Incyte Announces FDA Approval of Zynyz® (retifanlimab-dlwr), the First and Only Approved First-Line Treatment for Advanced Anal Cancer in the U.S.
Incyte Corporation (Nasdaq: INCY), a global biopharmaceutical company focused on delivering innovative therapies for patients with serious diseases, today announced a significant milestone in the treatment of advanced anal cancer. The U.S. Food and Drug Administration (FDA) has approved Zynyz® (retifanlimab-dlwr), a humanized monoclonal antibody targeting programmed death receptor-1 (PD-1), in combination with the platinum-based chemotherapy agents carboplatin and paclitaxel for the first-line treatment of adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC).
In addition to this combination approval, the FDA also authorized Zynyz as a monotherapy option for adult patients with locally recurrent or metastatic SCAC who have experienced disease progression on or are intolerant to platinum-based chemotherapy. This dual approval marks a major advance in the management of this rare but aggressive form of cancer, which has historically suffered from limited treatment options and poor patient outcomes.
A Pivotal Moment for Advanced Anal Cancer Patients
“This approval 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, Chief Executive Officer of Incyte. “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.”
SCAC is a rare cancer arising from the squamous cells lining the anal canal. While it is relatively uncommon, its incidence has been increasing globally, partly linked to human papillomavirus (HPV) infections. Standard treatment for early-stage disease often involves surgery or chemoradiation, but patients with advanced or metastatic disease face poor prognosis, with few approved systemic therapy options available.
Clinical Trial Data Underpinning FDA Approval
The FDA’s approval of Zynyz was granted under Priority Review based on compelling data from two key clinical trials: the Phase 3 POD1UM-303/InterAACT2 trial and the Phase 2 POD1UM-202 trial.
- POD1UM-303/InterAACT2 Trial: This randomized, double-blind Phase 3 study evaluated Zynyz in combination with carboplatin and paclitaxel chemotherapy versus chemotherapy plus placebo in adult patients with metastatic or inoperable locally recurrent SCAC who had not previously received systemic chemotherapy. The trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with the addition of Zynyz. Specifically, patients receiving Zynyz plus chemotherapy had a median PFS of 9.3 months, compared to 7.4 months in the placebo plus chemotherapy group—a 37% reduction in the risk of disease progression or death (P=0.0006).
Moreover, interim overall survival (OS) data revealed a 6.2-month improvement favoring the Zynyz combination group, with a hazard ratio indicating a significant survival benefit (P=0.0273). OS follow-up is ongoing to confirm these encouraging findings. Safety data from the trial were consistent with the known profiles of the agents involved, with no new safety signals identified.
Serious adverse reactions occurred in 47% of patients treated with Zynyz plus chemotherapy. The most common serious adverse events (≥2%) included sepsis and pulmonary embolism (each at 3.2%), as well as diarrhea and vomiting (each at 2.6%).
- POD1UM-202 Trial: This Phase 2 single-arm study evaluated Zynyz monotherapy in patients with locally advanced or metastatic SCAC who had progressed on or were intolerant to prior platinum-based chemotherapy. The trial reported an objective response rate (ORR) of 14%, indicating meaningful anti-tumor activity in this difficult-to-treat population. Additionally, the disease control rate (DCR) was 49%, reflecting the proportion of patients who experienced tumor shrinkage or stabilization.
The safety profile in this cohort aligned with expectations for PD-1 inhibitors, with no observed loss of human immunodeficiency virus (HIV) infection control among patients living with HIV, a population often affected by SCAC. Serious adverse reactions occurred in 40% of patients treated with Zynyz monotherapy, with the most frequent events (≥2%) including infections, pain, anemia, hemorrhage, diarrhea, fever, and respiratory symptoms.
Expert Commentary on Clinical Impact
“Patients with inoperable locally recurrent or metastatic anal cancer have historically faced poor five-year survival rates and limited treatment options,” said Dr. Marwan Fakih, Professor of Medical Oncology & Therapeutics Research and Associate Director of Clinical Sciences at City of Hope. “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.”
Dr. Fakih’s remarks underscore the unmet medical need addressed by this approval, as prior treatment regimens offered limited durable benefits and high toxicity burdens.
Patient Advocacy Perspective
David Winterflood, Chief Executive Officer of the Anal Cancer Foundation, also commented on the significance of the approval: “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. The approval of Zynyz 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.”
His statement highlights not only the clinical importance but also the societal and emotional impact that new treatment options like Zynyz bring to patients and their families.
Regulatory Submissions Beyond the U.S.
Following the FDA approval, Incyte has also made regulatory progress in other key markets. The company has submitted a Type II Variation Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) seeking approval of retifanlimab (Zynyz) for advanced SCAC. Additionally, Incyte filed a New Drug Application (J-NDA) with the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), which has been accepted for review. These efforts signify Incyte’s commitment to making Zynyz available to patients worldwide who face this difficult diagnosis.
Mechanism of Action and Therapeutic Potential
Zynyz (retifanlimab-dlwr) is a humanized monoclonal antibody that targets PD-1, a checkpoint receptor on immune cells. Under normal conditions, PD-1 acts as a regulatory brake that prevents overactivation of the immune system. However, many cancers exploit PD-1 signaling to evade immune detection. By blocking PD-1, Zynyz restores the immune system’s ability to recognize and attack tumor cells, leading to anti-cancer activity.
The success of PD-1 inhibitors in multiple tumor types has revolutionized cancer treatment, and the approval of Zynyz extends these benefits to the SCAC patient population for the first time.
The FDA approval of Zynyz provides a much-needed option for patients and oncologists facing advanced SCAC, a disease with historically poor prognosis and limited systemic therapies. As clinical follow-up continues, Incyte remains dedicated to expanding research and access to innovative therapies that improve patient outcomes.
With both combination and monotherapy indications, Zynyz is poised to become a cornerstone of advanced anal cancer treatment, offering hope and improved survival prospects for patients confronting this challenging disease.
