Comparative Efficacy of Atezolizumab plus Bevacizumab and Other Treatment Options for Patients with Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis

Abstract

<b><i>Background:</i></b> Most phase 3 clinical trials of systemic therapy for first-line unresectable hepatocellular carcinoma (HCC) have failed, with the exception of SHARP, REFLECT, and IMbrave150. We conducted indirect comparisons of therapies evaluated for first-line HCC treatment. <b><i>Summary:</i></b> We conducted a systematic review and meta-analysis of treatments for adults with locally advanced or metastatic unresectable HCC and no prior systemic treatment, including atezolizu­mab plus bevacizumab, sorafenib, lenvatinib, nivolumab, selective internal radiotherapy (SIRT), transarterial chemoembolization, and placebo or best supportive care. Randomized controlled trials published from January 1, 2007, to March 12, 2020, were retrieved from MEDLINE and Embase. Qualitative assessment of heterogeneity evaluated study designs, populations, and outcomes. Indirect comparisons used generalized linear models with random effects within a Bayesian framework and informative priors. We calculated relative efficacy estimates with 95% credible intervals (CrIs) and Bayesian posterior probability estimates of atezolizumab-bevacizumab being superior to other treatments. Nine clinical studies with a total of 3,897 participants were identified from 8,783 records and used to build the all-trials evidence network. Indirect comparisons suggested an improved overall survival (OS) with atezolizumab-bevacizumab versus lenvatinib (odds ratio, 0.63 [95% CrI 0.39–1.04]; with 97% Bayesian posterior probability of being superior), nivolumab (0.68 [95% CrI 0.41–1.14]; 94%), sorafenib (0.59 [95% CrI 0.39–0.87]; 99%), SIRT (0.51 [95% CrI 0.32–0.82]; 100%), or placebo/best supportive care (0.40 [95% CrI 0.25–0.64]; 100%). <b><i>Key Messages:</i></b> Within the context of indirect comparisons, analyses of OS favored atezolizumab-bevacizumab versus other treatment options for patients with locally advanced or metastatic unresectable HCC.

AGA Technical Review on Systemic Therapies for Hepatocellular Carcinoma

“…However, we did not include their findings in the Technical Review due to the overall very low to low CoE in the trials that provided direct comparisons. [32][33][34][35][36][37][38]…”

Bayesian Analysis Supports Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

“…First, the included trials presented heterogeneous study design, and the statistics quantifying the NMA heterogeneity were not reported. Second, although the authors reported that risk of bias was generally low across trials, lack of study blinding in 7 of 9 trials raises concerns, and in addition, risk of bias could not be assessed for CheckMate 459 [4]. Third, if certainly Bayesian NMA represents a powerful method that allows the sharing of information across different clinical trials, cross-trial comparisons may only partially compare adverse events and safety profiles [5].…”

“…Atezolizumab-bevacizumab has become the new benchmark for front-line treatment in unresectable HCC [1][2][3][4]; on the horizon, there is a host of phase III randomized clinical trials of novel combinations including immune checkpoint inhibitors combined with other antiangiogenic agents as well as PD-1 or PD-L1 inhibitors plus CTLA-4 inhibitors. The results of these studies are highly awaited and have the potential to further modify the first-line treatment scenario of this challenging malignancy.…”

“…In the current systemic review and network meta-analysis (NMA) conducted by Vogel and colleagues, the authors pulled together 9 clinical trials for a total of 3,897 patients with locally advanced or metastatic unresectable HCC [4]. According to the results of the NMA, Vogel et al [4] suggested that atezolizumab-bevacizumab reported the most consistent overall survival benefit compared to other treatment options.…”

“…In the current systemic review and network meta-analysis (NMA) conducted by Vogel and colleagues, the authors pulled together 9 clinical trials for a total of 3,897 patients with locally advanced or metastatic unresectable HCC [4]. According to the results of the NMA, Vogel et al [4] suggested that atezolizumab-bevacizumab reported the most consistent overall survival benefit compared to other treatment options. Bayesian NMA was used to optimize data extrapolation and to allow a comparison between different treatments when no direct comparative study was available and to obtain more precise effect estimated by jointly considering indirect and direct comparisons [5].…”