interview with OncLive®. “This ensures that the patient is exposed to immunotherapy earlier on, which is something patients want. Hopefully, we can improve overall survival [OS] as well.”

In the interview, Kim highlighted unmet needs and treatment gaps in frontline SCAC; discussed the implications of data from PODIUM-303 for the use of retifanlimab in combination in the first-line setting and as monotherapy in later lines; and spotlighted emerging immunotherapy strategies and combinations of interest in this space.

Kim is the service chief of Medical Gastrointestinal Oncology and a senior member in the Gastrointestinal Oncology Department at Moffitt Cancer Center. He is also a professor of oncology at the University of South Florida College of Medicine in Tampa, Florida.

OncLive: What are some of the current treatment gaps and unmet needs for patients with SCAC in the frontline?

Kim: In terms of the frontline gaps and unmet needs for a patient with advanced SCAC, there are a couple of things that we need to discuss. One is that we know the standard treatment at this time is chemotherapy plus immunotherapy, but currently, we do not have any predictive biomarkers for our treatment options. We know that PD-L1 positivity is very common and that HPV p16 [positivity] is prognostic, but neither reliably selects who benefits from adding immunotherapy. We could do a better job of trying to identify a biomarker to determine who will benefit most from immunotherapy.

A second unmet need is: what do you do after a patient [progresses on] chemoimmunotherapy in the first- or second-line setting? There aren’t much data regarding that. A third unmet need is that, although we have the option of using frontline chemotherapy and immunotherapy, I still think durability remains a core problem. We could do better in terms of improving the duration of response and, ultimately, improving median OS. Last but not least, in patients with advanced SCAC, there are special high-risk populations, such as patients with immunosuppression. [Treatment strategies for] these patients need to be explored more, as only a small proportion of them were actually included in the pivotal [PODIUM-303] study.

For patients with HPV-driven disease, what are the biological and clinical implications in terms of treatment and outcomes?

We know that one of the biggest risk factors these days for SCAC is HPV. Anal cancer is HPV-driven, and there is a viral antigen expressing E6/7, which I think supports the use of immunotherapy in this setting. We know that HPV positivity is prognostic, and those patients tend to have better outcomes, at least based on the meta-analyses that have been presented.

However, in the PODIUM-303 study, approximately 75% of [evaluable] patients were p16-positive, but it is unclear if that is a predictive biomarker for response to immunotherapy. That area has to be explored further to determine whether HPV status is a predictive biomarker for immunotherapy. One emerging implication of this is that we are now able to check HPV circulating tumor DNA [ctDNA]. That is becoming clinically meaningful for risk stratification, especially in patients [who received] chemoradiation for locally advanced disease, and maybe even advanced disease, because you can follow the HPV ctDNA to see how a patient is responding to immunotherapy.

How has the May 2025 FDA approval of retifanlimab plus carboplatin and paclitaxel affected the first-line treatment of adult patients with inoperable locally recurrent or metastatic SCAC?

Prior to the May 2025 FDA approval of retifanlimab plus carboplatin and paclitaxel, carboplatin and paclitaxel was considered the standard of care based on the [phase 2] InterAACT trial [NCT02051868], which showed that it was better than cisplatin/[5-fluorouracil (FU)] at the time.² PODIUM-303 was a phase 3 study comparing carboplatin and paclitaxel plus retifanlimab vs carboplatin and paclitaxel as the standard of care.

In [PODIU-303], by adding immunotherapy to the chemotherapy backbone, there was an improvement in [median PFS] from 7.4 months [(95% CI, 7.1-7.7) with placebo plus carboplatin/paclitaxel] to 9.3 months [(95% CI, 7.5-11.3) with retifanlimab plus chemotherapy]. There was also an increase in overall response rate [(ORR) with the retifanlimab combination], going from 44.2% [(95% CI, 36%-52.4%) with placebo] to 55.8% [95% CI, 47.6%-63.8%]. Regarding OS, there was a trend toward improved survival, even though it was not significant by P value at the interim analysis. We have to understand that 45% of patients crossed over [to receive retifanlimab] after progression. We will wait for the final OS [data to read out], but there was definitely a trend.

What has been your clinical experience with retifanlimab, either in combination with chemotherapy or as monotherapy in later-line settings? How do you decide whether to use retifanlimab in the frontline setting vs save it for the second line?

At this time, retifanlimab is approved in the first line [as a] combination [therapy], and it is also approved as a single agent in the second-line setting [after progression on or intolerance to platinum-based chemotherapy]. Based on the data we have seen with the PODIUM-303 study, it clearly makes sense to use it at the beginning. You are not only getting the benefit of PFS and a higher ORR, but OS is over 20 months. By giving it upfront, we are ensuring that the patient will get exposed at the beginning and not the end.

The only reason I would use it in the second-line setting as a single agent is for patients who have not received immunotherapy in the first line for whatever reason. If you have someone with an autoimmune disease, which is a relative contraindication, you have to be careful about whether you want to use immunotherapy. Otherwise, if there is no absolute contraindication, I do not see a reason not to use immunotherapy in the first-line setting for a patient with advanced SCAC.

When selecting a frontline treatment regimen, how do safety and quality of life (QOL) considerations influence treatment decisions?

In terms of QOL and safety, we know that carboplatin and paclitaxel was studied in the InterAACT trial, comparing it against cisplatin and 5-FU. In that study, the outcomes seemed to favor carboplatin and paclitaxel because it had a much lower [rate of] serious adverse effects [AEs] compared with 5-FU and cisplatin. PODIUM-303 used carboplatin and paclitaxel as a backbone, and in that study, by adding immunotherapy to the backbone, you are going to get some AEs related to the immunotherapy.

Serious AEs were seen [in 47% of patients in the experimental arm], and 11% of patients had to discontinue retifanlimab due to toxicity. However, if you balance the 2 sides, while there is a slight increase in immune-mediated AEs as expected, retifanlimab did not add much more toxicity compared with chemotherapy alone.

[Safety outcomes] must be balanced with the efficacy data. QOL is very important, but in my opinion, the efficacy data play a bigger role, although we must understand the toxicity that we get by adding immunotherapy to a chemotherapy regimen.

How do you see the role of immunotherapy continuing to evolve in SCAC?

At this time, there are a couple of ongoing studies that have not completely read out. There is the [phase 3] EA2176 study [NCT04444921], which is using nivolumab [Opdivo] with the same backbone of carboplatin and paclitaxel. Results [from this study] have not read out, so we will see if they are similar to the PODIUM-303 study.

There is also the use of immunotherapy in localized high-risk disease. There is the [phase 3 EA2165] trial [NCT03233711] using nivolumab after chemoradiation in [patients with] high-risk stage II and stage IIIB anal cancer. Another study from Germany—[the phase 2 RADIANCE trial (NCT04230759)—is using chemoradiation [with/without] durvalumab [Imfinzi] in [patients with locally advanced disease]. If it works in a first-line metastatic setting, do we try to move it up earlier? That is what is going on in anal cancer as well.

As I mentioned before, we are also looking at using HPV ctDNA as a risk stratification tool for immunotherapy. For example, we know with immunotherapy there could be pseudoprogression, so by following HPV ctDNA, you could determine whether a patient is responding in conjunction with imaging.

Last but not least are the next-generation combinations. There are a lot of studies ongoing with vaccines, even though dual immunotherapy has not clearly shown benefit in anal cancer yet. Some other ongoing studies are using novel immunotherapy agents and novel vaccines. That is the way of the future.

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 February 15, 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