Evaluating Retifanlimab for Advanced Squamous Cell Carcinoma of the Anal Canal in the Frontline Setting

Key Takeaways:

• Retifanlimab plus chemotherapy demonstrated clinically meaningful benefit in advanced squamous cell carcinoma of the anal canal, including improved progression-free survival (PFS), higher response rates, and encouraging overall survival (OS) trends vs chemotherapy alone.
• Although grade ≥3 and serious adverse events were more frequent, most were manageable immune-related toxicities, with established monitoring and treatment approaches consistent with other PD-1 inhibitors.
• The regimen represents a potential new frontline standard of care in this rare disease, with broad eligibility regardless of PD-L1 status or HIV status and a relatively low overall budget impact for payers.

Lingbin Meng, MD, a medical oncologist at The Ohio State University, discusses findings from the phase 3 POD1UM-303/InterAACT-2 trial evaluating retifanlimab in advanced squamous cell carcinoma of the anal canal. This pivotal study, published in The Lancet, demonstrated that adding retifanlimab to carboplatin and paclitaxel significantly improved clinical outcomes and may establish a new standard of care in the frontline setting for this rare malignancy.

Please introduce yourself by stating your name, title, organization, and relevant professional experience.

Lingbin Mend, MD, PhD: My name is Lingbin Meng, and I am an assistant professor of medical oncology at The Ohio State University Comprehensive Cancer Center. I'm happy to be invited to talk about this data that was published in the Lancet.

From a payer perspective, how clinically meaningful is the ~2-month improvement in PFS (9.3 vs 7.4 months) with retifanlimab, and how should that translate into coverage or reimbursement decisions?

Dr Meng: First of all, let's provide context. The hazard ratio of the PFS is about 0.63, which represents about a 37% reduction in the risk of the disease progression or death. That is a highly significant result with the P value <.025. Second, if you look beyond the PFS in isolation, the overall response rate was high up to 56% vs 44%, and the complete response was about 22% vs 14%. What is even more compelling from the value standpoint is the median duration of the response: 14 months for retifanlimab compared to only 7.4 months in the control arm. Last but not least, the OS data is robust—32.8 vs 22 months—which was updated at ESMO 2025 as well.

These robust data demonstrate the long-term benefits of this immunotherapy along with chemo as frontline treatment. Since anal cancer is a rare cancer, there are limited treatment options. That's why we should give more credit and value to this drug in the frontline setting.

Given the higher rates of grade ≥3 and serious adverse events with the addition of retifanlimab, how should payers weigh the trade-off between improved outcomes and increased toxicity management costs?

Dr Meng: It is important to be transparent that the safety profile is not ideal enough. However, it is acceptable and reasonable because the rate of grade 3 or higher adverse events was higher in the ritafinumab (83% vs 75%) and for severe adverse events it was only 47% vs 39%. When you look into the detail of those side effects, most are immunotherapy-related adverse events (AEs), such as hypothyroidism or hyperthyroidism, which are easy to manage. Besides, it will not be too much of a cost burden for the payer because it’s just a matter of increasing the lab frequency of checking for hormones like TSH/T4. If a patient has grade 1 or grade 2, they can be given a thyroid replacement. So, it is definitely manageable.

Regarding how payers should weigh this against the cost of the disease progression, in the metastatic setting for example, if a patient doesn’t receive a good regimen at the frontline, they will progress to the second line quickly. As a result, more money will need to be invested in hospitalization for pain control, bowel obstruction, fistula management, and other complications from this anal cancer. So, if we can find effective treatment at the frontline, I'm happy to use it.

For immunotherapy-related side effects, we are already familiar with how to manage pembrolizumab and nivolumab. Their side effects are similar, so new monitoring requirements or comparing diagnosis are not needed. The adverse AE management guideline is similar to those updated on the National Comprehensive Cancer Network (NCCN) guidelines, so it is manageable.

The study suggests this regimen could become a new standard of care in a rare cancer with historically limited options—how do you see payers approaching value assessment in such orphan or low-incidence indications?

Dr Meng: Anal cancer occupies a unique position in the payer landscape, and I think it works strongly in favor of the patient. There are more than 10 000 patients who are diagnosed with anal cancer per year in the US, and only a small fraction—around 1400—will develop metastatic disease. So, from this perspective, the drug cost for retifanlimab is roughly 200K per year, but the total budget impact is actually small. Even with managing hospitalization, pain control, and complications post-care, the cost is still reasonable.

Before 2025, we were short on treatment options as there wasn’t an effective US Food and Drug Administration (FDA)-approved somatic treatment for metastatic anal cancer except chemo. We used a lot of the carboplatin, paclitaxel, cisplatin, FOLFOX, but generally speaking, the options are limited. So, retifanlimab just became the first and only approved regimen in the frontline setting combined with chemo. I believe it will be beneficial for patients in this population, especially with the updated NCCN guidelines. The study makes it clear that patients do not need PD-L1 testing, the treatment is not restricted to academic centers, and there is no step therapy requirement, which is really convenient. It is a good option.

With evidence of a potential OS benefit still considered immature and influenced by crossover design, what level of evidence do payers typically require before broadly adopting a higher-cost immunotherapy combination in the frontline setting?

Dr Meng: The OS benefits are robust, according to the paper. From initial analysis, the median OS is about 29 months vs 23 months. The updated ESMO data also shows the OS benefits improved from 32 vs 22 months. Based on the robust OS benefits, statistically this data is very promising. Although we need long-term follow-up data to validate that in the real practice, the data from the study is still strong and promising.

In my view, this level of evidence has exceeded what the payer typically requires. The primary PFS endpoint is statistically significant, the duration of the response is nearly doubled, and there are consistent OS benefits trending across multiple analysis. So, a higher significant cross-adjusted OS and the confirmatory evidence show that the combination is better than the sequential treatment therapy, which we used to do before.

This is a strong evidence package that would support reimbursement for many immunotherapy combinations. We use a similar combination in lung cancer and breast cancer.

How might patient subgroups—such as those with HIV or varying PD-L1 expression—factor into payer decisions around access, step therapy, or prior authorization for this regimen?

Dr Meng: The paper shows that no PD-L1 testing is required for eligibility, which is great because you don't want to delay patient treatment by testing those markers. From the trial, the majority of patients with PD-L1 positivity are above or equal to 1%, and only a small population are PD-L1 negative. This group is far too small for any reliable subgroup interference. That is why from the payer standpoint, requiring the PD-L1 testing could be inconsistent with the FDA label or NCCN guideline. This is because in real practice, we frequently use pembrolizumab, nivolumab, atezolizumab, and durvalumab, and PD-1 is not required for the biomarker testing for all those groups. So, we can avoid testing this biomarker before we start treatment.

One thing to note is patients with anal cancer who have HIV. Health equity becomes especially important because HIV testing is sometimes neglected. There are a lot of people who are diagnosed several months before we started treatment. The eligibility criteria for the study require a patient’s CD4 count to have at least a 200 or undetectable viral load. If they are on active antiviral treatment, you cannot guarantee patients lack of the response is due to immunotherapy response or low loss of the HIV control. It is better to have controlled HIV status as well. The FDA label says HIV status has no clinical meaningful effect on the pharmacokinetics (PK) of this drug. And importantly, for the large real-world data on the checkpoint inhibitor in patients who have HIV, studies have demonstrated comparable safety and efficacy.

It's important to exclude patients who do not qualify for the study. However, the right approach is to cover the drug for all patients with advanced stage who meet the FDA-labeled indication—regardless of HIV status or PD-L1 expression—and confirm the diagnosis and appropriate clinic criteria. The hope is that all those patients can benefit from this drug.