Supplementary Material for: Anti-HER2 therapies in biliary tract cancers: A meta-analysis on disease location, HER2 status, and survival outcomes

Introduction In recent years, the therapeutic scenario of metastatic biliary tract cancers (BTC) beyond first-line has profoundly changed owing to target therapies. HER2 represents a promising molecular target that is frequently altered in BTC. The present meta-analyses are aimed to describe the response rates and survival outcomes in patients with HER2-positive locally advanced/metastatic BTC treated with anti-HER2 therapies. Moreover, the study is intended to provide an update on the evolving therapeutic scenario of HER2 overexpressed BTC. Methods We performed a systematic review of the literature to identify clinical trials investigating any regimen comprising a HER2 targeted therapy for metastatic BTC, and we conducted three subsequent meta-analyses on second-line phase II trials. The first one was performed to compare the group of HER2 3+ versus the group of HER2 2+ BTC patients for objective response rate (ORR). The second one compared patients according to the tumor location (gallbladder carcinoma [GBC] or extrahepatic cholangiocarcinoma [eCCA] versus intrahepatic cholangiocarcinoma [iCCA]) for ORR. The third one evaluated the overall outcomes in terms of overall survival (OS) and progression-free survival (PFS). Results Patients with advanced BTC and HER2 3+ had better ORR compared to HER2 2+, with a 3.7-fold higher probability of experiencing objective responses (HR 3.70, 95% CI 1.34-10.25, p=0.0119). Likewise, patients with GBC or eCCA had a 2.74-fold higher probability of experiencing an objective response compared to patients with iCCA (HR 2.74, 95% CI 1.12-6.73, p=0.0275). The weighted pooled analysis of trials with anti-HER2 agents in second-line or beyond revealed a mPFS of 4.9 months (95% CI 4.2-5.6), while mOS was 10.8 months (95% CI 9.0-12.8). Conclusions Our meta-analyses have revealed improved efficacy in patients with HER2 3+ metastatic BTC and in patients with GBC or eCCA treated with anti-HER2 therapies, with a considerable mPFS and mOS in the overall population of the phase II trials analyzed. Further studies are paramount to confirm our preliminary results.

引言 近年来，一线治疗失败后的转移性胆道癌（biliary tract cancers, BTC）的治疗格局因靶向治疗的发展发生了深刻变革。人表皮生长因子受体2（HER2）是BTC中常见异常改变的极具治疗前景的分子靶点。本项荟萃分析旨在描述接受抗HER2治疗的HER2阳性局部晚期/转移性BTC患者的缓解率与生存结局。此外，本研究还旨在更新HER2过表达BTC不断发展的治疗格局。方法 本研究对相关文献开展系统综述，以筛选评估包含HER2靶向治疗方案治疗转移性BTC的临床试验，并针对二线Ⅱ期临床试验开展三项后续荟萃分析。第一项分析旨在比较HER2 3+与HER2 2+ BTC患者的客观缓解率（objective response rate, ORR）。第二项分析根据肿瘤部位（胆囊癌（gallbladder carcinoma, GBC）或肝外胆管癌（extrahepatic cholangiocarcinoma, eCCA）vs 肝内胆管癌（intrahepatic cholangiocarcinoma, iCCA））对患者分组，比较其客观缓解率。第三项分析则评估了总生存期（overall survival, OS）与无进展生存期（progression-free survival, PFS）相关的整体结局。结果 相较于HER2 2+ BTC患者，HER2 3+晚期BTC患者的客观缓解率更优，获得客观缓解的概率是前者的3.7倍（风险比（hazard ratio, HR）3.70，95%置信区间（CI）1.34~10.25，P=0.0119）。同样，相较于肝内胆管癌患者，胆囊癌或肝外胆管癌患者获得客观缓解的概率高出2.74倍（HR 2.74，95%CI 1.12~6.73，P=0.0275）。对二线及以上线数抗HER2治疗临床试验的加权合并分析显示，中位无进展生存期（mPFS）为4.9个月（95%CI 4.2~5.6），中位总生存期（mOS）为10.8个月（95%CI 9.0~12.8）。结论 本项荟萃分析结果显示，接受抗HER2治疗的HER2 3+转移性BTC患者，以及胆囊癌或肝外胆管癌患者的疗效更优；在所分析的Ⅱ期临床试验整体人群中，中位无进展生存期与中位总生存期表现可观。未来仍需开展进一步研究以验证本研究的初步结果。