The addition of retifanlimab (Zynyz) to carboplatin and paclitaxel significantly improves progression-free survival (PFS) in patients with recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC), according to results from the phase 3 POD1UM-303/InterAACT 2 trial. The study's findings, presented at the 2024 ESMO Congress, suggest a potential new standard of care for this challenging cancer.
Enhanced Progression-Free Survival
The POD1UM-303 trial (NCT04472429) demonstrated that patients treated with retifanlimab in combination with carboplatin and paclitaxel (n = 154) experienced a median PFS of 9.3 months (95% CI, 7.5-11.3) as assessed by blinded independent central review (BICR). In comparison, patients who received placebo plus carboplatin and paclitaxel (n = 154) had a median PFS of 7.4 months (95% CI, 7.1-7.7). The hazard ratio (HR) was 0.63 (95% CI, 0.47-0.84; P = .0006), indicating a significant reduction in the risk of disease progression or death.
The median follow-up times for PFS were 7.6 months (range, 0.0-33.9) and 7.1 months (range, 0.0-27.4) in the retifanlimab and placebo arms, respectively.
Improved Overall Response and Duration of Response
In addition to the PFS benefit, the retifanlimab arm showed a higher overall response rate (ORR) of 56% (95% CI, 48%-64%), with a complete response (CR) rate of 22%, compared to 44% (95% CI, 36%-52%) with a 14% CR rate in the placebo arm (P = .0129). The median duration of response (DOR) was also longer in the retifanlimab arm, at 14.0 months (95% CI, 8.6-22.2), versus 7.2 months (95% CI, 5.6-9.3) in the placebo arm. The disease control rates were 87% (95% CI, 81%-92%) and 80% (95% CI, 73%-86%), respectively.
Overall Survival Trends
Interim overall survival (OS) analysis revealed a median OS of 29.2 months (95% CI, 24.2-not estimable) in the retifanlimab arm compared to 23.0 months (95% CI, 15.1-27.9) in the placebo arm (HR, 0.70; 95% CI, 0.49-1.01; P = .0273). After adjusting for patient crossover, the median OS was 29.2 months (95% CI, 24.2-NE) versus 19.1 months (95% CI, 13.4-27.9), respectively (HR, 0.63; 95% CI, 0.44-0.90; P = .0055).
Study Design and Patient Population
The POD1UM-303/InterAACT 2 trial was a global, double-blind study that enrolled patients with inoperable locally recurrent or metastatic SCAC who had not received prior systemic chemotherapy. Patients were randomized 1:1 to receive either intravenous retifanlimab at 500 mg every 4 weeks for 12 months or placebo, both in combination with standard dosing of carboplatin and paclitaxel for 6 months. Key stratification factors included PD-L1 expression, region, and extent of disease. Patients in the placebo arm were allowed to cross over to the retifanlimab arm upon BICR-verified disease progression.
Safety Profile
Treatment-emergent adverse events (TEAEs) of any grade occurred in all patients in both arms. Grade 3 or higher TEAEs were reported in 83.1% of patients in the retifanlimab arm and 75.0% in the placebo arm. The most common grade 3 or higher TEAEs included neutropenia, anemia, and decreased neutrophil count. Immune-related adverse events were more frequent in the retifanlimab arm, with common events including peripheral sensory neuropathy, hypothyroidism, and hyperthyroidism.
Clinical Implications
According to Dr. Sheela Rao, a consultant medical oncologist at the Royal Marsden Hospital NHS Foundation Trust, retifanlimab plus carboplatin and paclitaxel represents a potential new reference treatment and standard of care for patients with advanced SCAC. This is particularly significant given the increasing incidence of SCAC, especially among individuals with HIV, and the lack of treatment advancements in recent decades.
