Immune checkpoint inhibitor rechallenge in unresectable hepatocellularcarcinoma: a multicenter efficacy and safety study

Background and aims: Immune checkpoint inhibitors (ICIs) are a standard treatment for unresectable hepatocellular carcinoma, but sometimes they must be discontinued because of resistance or immune-related adverse events. The present study explored whether later resuming ICI therapy in such patients ("rechallenge") can improve their prognosis. Methods: Data were retrospectively analyzed for patients treated between March 2019 and May 2024 at 12 medical centers in China. Patients had unresectable hepatocellular carcinoma and were initially treated with ICIs, which were discontinued due to resistance or severe immune-related adverse events and then later resumed. Event-free survival, objective response and disease control based on RECIST 1.1 criteria, as well as incidence and severity of immune-related adverse events, were assessed separately during first- (ICI-1) and second-line ICI (ICI-2) therapy. Results: The final analysis included 272 patients (247 men) with a median age of 50 (IQR 43-58) years old at enrollment; ICI-1 were discontinued in 253 patients (93.0%) because of tumor progression. Both ICI-1 and ICI-2 therapies lasted a median of 3.0 months and, for approximately 80% of patients, involved the combination of ICIs and targeted agents rather than ICI monotherapy. During ICI-1 or ICI-2 therapy, respective median event-free survival times were 5.3 (95% CI 4.7–5.9) months and 4.4 (95% CI 3.8–5.0) months, objective response rates were 23.2% and 18.4%, disease control rates were 69.9% and 48.2%, and rates of immune-related adverse events of grades 3-4 were 18.4% and 19.9%. Objective response was observed in 26 patients (9.6%) during both therapy lines, while 10 (12.2%) suffered disease progression during ICI-1 therapy yet achieved partial response during ICI-2 treatment. No deaths due to immune-related adverse events occurred during the study. Conclusion: ICI rechallenge following tumor progression or severe immune-related adverse events can benefit some patients with unresectable hepatocellular carcinoma without posing additional safety risks.