What type of study is this?

This is a Pre-Registered Trial study.

What question did this study set out to answer?

This research aims to evaluate the efficacy of atezolizumab combined with a multikinase inhibitor in treating advanced hepatocellular carcinoma after progression on previous therapy.

January 14, 2026

A phase II randomized study of atezolizumab plus multikinase inhibitor (MKI) versus MKI alone in patients with advanced hepatocellular carcinoma previously treated with atezolizumab plus bevacizumab (Atezo/Bev).

Key Points

This research aims to evaluate the efficacy of atezolizumab combined with a multikinase inhibitor in treating advanced hepatocellular carcinoma after progression on previous therapy.
Multicenter, randomized phase II trial
Enrolled patients with unresectable advanced hepatocellular carcinoma who progressed after atezolizumab plus bevacizumab
Patients randomized 2:1 to receive atezolizumab plus MKI (cabozantinib or lenvatinib) or MKI alone
Endpoints included overall survival, progression-free survival, and safety
Median overall survival was 13.9 months for the combination therapy and 6.2 months for MKI alone
Median progression-free survival was 4.3 months for combination and 4.1 months for MKI alone
Objective response rate was 7.7% in the combination group and 0% in the MKI alone group
Grade ≥3 adverse events were reported in 46.2% of the combination group and 60.0% of the MKI alone group

Abstract

554 Background: Atezo/Bev is the 1 st -line standard for advanced hepatocellular carcinoma (aHCC). Optimal 2 nd -line therapy post-Atezo/Bev remains undefined. This study evaluates continuation of atezolizumab with a MKI versus MKI alone in the 2 nd -line setting. Methods: This multicenter, randomized phase II trial enrolled patients with unresectable aHCC who progressed on Atezo/Bev. Patients were randomized 2:1 to atezolizumab plus MKI (cabozantinib or lenvatinib; Arm A) or MKI alone (Arm B). Stratification factors included MKI choice, viral etiology, and alpha-fetoprotein levels. Dual primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response (DOR), and safety. With 84 death and 89 PFS events, from 122 patients, this trial had 80% power to detect a hazard ratio (HR) of 0.556 in OS and HR of 0.571 in PFS with a one-sided type I error (alpha) of 0.05 for each endpoint. Results: Twenty patients were accrued across 5 U.S. centers, between 01/2022 and 03/2025, before early closure due to slow accrual. Eighteen received treatment (Arm A: n=13; Arm B: n=5). Baseline characteristics: median age 68 yr, extrahepatic 56%, Hep B+ 0%, Hep C+ 33%, NASH 33% and CP A (5 to 6) 100%. MKIs used were cabozantinib (Arm A: 6/13; Arm B: 4/5) and lenvatinib (Arm A: 7/13; Arm B: 1/5). Median follow-up was 28.0 months (mo), with 14 deaths reported. Median (95% CI) OS were 13.9 (7.1-Not Estimable NE) and 6.2 (5.1-NE) mo (Arm A and B respectively); and that of PFS 4.3 (2.3-NE) and 4.1 (3.7-NE) mo. ORR was 7.7% (1/13) in Arm A (responder received lenvatinib) and 0% (0/5) in Arm B. Grade ≥3 adverse events (at least possibly related) occurred in 46.2% of Arm A and 60.0% of Arm B patients. G3+ events occurring in >10% of patients included hypertension, fatigue, anorexia, and ALT elevation in Arm A; and hypertension, hallucination, nausea, hypomagnesemia, hypokalemia, mucositis, AST increased and colitis in Arm B. Conclusions: In this limited cohort, continuation of atezolizumab with MKI showed relative activity and manageable safety in aHCC post-Atezo/Bev. The AE profile for atezo/MKI is consistent with the known profile of respective agents. These findings support further investigation of immunotherapy-based combinations in the 2nd-line setting. Clinical trial information: NCT05168163 .

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