Second-Line Practices in the Era of Immunotherapy in HCC: The CHIEF Cohort

BACKGROUND & AIMS: Unresectable hepatocellular carcinoma (HCC) remains a major global health burden. Immunotherapy-based combinations have become the standard of care in first-line (1L) treatment, but evidence on subsequent therapies is limited. This study aimed to describe access to and outcomes of second-line (2L) treatments following atezolizumab-bevacizumab (AB) compared with sorafenib (Sor), using real-world data from the French prospective CHIEF cohort. METHODS: Patients were included in the CHIEF cohort, part of the prospective, real-world STRETCH study (Systemic Treatment SEquences in patients with unresectable HCC). Adults with unresectable HCC who received 1L treatment with AB or Sor between September 2019 and September 2024 were analyzed. Median overall survival (mOS) and median progression-free survival (mPFS) were calculated from 2L initiation. RESULTS: Among 1,103 patients included (AB, n = 899; Sor, n = 204), baseline characteristics were broadly similar, with most patients having Child-Pugh A liver function (77.1% vs. 70.3%) and Barcelona Clinic Liver Cancer (BCLC) stage C disease (66.3% vs. 84.3%). mOS was 22.3 months [95% CI, 18.5-27.4] with AB and 9.4 months [7.3-12.7] with Sor (p < 0.0001). Following progression, 42.1% of AB-treated and 60.0% of Sor-treated patients received 2L (p < 0.001). After AB, 70.8% received tyrosine kinase inhibitors (TKIs) with a mOS of 13.0 months [9.8-15.5]; survival was not reached for patients receiving immunotherapy or combination regimens (p = 0.0009). mOS with 2L TKIs was similar after AB or Sor (13.0 vs. 8.6 months; p = 0.082). CONCLUSIONS: In this prospective real-world cohort, access to 2L treatment was lower after AB than Sor. Nonetheless, 2L TKIs achieved numerically similar survival outcomes irrespective of 1L therapy, while immunotherapy rechallenge yielded encouraging results in selected patients. IMPACT AND IMPLICATIONS: The increasing use of immunotherapy-based combinations in first-line treatment for unresectable hepatocellular carcinoma raises crucial questions about optimal sequencing strategies after progression. This study provides prospective, real-world evidence on second-line treatment access and outcomes in the post-immunotherapy setting. These findings are important for clinicians and researchers seeking to refine treatment algorithms and ensure equitable access to effective therapies. In practice, the numerically similar survival achieved with tyrosine kinase inhibitors across treatment sequences and the promising results of immunotherapy rechallenge may inform individualized patient management and guide the design of future clinical trials evaluating sequential strategies.