Retifanlimab Lengthens Survival for Patients With Anal Cancer

The FDA approved retifanlimab for use in SCAC in May.

Adding retifanlimab (Zynyz) to standard carboplatin and paclitaxel chemotherapy significantly extended progression-free survival (PFS) in patients with inoperable locally recurrent or metastatic advanced squamous cell carcinoma of the anal canal (SCAC) who have not had previous systemic therapy, according to results from the phase 3 POD1UM-303/InterAACT-2 trial (NCT04472429).¹

Findings on the global, multicenter, double-blind, randomized, controlled trial, published in The Lancet, suggest retifanlimab in combination with carboplatin and paclitaxel should be considered a new standard of care for this challenging disease.

“Although considered a rare malignancy, the incidence and prevalence of SCAC are increasing worldwide due to its association with endemic [human papillomavirus (HPV)] infection. Despite this, treatment options for SCAC have remained largely unchanged over several decades,” Sheela Rao, MD, et al, wrote in the study.

The disease disproportionately affects patients with compromised immune systems, particularly those with concurrent HIV infection, who are 25 to 35 times more likely to develop SCAC than HIV-negative individuals.

Despite the increasing incidence, treatment options for advanced SCAC have remained largely stagnant for several decades. Current guidelines recommend carboplatin with weekly paclitaxel, which offers modest PFS of 8.1 months and overall survival (OS) of 20.0 months. The unmet need for more effective treatments for advanced SCAC has been a critical focus for oncology researchers.

Study Design and Key Findings

The POD1UM-303/InterAACT-2 trial, conducted at 70 centers across 12 countries, enrolled 308 eligible patients aged 18 years or older with inoperable locally recurrent or metastatic SCAC, an ECOG performance status of 0 or 1, and no previous systemic therapy. Patients with well-controlled HIV (CD4+ count >200/μL and undetectable viral load) were also eligible.

Patients were randomized 1:1 to receive either retifanlimab (500 mg intravenous) or placebo every 4 weeks in combination with standard carboplatin-paclitaxel for up to 1 year. Patients in the placebo arm were permitted to cross over to retifanlimab monotherapy upon confirmed disease progression.

The primary end point of the study was independently assessed PFS, defined as the time from randomization to the first documented disease progression or death from any cause. At a median follow-up of 7.6 months for the retifanlimab group and 7.1 months for the placebo group, the trial met its primary end point.

Patients in the retifanlimab plus carboplatin-paclitaxel group experienced a median PFS of 9.3 months (95% CI, 7.5–11.3), compared with 7.4 months (95% CI, 7.1–7.7) in the placebo plus carboplatin-paclitaxel group. This translated to a statistically significant hazard ratio of 0.63 (95% CI, 0.47–0.84; 1-sided P =.0006), indicating a 37% reduction in the risk of disease progression or death with retifanlimab.

The overall response rate was also significantly higher in the retifanlimab arm at 55.8% (95% CI, 47.6%–63.8%) vs 44.2% (95% CI, 36.2%–52.4%) in the placebo arm (P nominal =.013). Complete responses were observed in 22% of patients in the retifanlimab group compared with 14% in the placebo group.

The median duration of response was 14.0 months (95% CI, 8.6–22.2) with retifanlimab, nearly double the 7.2 months (95% CI, 5.6–9.3) observed with placebo.

While data for OS remain relatively immature, an interim analysis suggested a possible improvement in OS in the retifanlimab group (median, 29.2 months) compared with the placebo group (median, 23.0 months), with a hazard ratio of 0.70 (95% CI, 0.49–1.01; P =.027). Patients continue to be followed for the final OS analysis.

The study population included 222 (72%) females and 86 (28%) males. Notably, 6 (4%) of 154 patients in the retifanlimab group and 5 (3%) of 154 patients in the placebo group were HIV positive. The majority of tumor samples (over 90% in both arms) had PD-L1 expression of ≥1%.

Safety Profile

The safety profile of retifanlimab combined with carboplatin-paclitaxel was generally manageable. Serious adverse events (AEs) and grade 3 or worse AEs were more frequent in the retifanlimab group (47.4% and 83.1%, respectively) compared with the placebo group (38.8% and 75.0%, respectively). The most common grade ≥3 AEs were neutropenia (35.1% vs 29.6%) and anemia (19.5% vs 20.4%).

Four fatal AEs occurred in the retifanlimab plus carboplatin-paclitaxel group, with 1 (pancytopenia) attributed to treatment. In the placebo group, 1 fatal AE occurred, which was not treatment related. Immune-related AEs were observed more frequently with retifanlimab (49% vs 26%), but most were grade 1 or 2 in severity and did not typically lead to dose interruption or discontinuation. Importantly, no loss of HIV control or opportunistic infections were observed in HIV-positive patients.

Implications for Clinical Practice

The positive results from the POD1UM-303/InterAACT-2 trial represent a significant step forward for patients with advanced SCAC. The demonstrated improvement in PFS and ORR, coupled with a manageable safety profile, positions retifanlimab plus carboplatin-paclitaxel as a strong candidate for the new first-line standard of care.

In May 2025, the FDA approved retifanlimab for this intent-to-treat population, both as a single agent and in combination with chemotherapy, supported by findings from this trial.²

Future research could explore combinations of retifanlimab with novel targeted agents and further investigate its benefits in specific subgroups, including the HIV-positive population, where the small sample size in this study limited definitive conclusions on subgroup benefit. The trial also provides a crucial benchmark for future studies in SCAC, a disease that continues to present significant challenges in oncology.

Reference

1. Rao S, Samalin-Scalzi E, Evesque L, et al. Retifanlimab with carboplatin and paclitaxel for locally recurrent or metastatic squamous cell carcinoma of the anal canal (POD1UM-303/InterAACT-2): a global, phase 3 randomised controlled trial. Lancet. 2025 Jun 14;405(10495):2144-2152. doi: 10.1016/S0140-6736(25)00631-2.
2. Incyte announces FDA approval of Zynyz (retifanlimab-dlwr) making it the first and only approved first-line treatment for advanced anal cancer patients in the United States. News release. Incyte. May 15, 2025. Accessed July 15, 2025. https://tinyurl.com/53bf8ufw