Retifanlimab Becomes First FDA-Approved Frontline Treatment for Advanced Anal Cancer

The FDA Thursday approved retifanlimab-dlwr (Zynyz; Incyte) in combination with platinum-based chemotherapy for the first-line treatment of adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal, as well as a monotherapy for those with disease progression or an intolerance to platinum-based chemotherapy.¹

Retifanlimab is a humanized monoclonal antibody targeting PD-1. The FDA's priority review and approval of retifanlimab was based on data from the phase 3 POD1UM-303/InterAACT2 trial (NCT04472429) and the phase 2 POD1UM-202 trial (NCT03597295), establishing it as the first and only approved first-line treatment for patients in the US with advanced anal cancer.

The phase 3 POD1UM-303/InterAACT2 trial evaluated retifanlimab in combination with platinum-based chemotherapy (carboplatin plus paclitaxel) in adult patients with metastatic or inoperable locally recurrent squamous cell carcinoma of the anal canal not previously treated with systemic chemotherapy. Results presented at the 2024 European Society for Medical Oncology Congress showed a clinically meaningful and statistically significant 37% reduction in the risk of progression or death (P = .0006).²

Patients in the retifanlimab and chemotherapy combination group achieved a median progression-free survival of 9.3 months (95% CI, 7.5-11.3) vs 7.4 months (95% CI, 7.1-7.7) among those in the placebo combination group (HR, 0.63; 95% CI, 0.47-0.84; P = .0006). At an interim analysis, the median overall survival (OS) was 29.2 months (95% I, 24.2–not evaluable) among the retifanlimab and chemotherapy combination group vs 23 months (95% CI, 15.1-27.9) in the control group (HR, 0.70; 95% CI, 0.49-1.01; P = .0273); OS follow-up is ongoing.

Additionally, retifanlimab elicited an overall response rate (ORR) of 56% (95% CI, 48-64), including a complete response rate of 22% and partial response rates of 34%. The median duration of response was 14.0 months (95% CI, 8.6-22.2).

In terms of safety, serious adverse reactions occurred in 47% of patients receiving retifanlimab in combination with chemotherapy. The most frequent serious adverse reactions were sepsis (3.2%), pulmonary embolism (3.2%), diarrhea (2.6%), and vomiting (2.6%).

"The data from POD1UM-303 show an impressive and meaningful improvement in progression-free survival with the addition of retifanlimab to carboplatin and paclitaxel," Sheela Rao, MBBS, FRCP, MD, lead investigator of the trial, said in an interview with The American Journal of Managed Care^®.³ "We also see a trend toward improved overall survival, although those data are not yet fully mature, and we also see an improvement in response rate, duration of response, and disease control. In addition to that, it was very well tolerated, and there were no concerning safety signals in terms of the toxicity."

Also, results from the POD1UM-202 study supported the approval of retifanlimab as a monotherapy.⁴ It demonstrated that retifanlimab monotherapy produced an ORR of 13.8% (95% CI, 7.6-22.5) and a disease control rate of 49% (95% CI, 38.5-59.5).

Serious adverse reactions occurred in 40% of patients receiving retifanlimab, with the most frequent (observed in ≥2% of patients) being non–urinary tract infection, perineal pain, abdominal pain, anemia, hemorrhage, diarrhea, pyrexia, urinary tract infection, musculoskeletal pain, and dyspnea.

"The FDA approval of Zynyz marks a pivotal moment, bringing effective combination and monotherapy options to patients with advanced anal cancer after decades of limited innovated," Hervé Hoppenot, Incyte's CEO, said in a press release.¹ "...I am proud of our scientists and development teams for their perseverance in delivering the first approved PD-1 inhibitor to US patients with SCAC [squamous cell carcinoma of the anal canal]."

References

1. Incyte announes FDA approval of Zynyz (retifanlimab-dlwr) making it the first and only approved first-line treatment for advancd anal cancer patients in the United States. News release. Incyte; May 15, 2025. Accessed May 16, 2025. https://investor.incyte.com/news-releases/news-release-details/incyte-announces-fda-approval-zynyzr-retifanlimab-dlwr-making-it
2. Rao S, Samalin-Scalzi E, Evesque L, et al. LBA2 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 Onc. 2024;35:S1217. doi:10.1016/j.annonc.2024.08.2262
3. McNulty R. POD1UM-303/InterAACT 2: potentially practice-changing findings in SCAC. AJMC. September 14, 2024. Accessed May 16, 2025. https://www.ajmc.com/view/pod1um-303-interaact-2-potentially-practice-changing-findings-in-scac
4. Rao S, Anandappa G, Capdevila J, et al. A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202). ESMO Open. 2022;7(4):100529. doi:10.1016/j.esmoop.2022.100529