Balancing Efficacy and Tolerability of First-Line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Network Meta-Analysis

Abstract

Background: Atezolizumab + bevacizumab represent the current standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, direct comparison with other combination treatments including immune checkpoint inhibitors (ICI) + tyrosine kinase inhibitors (TKIs) are lacking.

Objectives: This network meta-analysis (NMA) aims to indirectly compare the efficacy and the safety of first-line systemic therapies for unresectable advanced HCC.

Method: A literature search of MEDLINE, Embase, and SCOPUS databases was conducted up to October 31, 2022. Phase 3 randomized controlled trials (RCTs) testing TKIs, including sorafenib and lenvatinib, or ICIs reporting overall survival (OS) and progression-free survival (PFS) were included. Individual survival data were extracted from OS and PFS curves to calculate restricted mean survival time. A Bayesian NMA was performed to compare treatments in terms of efficacy (15- and 30-month OS, 6-month PFS) and safety, represented by grade ≥3 (severe) adverse events (SAEs). The incremental safety-effectiveness ratio as measure of net health benefit was calculated as the difference in SAE probability divided by survival difference between the 2 most effective treatments.

Results: Nine RCTs enrolling 6,600 patients were included. Atezolizumab plus bevacizumab showed the highest probability (88%) of achieving the 30-month OS landmark. Lenvatinib showed a probability of 86% of achieving best PFS outcomes. ICI monotherapies ranked as most tolerable. Atezolizumab plus bevacizumab showed the best net health benefit for OS, compared to durvalumab plus tremelimumab. When evaluating the net health benefit for PFS, at a willingness-to-risk threshold of 10% of SAEs for life-month gained, atezolizumab plus bevacizumab was favoured in 78% of cases, while at threshold of 30% of SAEs for life-month gained, lenvatinib was favoured in 76% of cases.

Conclusions: Atezolizumab plus bevacizumab is the best treatment in terms of net benefit and therefore it should be recommended as standard of care. Compared to atezolizumab plus bevacizumab, lenvatinib monotherapy had the best net benefit for PFS when physicians and patients are available to accept a higher risk of toxicity.

Keywords: Anti-vascular endothelial growth factor; First-line treatment; Hepatocellular carcinoma; Immunotherapy; Systemic treatment; Tyrosin-kinase inhibitors.

Fig. 1.

NMA of comparisons between first-line systemic treatments for advanced HCC.

Fig. 2.

Forest plot of NMA for OS of first-line systemic treatments for advanced HCC compared to atezolizumab plus bevacizumab. 30-month OS.

Fig. 3.

Forest plot of NMA for 6-month PFS of first-line systemic treatments for advanced HCC compared to atezolizumab plus bevacizumab.

Fig. 4.

Forest plot of NMA for adverse events (AEs) of first-line systemic treatments for advanced HCC compared to atezolizumab plus bevacizumab. a grade ≥3 (severe) AEs (SAEs). b AEs leading to treatment discontinuation.

Fig. 5.

Two-way sensitivity analysis of ISER (ISER, i.e., delta SAEs %/survival difference) to indicate which treatment is favoured according to different “willingness-to-risk” thresholds. Two different scenarios were reported with two different willingness-to-risk thresholds: 10% and 30% of SAEs for month-life gained. Top panel: comparison of ISER between atezolizumab plus bevacizumab and durvalumab plus tremelimumab for OS. Grey area favoured durvalumab plus tremelimumab, while white area favoured atezolizumab plus bevacizumab. Bottom panel: comparison of ISER between atezolizumab plus bevacizumab and lenvatinib monotherapy for PFS. Grey area favoured lenvatinib monotherapy, while white area favoured atezolizumab plus bevacizumab.