Supplementary Material for: Primary analysis of a phase II study of atezolizumab plus bevacizumab for TACE-unsuitable patients with tumor burden beyond up-to-seven criteria in intermediate-stage hepatocellular carcinoma: REPLACEMENT study

Introduction: Intermediate-stage hepatocellular carcinoma (HCC) presents varying tumor burdens. For patients unsuitable for transcatheter arterial chemoembolization (TACE) due to high tumor burden, recent guidelines recommend systemic therapy. This study evaluates the efficacy and safety of atezolizumab plus bevacizumab for TACE-unsuitable patients with unresectable intermediate-stage HCC beyond up-to-seven criteria.
Methods: This prospective, phase II, single-arm, non-blinded study enrolled TACE-naïve patients with unresectable intermediate-stage HCC beyond up-to-seven criteria, Child-Pugh A, no previous systemic therapy, and ECOG Performance Status score of 0-1 from 35 sites in Japan. Patients received atezolizumab 1200 mg and bevacizumab 15 mg/kg every 3 weeks. The primary endpoint was the 6-month progression-free survival (PFS) rate by modified RECIST (mRECIST). Key secondary endpoints included the objective response rate (ORR) and safety. Exploratory endpoints examined individual changes in tumor size, comparison by inverse probability weighting (IPW) of data with retrospective historical data of TACE-treated patients, and conversion rate to a curative intent therapy.
Results: In total, 74 patients were enrolled from December 2020 to September 2021 (median follow-up, 15.1 months). The 6-month PFS rate by mRECIST was 66.8% (90%CI: 56.8, 75.0), and the lower limit of the 90%CI exceeded the pre-specified threshold of 55%. ORR by mRECIST was 40.5%. After treatment with atezolizumab plus bevacizumab, 10 patients, including 5 patients who had a tumor burden beyond the up-to-11 criteria at baseline, were able to transition to curative intent therapy. PFS by mRECIST by IPW was 9.2 months with atezolizumab plus bevacizumab versus 5.7 months with TACE (hazard ratio 0.67, p = 0.029). Adverse events (AEs), mostly hypertension, proteinuria, and malaise, were common. AEs requiring corticosteroids occurred in 10 patients (13.5%).
Conclusion: Atezolizumab plus bevacizumab appears beneficial as first-line treatment for TACE-unsuitable patients with unresectable intermediate-stage unresectable HCC beyond up-to-seven criteria. Future strategies utilizing multimodal approaches may further improve outcomes.

Introduction: 中期肝细胞癌（hepatocellular carcinoma, HCC）患者的肿瘤负荷具有异质性。对于因肿瘤负荷过高而无法接受经导管动脉化疗栓塞术（transcatheter arterial chemoembolization, TACE）的患者，现行临床指南推荐采用全身系统治疗方案。本研究针对符合up-to-seven标准（up-to-seven criteria）的不可切除中期肝细胞癌且不适合TACE治疗的患者，评估阿替利珠单抗（atezolizumab）联合贝伐珠单抗（bevacizumab）的疗效与安全性。
Methods: 本研究为一项前瞻性、Ⅱ期单臂非盲临床试验，从日本35家研究中心纳入未接受过TACE治疗的符合up-to-seven标准的不可切除中期肝细胞癌患者，且患者需满足Child-Pugh分级A级、未接受过全身治疗、东部肿瘤协作组（Eastern Cooperative Oncology Group, ECOG）体能状态评分为0~1分。所有患者接受每3周一次的阿替利珠单抗1200mg联合贝伐珠单抗15mg/kg治疗。本研究的主要终点为基于改良实体瘤疗效评价标准（modified RECIST, mRECIST）评估的6个月无进展生存期（progression-free survival, PFS）率；关键次要终点包括客观缓解率（objective response rate, ORR）与安全性；探索性终点涵盖肿瘤大小的个体变化、采用逆概率加权法（inverse probability weighting, IPW）对比本研究数据与既往TACE治疗患者的回顾性队列数据，以及根治性意向治疗转化率。
Results: 本研究于2020年12月至2021年9月期间共纳入74例患者，中位随访时间为15.1个月。基于mRECIST评估的6个月PFS率为66.8%（90%置信区间：56.8~75.0），且90%置信区间的下限超出预设的55%阈值；基于mRECIST评估的ORR为40.5%。接受阿替利珠单抗联合贝伐珠单抗治疗后，共10例患者成功转换为根治性意向治疗，其中5例患者基线时肿瘤负荷超出up-to-11标准（up-to-11 criteria）。经逆概率加权法校正后，基于mRECIST评估的PFS显示：阿替利珠单抗联合贝伐珠单抗组为9.2个月，TACE治疗组为5.7个月（风险比hazard ratio, HR=0.67，P=0.029）。不良事件（adverse events, AEs）较为常见，主要包括高血压、蛋白尿与乏力；其中10例患者（13.5%）出现需使用糖皮质激素治疗的不良事件。
Conclusion: 阿替利珠单抗联合贝伐珠单抗作为一线治疗方案，对于符合up-to-seven标准且不适合TACE治疗的不可切除中期肝细胞癌患者具有临床获益潜力。未来采用多模式联合的治疗策略有望进一步改善此类患者的预后。