Supplementary Material for: Depth and Duration of Response Are Associated With Survival in Patients With Unresectable Hepatocellular Carcinoma: Exploratory Analyses of IMbrave150

Introduction IMbrave150 established first-line atezolizumab plus bevacizumab as a global standard of care for unresectable hepatocellular carcinoma (HCC). We report exploratory analyses of associations between overall survival (OS) and depth of response (DpR) or duration of response (DoR).
Methods IMbrave150 was a phase III randomized study of atezolizumab plus bevacizumab vs sorafenib in patients with unresectable HCC. DpR was defined as maximum tumor shrinkage from baseline based on the sum of longest diameters per independent review facility (IRF)–assessed RECIST 1.1. DoR was defined as time from first complete/partial response by IRF-assessed RECIST 1.1 until progression or death. Associations between OS and DpR or DoR were evaluated by scatterplot in both arms; OS and PFS were evaluated by DpR in atezolizumab plus bevacizumab-treated patients. To minimize immortal time bias, the DpR analysis included patients who survived ≥6 months.
Results Of 312 and 140 patients with baseline measurable disease in the atezolizumab plus bevacizumab and sorafenib arms, respectively, 264 and 99 surviving ≥6 months were included in the DpR analysis, and 97 and 18 in the DoR analysis. Tumor shrinkage occurred in 230/312 (74%) patients in the atezolizumab plus bevacizumab arm and 76/140 (54%) in the sorafenib arm; their mean (SD) DpR was −42.5% (32.4%) and −25.0% (21.9%), respectively. Atezolizumab plus bevacizumab-treated ≥6-month survivors with DpR <0% had improved OS vs those with DpR ≥0% (HR, 0.29; 95% CI, 0.19-0.44). Those with deeper responses (DpR −100% to −60%) had longer OS than those with DpR ≥20% (unstratified HR 0.08; 95% CI, 0.03-0.21). In scatterplots, DpR and DoR were generally associated with OS in both arms; interpretation was limited by censored patients.
Conclusions Depth and duration of response to atezolizumab plus bevacizumab and sorafenib were associated with OS in patients with unresectable HCC. More longer, deeper responses occurred with atezolizumab plus bevacizumab.

引言
IMbrave150研究确立了阿替利珠单抗联合贝伐珠单抗作为不可切除肝细胞癌（hepatocellular carcinoma, HCC）的全球一线治疗标准。本研究报告了总生存期（overall survival, OS）与应答深度（depth of response, DpR）或应答持续时间（duration of response, DoR）之间关联的探索性分析结果。

方法
IMbrave150是一项Ⅲ期随机研究，对比了阿替利珠单抗联合贝伐珠单抗与索拉非尼治疗不可切除肝细胞癌患者的疗效。应答深度（DpR）定义为经独立评审机构（independent review facility, IRF）依据实体瘤疗效评价标准1.1版（RECIST 1.1）评估的最长径之和计算的、自基线起的最大肿瘤缩小率。应答持续时间（DoR）定义为经IRF依据RECIST 1.1标准评估首次达到完全缓解/部分缓解至疾病进展或死亡的时间。对两组患者的总生存期与应答深度、应答持续时间的关联采用散点图进行分析；在接受阿替利珠单抗联合贝伐珠单抗治疗的患者中，进一步基于应答深度分析了总生存期与无进展生存期（progression-free survival, PFS）。为最大限度降低不朽时间偏倚（immortal time bias）的影响，应答深度分析纳入了生存期≥6个月的患者。

结果
在阿替利珠单抗联合贝伐珠单抗组与索拉非尼组中，基线存在可测量病灶的患者分别为312例和140例，其中纳入应答深度分析的分别为264例和99例（均为生存期≥6个月的患者），纳入应答持续时间分析的分别为97例和18例。阿替利珠单抗联合贝伐珠单抗组中，230/312例（74%）患者出现肿瘤缩小，索拉非尼组为76/140例（54%）；两组的平均（标准差）应答深度分别为-42.5%（32.4%）与-25.0%（21.9%）。在接受阿替利珠单抗联合贝伐珠单抗治疗且生存期≥6个月的患者中，应答深度<0%的患者较应答深度≥0%的患者总生存期更优（风险比[HR] 0.29；95%置信区间[CI] 0.19~0.44）。应答更深的患者（DpR为-100%~-60%）较应答深度≥20%的患者总生存期更长（未分层HR 0.08；95%CI 0.03~0.21）。散点图分析显示，两组中应答深度与应答持续时间均与总生存期存在一定关联，但受删失患者的限制，结果解读存在局限性。

结论
本研究结果表明，不可切除肝细胞癌患者接受阿替利珠单抗联合贝伐珠单抗或索拉非尼治疗后，应答深度与应答持续时间均与总生存期相关。阿替利珠单抗联合贝伐珠单抗治疗可诱导更多、更深且持续时间更长的肿瘤应答。