Importance: Immunotherapies are the preferred frontline treatment for most hepatocellular carcinomas (HCCs), but only a small subset of patients attain complete responses to immunotherapies, resulting in an absence of radiographic apparent disease. The clinical importance of these complete responses is unclear, and whether clinical or molecular features may define HCCs that are exquisitely sensitive to immunotherapies is ambiguous.

Objective: To describe the long-term survival outcomes of complete responders to immunotherapies, and to examine whether clinical and genomic characteristics are associated with complete response.

Design, Setting, and Participants: This cohort study includes a post hoc analysis of the IMbrave150 trial (which enrolled patients across 17 countries in North America, Europe, Asia, and Australia) and a multicenter cohort analysis of patients with advanced HCC treated with frontline immunotherapies across 3 institutions (2 in the US and 1 in Asia). Complete responders were defined as patients with a complete response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or modified RECIST. Statistical analyses were conducted from January to May 2024.

Main Outcomes and Measures: The main outcome was overall survival measured as the time from start of immunotherapy to the date of death. Kaplan-Meier curves were used to estimate progression-free and overall survival, and differences in survival outcomes were assessed using the log-rank test.

Results: The analytical sample included 279 patients (mean [SD] age, 64.7 [11.1] years; 228 male patients [81.7%]) treated with atezolizumab and bevacizumab in the IMbrave150 trial and 194 patients (mean [SD] age, 64.3 [11.4] years; 155 male patients [78.7%]) with frontline anti–programmed cell death 1 ligand 1 (PD-1/L1) therapies in a multicenter patient cohort. Complete responders had high disease-free survival rates at 2 years in the IMbrave150 (58.0%; 95% CI, 36.2%-74.7%) and multicenter (87.4%; 95% CI, 58.2%-96.7%) cohorts. Overall survival rates at 2 years for complete responders were 81.1% (95% CI, 64.4%-90.5%) in the IMbrave150 cohort and 93.3% (95% CI, 61.2%-99.0%) in the multicenter cohort. Among complete responders who discontinued treatment for reasons other than disease progression after a median duration of treatment of 24 months, disease recurrence was rare. Molecular profiling of HCC among complete responders did not reveal unique genetic alterations in these patients. However, cancers with complete responses had higher PD-L1 protein expression in the immune cell compartment and lower circulating tumor DNA levels.

Conclusions and Relevance: In this post hoc trial and multicenter cohort analysis of patients with HCC treated with immunotherapy, complete responders demonstrated prolonged survival and durable disease control even after discontinuation of therapy. Biological features of complete responders were also distinct, and further evaluation of immune cell PD-L1 protein expression and circulating tumor DNA as potential biomarkers is warranted.