Primary Analysis of a Phase II Study of Atezolizumab plus Bevacizumab for TACE-Unsuitable Patients with Tumor Burden beyond Up-To-Seven Criteria in Intermediate-Stage Hepatocellular Carcinoma: REPLACEMENT Study.
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INTRODUCTION: Intermediate-stage hepatocellular carcinoma (HCC) presents varying tumor burdens. For patients unsuitable for transcatheter arterial chemoembolization (TACE) due to high tumor burden, recent guidelines recommend systemic therapy. This study evaluates the efficacy and safety of atezolizumab plus bevacizumab for TACE-unsuitable patients with unresectable intermediate-stage HCC beyond up-to-seven criteria. METHODS: This prospective, phase II, single-arm, non-blinded study enrolled TACE-naïve patients with unresectable intermediate-stage HCC beyond up-to-seven criteria, Child-Pugh A, no previous systemic therapy, and ECOG Performance Status score of 0-1 from 35 sites in Japan. Patients received atezolizumab 1,200 mg and bevacizumab 15 mg/kg every 3 weeks. The primary endpoint was the 6-month progression-free survival (PFS) rate by modified RECIST (mRECIST). Key secondary endpoints included the objective response rate (ORR) and safety. Exploratory endpoints examined individual changes in tumor size, comparison by inverse probability weighting (IPW) of data with retrospective historical data of TACE-treated patients, and conversion rate to a curative intent therapy. RESULTS: In total, 74 patients were enrolled from December 2020 to September 2021 (median follow-up, 15.1 months). The 6-month PFS rate by mRECIST was 66.8% (90% CI: 56.8, 75.0), and the lower limit of the 90% CI exceeded the pre-specified threshold of 55%. ORR by mRECIST was 40.5%. After treatment with atezolizumab plus bevacizumab, 10 patients, including 5 patients who had a tumor burden beyond the up-to-11 criteria at baseline, were able to transition to curative intent therapy. PFS by mRECIST by IPW was 9.2 months with atezolizumab plus bevacizumab versus 5.7 months with TACE (hazard ratio 0.67, p = 0.029). Adverse events (AEs), mostly hypertension, proteinuria, and malaise, were common. AEs requiring corticosteroids occurred in 10 patients (13.5%). CONCLUSION: Atezolizumab plus bevacizumab appears beneficial as first-line treatment for TACE-unsuitable patients with unresectable intermediate-stage unresectable HCC beyond up-to-seven criteria. Future strategies utilizing multimodal approaches may further improve outcomes.