Efficacy and Safety of Durvalumab Rechallenge in Advanced Hepatocellular Carcinoma Patients Refractory to Prior Anti-PD-1 Therapy

Background/Purpose: Recently, anti-programmed cell death protein-1 (anti-PD-1) and anti-PD-L1 therapies were approved for hepatocellular carcinoma (HCC). However, the effectiveness of rechallenging with one immune checkpoint inhibitor (ICI) after failure of another remains unclear. This study explores the efficacy and safety of anti-PD-L1 rechallenge in patients who failed anti-PD-1 therapy. Methods: From January 2016 to December 2023, 65 advanced HCC patients previously treated with anti-PD-1 therapy were retrospectively enrolled and rechallenged with durvalumab (480 mg IV every two weeks). Results: Overall, 86.2% of patients received nivolumab and 13.8% pembrolizumab as prior anti-PD-1 therapy. The overall response rate (ORR) to durvalumab was 13.8%. Patients who responded to prior anti-PD-1 had a higher ORR compared to non-responders (31.3% vs. 8.7%, p = 0.04). Patients with any grade of immune-related adverse events (irAEs) from durvalumab had a higher ORR than those without irAEs (35.3% vs. 6.7%, p = 0.01). The median PFS was 5.4 months, and the median OS was 9.6 months. Responders to prior anti-PD-1 showed longer OS (33.9 vs. 8.2 months, p < 0.01) and a trend toward longer PFS (13.8 vs. 4.9 months, p = 0.07) compared to non-responders. Multivariate analysis identified prior anti-PD-1 response (HR: 0.31) as the only protective factor for death. Common irAEs were skin toxicity (13.8%) and hepatitis (7.7%); no correlation was found between irAEs from prior anti-PD-1 and durvalumab treatment. Conclusion: This study provides the first, concrete evidence that durvalumab rechallenge is effective for HCC patients who are refractory to anti-PD-1 therapy, especially for those who previously responded to anti-PD-1 treatment.