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.

中文翻译：

---

平衡晚期肝细胞癌一线系统治疗的疗效和耐受性：网络荟萃分析。


背景 Atezolizumab + 贝伐单抗代表了目前晚期肝细胞癌 (HCC) 一线治疗的护理标准。然而，缺乏与免疫检查点抑制剂（ICI）+酪氨酸激酶抑制剂（TKI）等其他联合治疗的直接比较。目的 该网络荟萃分析 (NMA) 旨在间接比较不可切除的晚期 HCC 一线系统疗法的疗效和安全性。方法 对 MEDLINE、Embase 和 SCOPUS 数据库进行截至 2022 年 10 月 31 日的文献检索。第 3 期随机对照试验 (RCT) 测试 TKI，包括索拉非尼和仑伐替尼，或报告总生存期 (OS) 和无进展生存期的 ICI （PFS）也包括在内。从 OS 和 PFS 曲线中提取个体生存数据，以计算限制平均生存时间。进行贝叶斯 NMA 来比较治疗的疗效（15 个月和 30 个月 OS、6 个月 PFS）和安全性（以 ≥3 级（严重）不良事件 (SAE) 为代表）。作为衡量净健康效益的增量安全有效性比的计算方法为 SAE 概率的差异除以 2 种最有效治疗方法之间的生存差异。结果 纳入 9 项随机对照试验，共纳入 6,600 名患者。 Atezolizumab 加贝伐单抗显示实现 30 个月 OS 里程碑的最高概率 (88%)。仑伐替尼显示实现最佳 PFS 结果的概率为 86%。 ICI 单一疗法被评为最耐受的疗法。与 durvalumab 加 tremelimumab 相比，Atezolizumab 加贝伐珠单抗显示出最佳的 OS 净健康益处。 在评估 PFS 的净健康效益时，在生命月内发生 10% 的 SAE 的风险意愿阈值下，78% 的病例倾向于使用阿替利珠单抗加贝伐珠单抗，而在生命月内发生 30% 的 SAE 的阈值下，阿替利珠单抗加贝伐单抗受到青睐。一个月后，乐伐替尼在 76% 的病例中受到青睐。结论 就净效益而言，阿特珠单抗联合贝伐珠单抗是最佳治疗方法，因此应推荐作为标准治疗。与 atezolizumab 加贝伐单抗相比，当医生和患者能够接受较高的毒性风险时，乐伐替尼单药治疗对 PFS 具有最佳的净效益。