Advanced intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis. Here, we report the efficacy and safety of combining toripalimab, lenvatinib, and gemcitabine plus oxaliplatin (GEMOX) as first-line therapy for advanced ICC. Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine (1 g/m²) on Days 1 and 8 and oxaliplatin (85 mg/m²) Q3W for six cycles along with intravenous toripalimab (240 mg) Q3W and oral lenvatinib (8 mg) once daily for one year. The expression of programmed death-ligand 1 (PD-L1) and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing (WES) analysis. The primary endpoint was the objective response rate (ORR). Secondary outcomes included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and duration of response (DoR). As of July 1, 2022, the median follow-up time was 23.5 months, and the ORR was 80%. Twenty-three patients achieved partial response, and one achieved complete response. Patients (21/30) with DNA damage response (DDR)-related gene mutations showed a higher ORR, while patients (14/30) with tumor area positivity ≥1 (PD-L1 staining) showed a trend of high ORR, but without significant difference. The median OS, PFS, and DoR were 22.5, 10.2, and 11.0 months, respectively. The DCR was 93.3%. Further, 56.7% of patients experienced manageable grade ≥3 adverse events (AEs), commonly neutropenia (40.0%) and leukocytopenia (23.3%). In conclusion, toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. A phase-III, multicenter, double-blinded, randomized study to validate our findings was approved by the National Medical Products Administration (NMPA, No. 2021LP01825).

Trial registration Clinical trials: NCT03951597.

晚期肝内胆管癌（ICC）的预后很差。在此，我们报告了特瑞普利单抗、乐伐替尼和吉西他滨加奥沙利铂 (GEMOX) 联合作为晚期 ICC 一线治疗的疗效和安全性。 30 名经病理证实的晚期 ICC 患者在第 1 天和第 8 天接受静脉注射吉西他滨 (1 g/m ² ) 和奥沙利铂 (85 mg/m ² ) Q3W 六个周期，同时静脉注射特瑞普利单抗 (240 mg) Q3W 和口服乐伐替尼 (8 mg) ）每天一次，持续一年。使用免疫组织化学和全外显子组测序 (WES) 分析研究石蜡包埋组织中程序性死亡配体 1 (PD-L1) 的表达和遗传状态。主要终点是客观缓解率（ORR）。次要结局包括安全性、总生存期（OS）、无进展生存期（PFS）、疾病控制率（DCR）和缓解持续时间（DoR）。截至2022年7月1日，中位随访时间为23.5个月，ORR为80%。 23 名患者获得部分缓解，1 名患者获得完全缓解。 DNA损伤反应（DDR）相关基因突变的患者（21/30）表现出较高的ORR，而肿瘤区域阳性≥1（PD-L1染色）的患者（14/30）表现出高ORR的趋势，但没有显着差异。中位 OS、PFS 和 DoR 分别为 22.5、10.2 和 11.0 个月。 DCR为93.3%。此外，56.7% 的患者经历了可控制的 3 级以上不良事件 (AE)，通常为中性粒细胞减少症 (40.0%) 和白细胞减少症 (23.3%)。总之，特瑞普利单抗联合乐伐替尼和 GEMOX 是治疗晚期 ICC 的有前景的一线方案。 一项验证我们研究结果的 III 期、多中心、双盲、随机研究已获得国家药品监督管理局批准（NMPA，编号：2021LP01825）。

试验注册 临床试验：NCT03951597。