Adding Retifanlimab to Chemo Yields Clinical Benefit in Inoperable SCAC

Results from the phase 3 POD1UM-303/InterAACT-2 trial demonstrated improved PFS and OS in patients with locally recurrent or metastatic SCAC.

Primary results from the phase 3 POD1UM-303/InterAACT-2 trial (NCT04472429) showed that retifanlimab-dlwr (Zynyz) added to carboplatin and paclitaxel provided clinical benefit with a manageable safety profile in patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) who have not been treated with systemic chemotherapy, according to a press release from the developer, Incyte.¹ Results were shared in The Lancet concurrently with the press release.²

Previously, in May 2025, the FDA approved retifanlimab plus carboplatin and paclitaxel in the same indication.³

At the data cutoff of April 15, 2024, the median progression-free survival (PFS) was 9.3 months (95% CI, 7.5-11.3) with retifanlimab plus carboplatin and paclitaxel vs 7.4 months (95% CI, 7.1-7.7) with placebo plus carboplatin and paclitaxel (HR, 0.63; 95% CI, 0.47-0.84; P = .0006). Across all predefined subgroups with sufficient patients for comparison, a consistent benefit was observed with retifanlimab.

The median overall survival (OS) was 29.2 months (95% CI, 24.2-not evaluable) with retifanlimab vs 23.0 months (95% CI, 15.1-27.9) with placebo; there was evidence of improved survival despite the immaturity of the data and high proportion of patients who received placebo who entered the crossover period (HR, 0.70; 95% CI, 0.49-1.01; P = .027). Across all predefined subgroups except for those with PD-L1–negative tumors and who have HIV-positive status, an OS benefit was observed with retifanlimab.

The overall response rate (ORR) was 55.8% (95% CI, 47.6%-63.8%) with retifanlimab vs 44.2% (95% CI, 36.2%-52.4%) with placebo; the disease control rate (DCR) was 87.0% (95% CI, 80.7%-91.9%) and 79.9% (95% CI, 72.2%-85.9%). Complete responses were observed in 22% and 14%, respectively, partial responses in 34% and 31%, and stable disease in 29% and 34%.

“The incidence of SCAC is increasing by approximately 3% annually, driven mainly by endemic human papillomavirus. With no approved treatments available for advanced cases until recently, it is crucial to develop effective therapies for this orphan disease,” stated lead study author Sheela Rao, MD, consultant medical oncologist at The Royal Marsden National Health Service Foundation Trust, in the press release.¹

A total of 308 patients were randomly assigned, in a 1:1 ratio, to receive either 500 mg of retifanlimab via 30-minute intravenous infusion prior to scheduled carboplatin/paclitaxel on day 1 of each 28-day cycle (n = 154) or matching placebo (n = 154). Carboplatin was administered at area under the curve 5 mg/mL via intravenous infusion on day 1 and paclitaxel at 80 mg/m² via intravenous infusion on days 1, 8, and 15. During the crossover period, patients were eligible to receive retifanlimab monotherapy for up to 1 year.

Patients were 18 years or older with inoperable locally recurrent or metastatic SCAC; additional enrollment criteria included an ECOG performance status of 0 or 1, no prior receipt of systemic therapy, and well-controlled HIV. Those with previous PD-L1–directed therapy were excluded from participation.

The trial’s primary end point was PFS. Secondary end points included OS, ORR by masked independent central review, duration of response, DCR, pharmacokinetics, and safety.

Those who received the retifanlimab regimen remained on treatment for a median of 7.4 months (range, 0.03-14.6) compared with 6.8 months (range, 0.03-14.6) for those on placebo.

Any adverse events (AEs) occurred in 100% of both groups, and grade 3 or higher AEs occurred in 83% and 75%, respectively. Serious AEs were observed in 47% vs 39%, and treatment-related serious AEs in 16% vs 7%. AEs that led to discontinuation of retifanlimab or placebo occurred in 11% and 3%, and deaths occurred in 3% of the retifanlimab group and 1% of the placebo group.

“The publication of the POD1UM-303/InterAACT 2 trial in The Lancet is a testament to the strength of the data generated for retifanlimab in patients with inoperable locally recurrent or metastatic SCAC, a disease which until recently had seen limited innovation for decades,” Steven Stein, MD, chief medical officer at Incyte, concluded.¹ “SCAC can be a devastating disease, and patients often have a poor prognosis. These data supported the FDA approval of retifanlimab in May 2025, providing US patients the first and only first-line treatment for inoperable locally recurrent or metastatic SCAC.”

References

1. Phase 3 data for Incyte’s retifanlimab (Zynyz®) in patients with squamous cell carcinoma of the anal canal (SCAC) published in The Lancet. News release. Incyte. June 12, 2025. Accessed June 13, 2025. https://tinyurl.com/m3uucn3m
2. 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;405(10495):2144-52. doi:10.1016/S0140-6736(25)00631-2
3. 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 June 13, 2025. https://tinyurl.com/48aaubht