In a Phase III trial presented at the European Society for Medical Oncology Congress (ESMO) 2024, Incyte's PD-1 checkpoint inhibitor Zynyz (retifanlimab) in combination with chemotherapy demonstrated a significant improvement in progression-free survival for patients with previously untreated advanced anal cancer. This study marks a significant advancement in treating a cancer with limited therapeutic options, potentially establishing a new standard of care.
Study Details and Findings
The POD1UM-303/InterAACT2 trial (NCT04472429) enrolled 308 participants with inoperable locally recurrent or metastatic squamous cell anal carcinoma who had not previously received systemic chemotherapy. The trial compared Zynyz plus platinum-based chemotherapy (carboplatin and paclitaxel) to a placebo plus chemotherapy. Patients received treatment for up to six monthly cycles, followed by Zynyz or placebo alone for up to one year. Notably, the study included people living with HIV, representing approximately 4% of the study population.
The results indicated a progression-free survival of 9.3 months in the Zynyz group compared to 7.4 months in the placebo group, reflecting a 37% reduction in the risk of disease progression or death. The overall response rates were 56% and 44% in the Zynyz and placebo groups, respectively. The median duration of response was significantly longer with Zynyz (14.0 months versus 7.2 months). While overall survival data are still maturing, early results suggest a potential six-month advantage for Zynyz (29.2 versus 23.0 months).
Clinical Significance and Safety
According to Dr. Sheela Rao of the Royal Marsden National Health Service Foundation Trust, the findings suggest that Zynyz plus platinum-based chemotherapy may represent a new standard of care for advanced squamous cell anal cancer, a disease with "high unmet medical need." Treatment-emergent adverse events of Grade 3 or higher were common in both groups. The most frequent side effects in the Zynyz plus chemotherapy arm included anemia, nausea, and hair loss. Immune-mediated adverse events occurred in 46% of Zynyz recipients versus 24% in the placebo group. Importantly, HIV-positive participants maintained viral suppression without experiencing additional or worsened side effects.
Mechanism of Action and Regulatory Context
Zynyz is a monoclonal antibody that targets PD-1, an immune checkpoint protein on T cells. By blocking the interaction between PD-1 and its PD-L1 ligand on cancer cells, Zynyz can restore T-cell activity and enhance the immune response against tumors. The FDA previously granted accelerated approval to Zynyz for advanced Merkel cell carcinoma in 2023. Currently, no checkpoint inhibitors are specifically indicated for anal cancer, although some are approved for solid tumors with specific genetic features, regardless of location.
Anal Cancer: An Overview
Anal cancer, often linked to the human papillomavirus (HPV), is distinct from rectal cancer and is more prevalent among people living with HIV. While HPV vaccines and early screening can reduce the risk, the incidence of advanced squamous cell anal carcinoma is increasing, and treatment options have remained limited for decades. The current standard of care typically involves chemotherapy and radiation, but relapse is common, highlighting the need for more effective therapies.
Future Directions
Incyte plans to submit an application to the FDA for approval of Zynyz for anal cancer by the end of the year. If approved, Zynyz could provide a much-needed new treatment option for patients with this challenging disease.
