Multicenter Phase 2 Trial of Second-Line Regorafenib in Patients with Unresectable Hepatocellular Carcinoma after Progression on Atezolizumab plus Bevacizumab
Jaekyung Cheon, Baek‐Yeol Ryoo, Hong Jae Chon, Hyung‐Don Kim, Min‐Hee Ryu, Kyu‐pyo Kim, Beodeul Kang, Richard S. Finn, Stephen L. Chan, Changhoon Yoo
Abstract
Introduction: Atezolizumab-bevacizumab (Atezo-Bev) has become the standard first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). However, data on subsequent treatment after Atezo-Bev failure are lacking. We aimed to investigate the efficacy and safety of regorafenib for uHCC progression after first-line Atezo-Bev. Methods: This investigator-initiated, single-arm, phase 2 trial involved two academic centers in Korea. Eligibility criteria included a diagnosis of HCC, prior treatment with at least 2 cycles of Atezo-Bev, and Child-Pugh A liver function. Eligible patients received regorafenib 160 mg once daily for 3 weeks of every 4-week cycle (i.e., 3 weeks on, 1 week off) until progressive disease or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, disease control rate according to RECIST v1.1, overall survival (OS), and treatment-related adverse events. Results: Forty patients were enrolled from December 2021 through May 2023. The median follow-up duration was 10.1 months (95% confidence interval [CI]: 8.3–12.0). The median PFS was 3.5 months (95% CI: 3.0–3.9). The median OS was 10.5 months (95% CI: 7.1–13.8), and the 6-month OS rate was 65.0%. The objective response rate and disease control rate were 10.0% and 82.5%, respectively. The most common grade 3–4 treatment-related adverse event was thrombocytopenia (5.0%). When stratified according to time to progression on prior Atezo-Bev (first quartile [<2.3 months] vs. second to fourth quartiles [≥2.3 months]), patients with longer time to progression on prior Atezo-Bev had better OS (15.0 vs. 3.6 months, p < 0.001), objective response rate (13.3% vs. 0%, p = 0.009), and a tendency toward better PFS with regorafenib (3.8 vs. 2.5 months; p = 0.054). Conclusion: Second-line regorafenib was effective for treating uHCC progression after first-line Atezo-Bev. The efficacy and safety outcomes from our study were consistent with those observed in the pivotal phase 3 RESORCE trial, which included sorafenib-tolerant/-progressed patients.