Retifanlimab-Dlwr Becomes First and Only FDA-Approved First-Line Treatment for Advanced Anal Cancer

The FDA approved retifanlimab-dlwr (Zynyz; Incyte Corporation) in combination with platinum-based chemotherapies carboplatin (Paraplatin; Bristol-Myers Squibb) and paclitaxel (Taxol; Bristol-Myers Squibb) for the first-line treatment of adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC). Additionally, retifanlimab was also granted approval as a single agent for the treatment of adult patients with either locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy.¹

Retifanlimab is a humanized monoclonal antibody that targets programmed death receptor-1 (PD-1). The priority review and FDA approval of its supplemental biologics license application were based on data from the phase 3 POD1UM-303/InterAACT2 (NCT04472429)² and phase 2 POD1UM-202 (NCT03597295)³ trials. In addition to its indications in SCAC, retifanlimab is also granted accelerated approval for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma in the US.¹

"The FDA approval of [retifanlimab] marks a pivotal moment, bringing effective combination and monotherapy treatment options to patients with advanced anal cancer after decades of limited innovation," Hervé Hoppenot, CEO of Incyte, said in a news 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 US patients with SCAC.”¹

SCAC is the most common type of anal cancer and makes up approximately 85% of cases. It is a rare disease despite its incidence increasing about 3% per year. In addition, about 90% of cases are associated with human papillomavirus infection, which is the number 1 risk factor for anal cancer. HIV is an important amplifier of anal cancer, as people with HIV are about 25 to 35 times more likely to develop it. Cancerous symptoms are often similar to noncancerous conditions (eg, hemorrhoids) and include pain, itching, lumps or masses, and changes in bowel movements. For these reasons, SCAC can go undetected; therefore, patients are often diagnosed with locally advanced disease.¹

POD1UM-303/InterAACT2 trial was a global, multicenter, double-blind, randomized phase 3 clinical trial in which retifanlimab was evaluated in combination with platinum-based chemotherapy (carboplatin-paclitaxel) in adult patients with metastatic or inoperable locally recurrent SCAC who were not previously treated with systemic chemotherapy. The phase 2 POD1UM-202 trial evaluated retifanlimab monotherapy in previously treated patients with locally advanced or metastatic SCAC who progressed on or were intolerant of platinum-based chemotherapy.^1,2

Findings from the POD1UM-303/InterAACT2 trial presented at the European Society of Medical Oncology 2024 Congress showed that retifanlimab with platinum-based chemotherapy demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) in the patient population. In addition, adding retifanlimab to standard of care chemotherapy resulted in a clinically meaningful 37% reduction in the risk of progression or death (HR: 0.63 [95% CI 0.47, 0.84]; P = .0006). Patients who were in the retifanlimab and chemotherapy combination group achieved a median PFS of about 9.3 months compared to 7.4 months for patients in the placebo combination group.^1,4

Further, patients that received retifanlimab in combination with chemotherapy achieved an approximately 6-month improvement in median overall survival (OS) compared with the placebo group (median OS: 29.2 months vs. 23 months; HR: 0.70 [95% CI 0.49, 1.01]; P = .0273]). At the time of these results, OS remained ongoing. Retifanlimab also showed a superior overall response rate (ORR: 56% [95% CI 48, 64]) and duration of response (DOR: 14 months [95% CI 8.6, 22.2]) when compared with placebo (ORR: 44% [95% CI 36, 52]; DOR: 7 months [95% CI 5.6, 9.3]).⁴

"Patients with inoperable locally recurrent or metastatic anal cancer have historically faced poor 5-year survival rates and limited treatment options. The POD1UM data highlight the potential of [retifanlimab] to be a meaningful new option, and notably demonstrate that the addition of [retifanlimab] to platinum-based chemotherapy significantly improves progression-free survival," professor Marwan Fakih, MD, associate director of clinical sciences, medical director of Briskin Center for Clinical Research, division chief of gastrointestinal medical oncology, and co-director of gastrointestinal cancer program, City of Hope, said in the news release. "This approval marks an important advancement as it makes a new treatment approach available for this challenging cancer."¹

In the POD1UM-303/InterAACT2 trial, retifanlimab was generally well-tolerated, and safety was consistent with other chemotherapy plus checkpoint inhibitor regimens. The most common treatment-emergent adverse events (AEs) observed in the retifanlimab and chemotherapy combination group were anemia (66.2%), nausea (56.5%), and alopecia (51.3%).⁴ Serious AEs included sepsis (3.2%), pulmonary embolism (3.2%), diarrhea (2.6%), and vomiting (2.6%).¹

“Patients with anal cancer often face a troubling lack of public awareness and understanding when it comes to risk factors, symptoms and their overall cancer journey,” said David Winterflood, CEO of the Anal Cancer Foundation. “The approval of [retifanlimab] marks a step forward for advanced SCAC treatment, brings attention to a long-overlooked condition with limited treatment options and offers patients whose anal cancer has returned or spread an option to treat their disease.”¹

REFERENCES

1. Businesswire. 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. May 15, 2025. Accessed May 15, 2025. https://www.businesswire.com/news/home/20250508024371/en/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

2.Carboplatin-paclitaxel With Retifanlimab or Placebo in Participants With Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (POD1UM-303/​InterAACT 2). ClinicalTrials.gov identifier: NCT04472429. Updated December 20, 2024. Accessed May 15, 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 identifier: NCT03597295. Updated November 17, 2022. Accessed May 15, 2025. https://clinicaltrials.gov/study/NCT03597295

4. Incyte. Incyte’s Retifanlimab (Zynyz®) Extends Progression-Free Survival in Patients with Squamous Cell Anal Carcinoma (SCAC); Data Featured at ESMO 2024 Presidential Symposium. News release. September 14, 2024. Accessed May 15, 2025. https://investor.incyte.com/news-releases/news-release-details/incytes-retifanlimab-zynyzr-extends-progression-free-survival