Supplementary Material for: Objective response by mRECIST to initial lenvatinib therapy is an independent factor contributing to deep response in hepatocellular carcinoma treated with lenvatinib-transcatheter arterial chemoembolization sequential therapy

Objective: There is limited information regarding the benefits of Lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for unresectable hepatocellular carcinoma (u-HCC). We compared the efficacy and safety of LEN-TACE sequential therapy to LEN monotherapy and investigated the factors contributing to the LEN-TACE sequential therapy deep response. Methods: We enrolled a multi-center cohort of 247 patients with u-HCC treated with LEN between 2018 and 2020. Propensity score matching identified sixty-three matching pairs of patients with well-balanced characteristics. We retrospectively compared the clinical outcomes, including overall survival (OS), progression-free survival (PFS), and incidence of adverse events (AEs), between the LEN-TACE and LEN monotherapy groups. Additionally, we evaluated the tumor response, change in albumin-bilirubin (ALBI) score, factors affecting PFS and OS, and independent predictors contributing to the LEN-TACE sequential therapy deep response. In this study, at eight weeks after resumption of LEN after initial TACE, "deep response" was defined as achieving CR or PR on mRECIST, and at least a 30% decrease in the sum of diameters of target lesions, taking the baseline sum diameters as the reference. Results: The OS and PFS in the LEN-TACE group were significantly higher than those in the LEN monotherapy group (P = 0.002 and P = 0.037, respectively). The incidence of AEs related to LEN was not significantly different between the two groups. In LEN-TACE sequential therapy, the objective response rate was 61.9%, and the disease control rate was 74.6%, according to the mRECIST criteria. No significant change in the ALBI score was observed during sequential LEN-TACE therapy. Multivariable analyses revealed that deep response was independently associated with the outcome of the initial response to LEN by mRECIST: PR (odds ratio: 13.75, 95% CI: 0.41–1.32, P <0.001). Conclusions: LEN-TACE sequential therapy may provide more clinical benefits than LEN monotherapy in u-HCC patients who responded to initial LEN treatment. Objective response according to mRECIST to initial LEN is an independent factor contributing to LEN-TACE sequential therapy deep response.

研究目的：目前关于仑伐替尼（Lenvatinib）联合经导管动脉化疗栓塞术（transcatheter arterial chemoembolization, LEN-TACE）序贯疗法治疗不可切除肝细胞癌（unresectable hepatocellular carcinoma, u-HCC）的获益相关研究信息较为有限。本研究对比了LEN-TACE序贯疗法与仑伐替尼单药疗法的疗效与安全性，并探究了影响LEN-TACE序贯疗法达到深度应答的相关因素。
研究方法：本研究纳入2018年至2020年期间接受仑伐替尼治疗的247例不可切除肝细胞癌患者组成的多中心队列。通过倾向得分匹配（propensity score matching）筛选出63对特征均衡匹配的患者。本研究回顾性对比了LEN-TACE组与仑伐替尼单药组的临床结局，包括总生存期（overall survival, OS）、无进展生存期（progression-free survival, PFS）以及不良事件（adverse events, AEs）发生率。此外，本研究还评估了肿瘤应答情况、白蛋白-胆红素（albumin-bilirubin, ALBI）评分变化、影响PFS与OS的因素，以及与LEN-TACE序贯疗法深度应答相关的独立预测因子。本研究中将初始经导管动脉化疗栓塞术后恢复仑伐替尼治疗8周时的深度应答定义为：基于改良实体瘤疗效评价标准（modified Response Evaluation Criteria in Solid Tumors, mRECIST）达到完全缓解（complete response, CR）或部分缓解（partial response, PR），且以基线靶病灶直径总和为参照，靶病灶直径总和较基线至少降低30%。
研究结果：LEN-TACE组的总生存期与无进展生存期均显著高于仑伐替尼单药组（分别为P=0.002与P=0.037）。两组与仑伐替尼相关的不良事件发生率无显著差异。在LEN-TACE序贯疗法中，基于mRECIST标准的客观缓解率为61.9%，疾病控制率为74.6%。在LEN-TACE序贯治疗期间，患者的ALBI评分无显著变化。多变量分析显示，深度应答与初始仑伐替尼治疗的mRECIST应答结局独立相关：部分缓解（odds ratio: 13.75, 95% CI: 0.41–1.32, P <0.001）。
研究结论：对于初始仑伐替尼治疗产生应答的不可切除肝细胞癌患者，LEN-TACE序贯疗法相较于仑伐替尼单药疗法可带来更优的临床获益。初始仑伐替尼治疗的mRECIST客观应答是影响LEN-TACE序贯疗法达到深度应答的独立因素。