The FDA has approved Incyte’s Zynyz (retifanlimab-dlwr), a PD-1 inhibitor, for two first-in-class indications in advanced anal cancer. The drug is now approved in combination with platinum-based chemotherapy (carboplatin and paclitaxel) as the first and only FDA-approved first-line treatment for adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC).

How is Zynyz Changing the Treatment Landscape for Advanced Anal Cancer?

Zynyz has been approved as a monotherapy for patients with recurrent or metastatic SCAC whose disease has progressed on or who are intolerant to platinum-based chemotherapy. These approvals are supported by results from the Phase III POD1UM-303/InterAACT2 trial and the Phase II POD1UM-202 trial.¹

"The FDA approval of Zynyz marks a pivotal moment, bringing effective combination and monotherapy treatment options to patients with advanced anal cancer after decades of limited innovation," said Hervé Hoppenot, CEO, Incyte, in a press release. "At Incyte, we focus our efforts where we can make the biggest impact for patients. I am proud of our scientists and development teams for their perseverance in delivering the first approved PD-1 inhibitor to U.S. patients with SCAC.”

POD1UM-303/InterAACT2: Improved Survival and Disease Control

The global, multicenter, randomized, double-blind, placebo-controlled POD1UM-303/InterAACT2 trial evaluated Zynyz in combination with carboplatin and paclitaxel in 308 patients. The primary endpoint was progression-free survival (PFS), defined as the time from randomization to disease progression per RECIST v1.1, based on blinded independent central review. Key secondary endpoints included overall survival (OS), objective response rate, duration of response (DOR), and disease control rate (DCR).²

The results showed a 37% reduction in the risk of disease progression or death and a 6.2-month improvement in median OS among patients administered Zynyz plus chemotherapy. Median PFS was 9.3 months in the Zynyz cohort compared with 7.4 months for the placebo combination group. No new safety signals were reported, though serious adverse events (SAEs) occurred in 47% of patients in the Zynyz combination arm. The most frequent SAEs included sepsis, pulmonary embolism, diarrhea, and vomiting.¹

POD1UM-202: Zynyz Monotherapy Provides Additional Option

The POD1UM-202 trial evaluated Zynyz monotherapy in 94 patients with locally advanced or metastatic SCAC who had progressed on platinum-based chemotherapy. The primary endpoint was ORR, defined as the proportion of patients achieving a complete or partial response per RECIST v1.1, as assessed by independent central review. Secondary endpoints included DOR, DCR, PFS, and OS.³

Zynyz demonstrated a 14% ORR and a 49% DCR in this setting. While no new safety signals were observed, SAEs occurred in 40% of patients in the monotherapy group. Common SAEs included non-urinary tract infection; perineal and abdominal pain; anemia; hemorrhage; diarrhea; pyrexia; urinary tract infection; musculoskeletal pain; and dyspnea.¹

"Patients with inoperable locally recurrent or metastatic anal cancer have historically faced poor five-year survival rates and limited treatment options,” said Marwan Fakih, MD, professor, medical oncology, therapeutics research, associate director, clinical sciences, medical director, Briskin Center for Clinical Research, division chief, GI medical oncology, co-director, gastrointestinal cancer program, City of Hope, in the press release. “The POD1UM data highlight the potential of Zynyz to be a meaningful new option and notably demonstrate that the addition of Zynyz to platinum-based chemotherapy significantly improves progression-free survival. This approval marks an important advancement as it makes a new treatment approach available for this challenging cancer."

Global Expansion Efforts Underway

Beyond the United States, Incyte has submitted a Type II variation Marketing Authorization Application to the European Medicines Agency and a Japanese New Drug Application to the Pharmaceuticals and Medical Devices Agency.1

References

1. 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. 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. Carboplatin-paclitaxel With Retifanlimab or Placebo in Participants With Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (POD1UM-303/​InterAACT 2). Clinicaltrials.gov. Accessed May 16, 2025. https://clinicaltrials.gov/study/NCT04472429

3. A Study of INCMGA00012 in Squamous Carcinoma of the Anal Canal Following Platinum-Based Chemotherapy (POD1UM-202). Clinicaltrials.gov. Accessed May 16, 2025. https://clinicaltrials.gov/study/NCT03597295