In patients with unresectable hepatocellular carcinoma (HCC) included in the IMbrave150 study, the combination of atezolizumab and bevacizumab was associated with better progression-free survival (PFS) and overall survival (OS) outcomes, response rate and preservation of quality of life (QoL) than a treatment with sorafenib. Serious side effects were recorded in 38% of patients, similar to that seen in previous studies of these agents. The results are published by Richard S. Finn and IMbrave150 investigators on 14 May 2020 in The New England Journal of Medicine.
The authors wrote in the study background that most HCC patients present with unresectable disease and have a poor prognosis. First-line systemic treatments for unresectable HCC are the multikinase inhibitors sorafenib and lenvatinib. The studies showed modestly longer survival with sorafenib than with placebo and non-inferiority of lenvatinib to sorafenib. However, both drugs are associated with considerable side effects that impair QoL.
Based on results from phase I/II studies, PD-1 inhibitors showed promising clinical activity as second-line treatment for HCC. However, in phase III studies despite being associated with response rates in the range of 15% to 20%, single-agent treatment in first- and second-line settings did not result in improved OS. Anti-VEGF therapies reduce VEGF-mediated immunosuppression within the tumour and its microenvironment and may enhance efficacy of immune checkpoint inhibitors.
Previously, a phase Ib study of atezolizumab combined with bevacizumab in patients with untreated unresectable HCC showed an acceptable side effects profile and promising antitumour activity, with an objective response rate of 36% and a median PFS of 7 months.
The IMbrave150 is a global, multicentre, open-label, phase III randomised trial, conducted to determine the safety and efficacy of atezolizumab combined with bevacizumab as compared with sorafenib in patients with unresectable HCC who had not previously received systemic therapy. Patients were randomly assigned in a 2:1 ratio to receive either atezolizumab combined with bevacizumab or sorafenib until unacceptable side effects occurred or there was a loss of clinical benefit.
The study co-primary endpoints were OS and PFS in the intention-to-treat (ITT) population, as assessed at an independent review facility according to RECIST v1.1.
The ITT population included 336 patients in the atezolizumab combined with bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis on 29 August 2019, the hazard ratio (HR) for death with atezolizumab combined with bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; p < 0.001). The OS at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab combined with bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median PFS was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6), HR for disease progression or death, 0.59 (95% CI, 0.47 to 0.76; p < 0.001).
Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab combined with bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab combined with bevacizumab group. Other high grade side effects were not frequent.
The authors pointed out that their study has several limitations. The open-label design was used to spare patients from two placebo infusions. To minimise the potential bias associated with the open-label design, a blinded independent review of imaging for PFS was selected for the co-primary endpoint. The trial was conducted in a patient population that had preserved liver function (Child–Pugh class A) and a decreased risk of variceal bleeding. The safety of the combination in a broader population warrants further study.
The authors concluded that treatment with atezolizumab combined with bevacizumab was associated with significantly better OS and PFS outcomes than sorafenib in patients with advanced unresectable HCC not previously treated with systemic therapy. Serious side effects were noted in 38% of the patients who received the combination therapy, but no new or unexpected side effects were observed. The combination therapy also resulted in a longer time to deterioration of patient reported QoL and functioning than treatment with sorafenib.
The study was supported by F. Hoffmann–La Roche/Genentech.
Finn R, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020; 382:1894-1905.