SUMMARY: The FDA on May 15, approved Retifanlimab-dlwr (ZYNYZ®), a PD-1–blocking monoclonal antibody, with Carboplatin and Paclitaxel for the first-line treatment of adults with inoperable locally recurrent or metastatic Squamous Cell carcinoma of the Anal Canal (SCAC). The FDA also approved Retifanlimab as a single agent for adults with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy.
The American Cancer Society estimates that 10,930 new cases of Anus, anal canal, and anorectum cancers will be diagnosed in 2025, and 2030 individuals will die of the disease. Squamous Cell carcinoma of the Anal Canal (SCAC) is a rare but increasingly prevalent malignancy, closely associated with persistent infection by high-risk Human PapillomaVirus (HPV), particularly HPV-16 and HPV-18. HPV-driven oncogenesis plays a pivotal role in SCAC development by disrupting tumor suppressor proteins such as p53 and Rb via viral oncoproteins E6 and E7. These oncoproteins also generate a highly immunogenic Tumor MicroEnvironment (TME), recruiting Tumor-Infiltrating Lymphocytes (TILs) and expressing immune checkpoints like PD-L1, providing a compelling rationale for the use of Immune Checkpoint Inhibitors (ICIs) in this disease.
While early-stage SCAC is often curable with chemoradiation, outcomes in advanced or metastatic cases remain poor, with 5-year survival dropping to 30% in Stage IV disease. Platinum-based chemotherapy, particularly the combination of Carboplatin and Paclitaxel as established by the InterAAct trial, has been the frontline standard. However, outcomes have remained suboptimal, fueling efforts to explore combination regimens that leverage the immunogenicity of HPV-driven SCAC.
Rationale for Immunotherapy in SCAC
HPV-positive tumors are characterized by an “inflamed” TME, enriched with TILs and immune regulatory molecules such as PD-1 and PD-L1. This immune signature is associated with both favorable prognosis and responsiveness to immunotherapy. ICIs like Pembrolizumab and Nivolumab have demonstrated modest activity as monotherapy in pretreated SCAC, with Overall Response Rates (ORR) ranging from 13% to 30% and median Progression-Free Survival (PFS) of approximately 2-4 months. However, these agents alone have not transformed outcomes, prompting exploration of synergistic strategies.
Preclinical studies indicate that chemotherapy can enhance immunogenic cell death, promote antigen presentation, and reduce immunosuppressive myeloid populations, thus priming the TME for immune-based therapies. These insights provided the foundation for evaluating the anti–PD-1 antibody Retifanlimab in combination with Carboplatin and Paclitaxel.
Retifanlimab (ZYNYZ®) is a humanized monoclonal antibody targeting PD-1, thereby restoring T-cell activity against tumor cells.
POD1UM-303 (InterAACT 2; NCT04472429) was a randomized, double-blind, multicenter Phase 3 trial that enrolled 308 patients across 81 centers with inoperable, locally recurrent, or metastatic SCAC who were chemotherapy-naive in the advanced setting. Participants received standard Carboplatin (AUC 5, IV day 1) and Paclitaxel (80 mg/m² IV, days 1, 8, and 15) for six cycles, and were randomized 1:1 to receive either:
- Retifanlimab 500 mg IV every 4 weeks, or
- Placebo IV every 4 weeks
Treatment was continued for up to one year or until disease progression or unacceptable toxicity. Cross-over to single-agent Retifanlimab was allowed for patients in the placebo arm upon disease progression.
The Primary endpoint was Progression-Free Survival (PFS) per RECIST v1.1 by Blinded Independent Central Review. Key Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), and Duration of Response (DoR).
Clinical Outcomes
- Progression-Free Survival:
- Retifanlimab arm: 9.3 months (95% CI, 7.5–11.3)
- Placebo arm: 7.4 months (95% CI, 7.1–7.7)
- Hazard ratio: 0.63 (95% CI, 0.47–0.84; P=0.0006)
- Overall Survival (Interim Analysis):
- Retifanlimab arm: 29.2 months (95% CI, 24.2–NE)
- Placebo arm: 23.0 months (95% CI, 15.1–27.9)
- HR: 0.70 (95% CI, 0.49–1.01), not yet statistically significant
- Overall Response Rate:
- Retifanlimab arm: 56% (95% CI, 48%–64%)
- Placebo arm: 44% (95% CI, 36%–52%)
- Disease Control Rate: 87% vs 80%, respectively
- Crossover Allowed: 45% of patients in the placebo arm received Retifanlimab upon progression.
Safety and Tolerability
The combination of Retifanlimab and chemotherapy was generally well tolerated. Immune-related Adverse Events (AEs) increased, as expected with PD-1 blockade, but were manageable and did not significantly impact chemotherapy delivery or dose intensity.
Monotherapy Insights: POD1UM-202
Retifanlimab was also studied as a single agent in POD1UM-202 (NCT03597295), a Phase 2 trial of 94 patients with previously treated, platinum-refractory SCAC:
- ORR: 14% (95% CI, 8%–23%)
- Median DOR: 9.5 months
- Notable Findings: Better responses observed in p16-positive and PD-L1–positive tumors; tumor inflammation signature scores correlated with improved survival.
Conclusion and Clinical Implications
The POD1UM-303 trial marks a major advancement in the treatment of advanced SCAC. Retifanlimab in combination with Carboplatin and Paclitaxel not only met its Primary endpoint but also demonstrated consistent improvements in response rates, survival outcomes, and disease control, without compromising safety.
As the first positive Phase 3 study in this setting, POD1UM-303 establishes a new standard of care for patients with advanced SCAC and solidifies the role of immunotherapy in HPV-associated malignancies. Continued exploration of predictive biomarkers and deeper understanding of the TME will be critical to refining treatment strategies in this rare but challenging cancer.
POD1UM-303/InterAACT 2: Phase 3 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). Rao S, et al. ESMO Congress 2024, LBA2
