Atezolizumab-bevacizumab with or without cisplatin-based HAIC for unresectable HCC: A randomized phase II trial

Atezolizumab plus bevacizumab (ATZ/BEV) is the global standard first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate (ORR) is approximately 30%. Hepatic arterial infusion chemotherapy (HAIC) with cisplatin may enhance its efficacy through locoregional cytoreduction and immunological modulation. We conducted a randomized phase II trial to evaluate whether sequential cisplatin HAIC plus ATZ/BEV (CDDP+ATZ/BEV) improves clinical outcomes compared to ATZ/BEV alone.

In this multicenter, open-label trial, patients with unresectable HCC were randomized 1:1 to receive cisplatin HAIC within 8 weeks before initiation of ATZ/BEV or ATZ/BEV alone. The primary endpoint was ORR.

Between December 2021 and December 2024, 70 patients were enrolled in this study (CDDP+ATZ/BEV, n = 35; ATZ/BEV, n = 35). The primary endpoint, ORR, was numerically higher in the CDDP+ATZ/BEV group than in the ATZ/BEV group but did not reach statistical significance (45.7% vs. 28.6%; p = 0.095). Median progression-free survival (PFS) was longer in the CDDP+ATZ/BEV group (8.3 vs. 6.6 months; HR 0.53; p = 0.036), and median duration of response was not reached vs. 4.6 months (HR 0.4; p = 0.11). The median overall survival (OS) was 28.1 vs. 31.0 months (HR 0.95; p = 0.88). Grade 3-4 treatment-related adverse events occurred in 20.0% and 22.9% of patients, respectively.

The primary endpoint of ORR was not met. However, exploratory analyses demonstrated longer PFS without additional safety concerns. Further evaluation in phase III trials is warranted.

This multicenter randomized phase II trial provides evidence that sequential cisplatin hepatic arterial infusion chemotherapy followed by atezolizumab-bevacizumab may prolong disease control without increasing toxicity in patients with unresectable hepatocellular carcinoma. Although the primary endpoint was not met and the progression-free survival benefit was observed in exploratory analyses, these findings support further investigation of this strategy in phase III trials and provide a rationale for evaluating liver-directed combination approaches to optimize first-line immunotherapy.

Japan Registry of Clinical Trials (jRCTs061210065).