As reported in The New England Journal of Medicine by Richard S. Finn, MD, of Jonsson Comprehensive Cancer Center, Geffen School of Medicine at the University of California, Los Angeles, and colleagues, the phase III IMbrave150 trial has shown that anti–programmed cell death ligand 1 (PD-L1) plus anti-VEGF therapy with atezolizumab plus bevacizumab improved progression-free and overall survival vs sorafenib in patients with unresectable hepatocellular carcinoma who had received no prior systemic therapy and had well-compensated liver disease.¹

Richard S. Finn, MD

Study Details

In the open-label trial, 501 patients from 111 sites in 17 countries with unresectable hepatocellular carcinoma were randomly assigned 2:1 between March 2018 and January 2019 to receive atezolizumab plus bevacizumab (n = 336) or sorafenib (n = 165). Treatment consisted of atezolizumab at 1,200 mg and bevacizu­mab at 15 mg/kg intravenously every 3 weeks and oral sorafenib at 400 mg twice daily, with treatment continuing until loss of clinical benefit or unacceptable toxicity. Randomization was stratified by geographic region (Asia excluding Japan vs the rest of the world), macrovascular invasion or extrahepatic spread of disease, baseline alpha-fetoprotein (AFP) level (< 400 vs ≥ 400 ng/mL), and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1). The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population as assessed at an independent review facility using Response Evaluation Criteria in Solid Tumors version 1.1.

For the atezolizumab/bevacizumab vs sorafenib groups, the median age was 64 vs 66 years; 82% vs 83% were male; 40% vs 41% were from Asia, excluding Japan, and the remainder were from the United States, Australia, New Zealand, and Japan; all patients had an ECOG performance status of 0 (62% in both) or 1 (38% in both); 72% vs 73% had a Child-Pugh score of A5; 82% vs 81% had Barcelona Clinic Liver Cancer stage C disease; 38% vs 37% had AFP ≥ 400 ng/mL; 77% vs 73% had macrovascular invasion (38% vs 43%) or extrahepatic spread (63% vs 56%) or both; 26% vs 26% had varices at baseline; causes of hepatocellular carcinoma were hepatitis B in 49% vs 46%, hepatitis C in 21% vs 22%, and nonviral in 30% vs 32%; and 48% vs 52% had received local therapy for hepatocellular carcinoma. Among 182 patients with known status, 64% vs 67% had PD-L1–positive tumors.

Progression-Free and Overall Survival

At data cutoff (August 2019), the median follow-up was 8.6 months. At the time of the primary analysis, 28.6% of patients in the atezolizumab/bevacizumab group and 39.4% of patients in the sorafenib group had died, with overall survival being significantly improved in the atezolizumab/bevacizumab group vs the sorafenib group (stratified hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.42–0.79, P < .001). Overall survival at 12 months was 67.2% vs 54.6%. Median progression-free survival was 6.8 months vs 4.3 months (stratified HR = 0.59, 95% CI = 0.47–0.76, P < .001), with 6-month rates of 54.5% vs 37.2%. Objective response rates were 27.3% vs and 11.9% (P < .001), with a complete response in 18 vs 0 patients. The duration of response was at least 6 months in 87.6% vs 59.1%.

In overall survival subgroup analyses, hazard ratios for atezolizumab/bevacizumab vs sorafenib were 0.53 (95% CI = 0.32–0.87) in Asia excluding Japan and 0.65 (95% CI = 0.44–0.98) for the rest of the world; 0.67 (95% CI = 0.43–1.06) for a performance status of 0 and 0.51 (95% CI = 0.33–0.80) for a performance status of 1; 0.69 (95% CI = 0.29–1.65) for those without and 0.55 (95% CI = 0.39–0.77) for those with macrovascular invasion or extrahepatic spread or both; 0.52 (95% CI = 0.34–0. 81) for those with AFP < 400 ng/mL and 0.68 (95% CI = 0.43–1.08) for those with AFP ≥ 400 ng/mL; and 0.57 (95% CI = 0.38–0.87) for those without and 0.63 (95% CI = 0.39–1.01) for those with prior local therapy.

In progression-free survival subgroup analyses, hazard ratios were 0.46 in Asia excluding Japan and 0.70 for the rest of the world; 0.57 for a performance status of 0 and 0.63 for a performance status of 1; 0.72 for those without and 0.53 for those with macrovascular invasion or extrahepatic spread or both; 0.49 for those with AFP < 400 ng/mL and 0.79 for those with AFP ≥ 400 ng/mL; and 0.68 for those without and 0.51 for those with prior local therapy.

For patient-reported outcomes assessed with the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire QLQ-C30, patients receiving atezolizumab/bevacizumab had statistically significantly longer median times to deterioration of overall quality of life (11.2 vs 3.6 months), physical functioning (13.1 vs 4.9 months), and role functioning (9.1 months vs 3.6 months).

Adverse Events

The median durations of treatment were 7.4 months with atezolizumab, 6.9 months with bevacizumab, and 2.8 months with sorafenib. Grade 3 or 4 adverse events occurred in 56.5% of patients in the atezolizumab/bevacizumab group vs 55.1% of patients in the sorafenib group. The most common adverse events in the atezolizumab/bevacizumab group were hypertension (15.2% vs 12.2%), increased aspartate aminotransferase (7.0% vs 5.1%), and increased alanine aminotransferase (3.6% vs 1.3%).

Serious adverse events occurred in 38.0% vs 30.8% of patients; no specific serious adverse event had an incidence that differed in the two groups by ≥ 2%. Adverse events led to discontinuation of treatment in 15.5% (both atezolizumab and bevacizumab in 7.0%) vs 10.3% of patients. Adverse events led to death in 15 patients (4.6%) vs 9 patients (5.8%). Grade 3 or 4 adverse events of special interest in the atezolizumab/bevacizumab group included potential atezolizumab-related (immune-mediated) events in 25.8% (vs similar events in 30.1% of the sorafenib group), with the most common being hepatitis (21.3% as diagnosis or laboratory abnormality) and infusion-related reactions (2.4%). Potential bevacizumab-related (VEGF inhibitor–related) grade 3 or 4 events occurred in 23.1% (vs similar events in 18.6% of the sorafenib group), with the most common being hypertension (15.2%) and bleeding/hemorrhage (6.4%) as compared to 12.2% and 5.8%, respectively, with sorafenib. Of note, patients were required to have an upper endoscopy within 6 months of starting on study.

The investigators concluded: “Treatment with atezolizumab plus bevacizumab was associated with significantly better overall survival and progression-free survival outcomes than sorafenib in patients with advanced unresectable hepatocellular carcinoma not previously treated with systemic therapy. Serious toxic effects were noted in 38% of the patients who received the combination therapy; however, no new or unexpected toxic effects were observed. The combination therapy also resulted in a longer time to deterioration of patient-reported quality of life and functioning than sorafenib.” 

DISCLOSURE: The study was funded by F. Hoffmann–La Roche/Genentech. For full disclosures of the study authors, visit nejm.org.

REFERENCE

1. Finn RS, Qin S, Ikeda M, et al: Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894-1905, 2020.