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

<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.

**背景**：目前针对一线不可切除肝细胞癌（hepatocellular carcinoma, HCC）的全身治疗Ⅲ期临床试验大多以失败告终，仅SHARP、REFLECT及IMbrave150三项研究取得成功。本研究针对一线HCC治疗中评估的多种疗法开展了间接比较分析。
**研究总结**：本研究针对未接受过既往全身治疗的局部晚期或转移性不可切除肝细胞癌成人患者的治疗方案开展了系统评价与荟萃分析（systematic review and meta-analysis），纳入的治疗方案包括阿替利珠单抗（atezolizumab）联合贝伐珠单抗（bevacizumab）、索拉非尼（sorafenib）、仑伐替尼（lenvatinib）、纳武利尤单抗（nivolumab）、选择性内放射治疗（selective internal radiotherapy, SIRT）、经动脉化疗栓塞术以及安慰剂或最佳支持治疗。研究从MEDLINE和Embase数据库中检索了2007年1月1日至2020年3月12日发表的随机对照试验（randomized controlled trials）。通过定性评估异质性，对研究设计、入组人群及结局指标进行分析。间接比较采用贝叶斯框架（Bayesian framework）下带随机效应的广义线性模型（generalized linear models），并设定信息先验（informative priors）。本研究计算了相对疗效估计值及95%可信区间（credible intervals, CrIs），同时估算了阿替利珠单抗联合贝伐珠单抗优于其他治疗方案的贝叶斯后验概率（Bayesian posterior probability）。最终从8783条文献记录中筛选出9项临床研究，共计3897名受试者，用于构建全试验证据网络。间接比较结果显示，阿替利珠单抗联合贝伐珠单抗的总生存期（overall survival, OS）优于仑伐替尼（比值比（odds ratio）=0.63，95%CrI 0.39~1.04；贝叶斯后验优效概率为97%）、纳武利尤单抗（0.68，95%CrI 0.41~1.14；94%）、索拉非尼（0.59，95%CrI 0.39~0.87；99%）、SIRT（0.51，95%CrI 0.32~0.82；100%）以及安慰剂/最佳支持治疗（0.40，95%CrI 0.25~0.64；100%）。
**核心结论**：在间接比较的研究框架下，针对局部晚期或转移性不可切除HCC患者，总生存期分析显示阿替利珠单抗联合贝伐珠单抗的疗效优于其他治疗选项。