Supplementary Material for: Balancing efficacy and tolerability of first-line systemic therapies for advanced hepatocellular carcinoma: a network metanalysis

Background: Atezolizumab+Bevacizumab represents the current standard of care for first-line treatment of advanced 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 31st October, 2022. Phase III 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 (RMST). 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(ISER) as measure of net health benefit was calculated as the difference in SAEs probability divided by survival difference between the 2 most effective treatments. Results:Nine RCTs enrolling 6600 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 favored in 78% of cases, while at threshold of 30% of SAEs for life-month gained, Lenvatinib was favored 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.

背景：阿替利珠单抗+贝伐珠单抗（Atezolizumab+Bevacizumab）目前是晚期肝细胞癌（hepatocellular carcinoma, HCC）一线治疗的标准治疗方案。然而，目前尚缺乏其与包括免疫检查点抑制剂（immune-checkpoint inhibitors, ICI）+酪氨酸激酶抑制剂（tyrosine-kinase inhibitors, TKIs）在内的其他联合治疗方案的头对头直接比较研究。
目的：本网络Meta分析（network meta-analysis, NMA）旨在间接比较不可切除晚期肝细胞癌一线系统治疗的有效性与安全性。
方法：研究检索了截至2022年10月31日的MEDLINE、EMBASE及SCOPUS数据库。纳入评估酪氨酸激酶抑制剂（含索拉非尼（Sorafenib）、仑伐替尼（Lenvatinib））或免疫检查点抑制剂的Ⅲ期随机对照试验（randomized controlled trials, RCTs），且需报告总生存期（overall survival, OS）与无进展生存期（progression-free survival, PFS）。从OS及PFS曲线中提取个体生存数据，以计算限制性平均生存时间（restricted mean survival time, RMST）。采用贝叶斯网络Meta分析，从有效性（15个月、30个月OS率，6个月PFS率）及安全性（以≥3级（重度）不良事件（severe adverse events, SAEs）为指标）两方面对各治疗方案进行比较。以增量安全效益比（incremental safety-effectiveness ratio, ISER）作为净健康获益的评估指标，其计算方式为两种最有效治疗方案间的严重不良事件概率差值除以生存差值。
结果：本研究共纳入9项随机对照试验，合计纳入6600例患者。阿替利珠单抗联合贝伐珠单抗达到30个月OS终点的概率最高（88%）。仑伐替尼获得最优PFS结局的概率为86%。免疫检查点抑制剂单药治疗的耐受性最佳。与度伐利尤单抗（Durvalumab）联合替西木单抗（Tremelimumab）相比，阿替利珠单抗联合贝伐珠单抗的OS净健康获益最优。当以每获得1个生命月愿意承担10%的严重不良事件风险作为阈值评估PFS的净健康获益时，78%的场景下阿替利珠单抗联合贝伐珠单抗更受青睐；而当阈值提升至每获得1个生命月愿意承担30%的严重不良事件风险时，76%的场景下仑伐替尼更受青睐。
结论：阿替利珠单抗联合贝伐珠单抗的净健康获益最优，因此推荐其作为晚期肝细胞癌一线治疗的标准方案。与阿替利珠单抗联合贝伐珠单抗相比，当医患双方愿意接受更高的毒性风险时，仑伐替尼单药治疗在PFS方面的净健康获益最优。