Cao Fei, Wen Chunyong, Wang Yujia, Tan Hongtong, Hao Shaohuan, Chen Jinbin, Chen Shuanggang, Shen Lujun, Xie Lin, Qi Han, Huang Tao, Zhang Yaojun, Huang Zilin
Department of Minimally Invasive and Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, China.
Front Immunol. 2025 Jun 12;16:1602031. doi: 10.3389/fimmu.2025.1602031. eCollection 2025.
BACKGROUND: PD-1/PD-L1 inhibitors have shown efficacy in improving the prognosis of patients with hepatocellular carcinoma (HCC) accompanied by portal vein tumor thrombosis (PVTT) in pivotal clinical trials including the landmark IMbrave150 study. However, not all the patients benefit from the PD-1/PD-L1 blockade immunotherapy. This study aimed to improve the identification of PVTT-associated HCC patients who may benefit from the combination of PD-1 inhibitor and hepatic arterial infusion chemotherapy (HAIC) and tyrosine kinase inhibitor (TKI) treatment under real-world conditions. METHODS: From 377 HCC-PVTT patients receiving HAIC-TKI ± PD-1 inhibitors (2016-2023), we compared 76 dual-therapy (HT) and 175 triple-therapy (HTP) cases. Median follow-up period was 34.8 months in the HT group and 33.4 months in the HTP group (=0.175). Propensity score matching (1:1 caliper=0.2) was used to balance baseline characteristics. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated in both groups. Specific subgroups including Vp4 type PVTT, extrahepatic metastases, and patients over 60 years old, were analyzed. RESULTS: Triple therapy significantly improved median OS (24.6 vs. 13.5 months; HR=0.58, 95%CI:0.42-0.80; =0.001) and PFS (11.1 vs. 6.4 months; HR=0.56, <0.001), with a 15% absolute ORR increase (66.3% vs. 51.3%, =0.034). In subgroup analysis, for patients with Vp4 type PVTT, the addition of PD-1 inhibitor prolonged overall survival by 6.0 months (=0.04). For patients aged 60 years and above, the addition of PD-1 inhibitor prolonged overall survival by 1.9 months (=0.363). For patients with extrahepatic metastasis, the addition of PD-1 inhibitor prolonged overall survival by 3.0 months (=0.913). Grade 3-4 adverse events were comparable (30.9% vs. 19.7%, =0.09), but two patients experienced immune treatment-related fatalities in the HTP group. CONCLUSION: The triple therapy (HAIC-TKI-PD-1) demonstrated superior efficacy over HAIC-TKI dual therapy in HCC patients with PVTT, achieving significant improvements in ORR, mOS, and mPFS, with an acceptable safety profile. However, PD-1 inhibitors showed minimal survival benefits in patients aged >60 or with extrahepatic metastases.
背景：在包括具有里程碑意义的IMbrave150研究在内的关键临床试验中，PD-1/PD-L1抑制剂已显示出改善伴有门静脉肿瘤血栓形成（PVTT）的肝细胞癌（HCC）患者预后的疗效。然而，并非所有患者都能从PD-1/PD-L1阻断免疫治疗中获益。本研究旨在改善在现实世界条件下对可能从PD-1抑制剂与肝动脉灌注化疗（HAIC）及酪氨酸激酶抑制剂（TKI）联合治疗中获益的PVTT相关HCC患者的识别。 方法：从377例接受HAIC-TKI±PD-1抑制剂治疗的HCC-PVTT患者（2016 - 2023年）中，我们比较了76例双药治疗（HT）和175例三药治疗（HTP）病例。HT组的中位随访期为34.8个月，HTP组为33.4个月（P = 0.175）。采用倾向评分匹配（卡尺=0.2的1:1匹配）来平衡基线特征。对两组的总生存期（OS）、无进展生存期（PFS）、客观缓解率（ORR）和安全性进行评估。对包括Vp4型PVTT、肝外转移和60岁以上患者的特定亚组进行了分析。 结果：三药联合治疗显著改善了中位OS（24.6个月对13.5个月；HR = 0.58，95%CI：0.42 - 0.80；P = 0.001）和PFS（11.1个月对6.4个月；HR = 0.56，P < 0.001），绝对ORR提高了15%（66.3%对51.3%，P = 0.034）。在亚组分析中，对于Vp4型PVTT患者，添加PD-1抑制剂使总生存期延长了6.0个月（P = 0.04）。对于60岁及以上患者，添加PD-1抑制剂使总生存期延长了1.9个月（P = 0.363）。对于有肝外转移的患者，添加PD-1抑制剂使总生存期延长了3.0个月（P = 0.913）。3 - 4级不良事件相当（30.9%对19.7%，P = 0.09），但HTP组有2例患者发生了免疫治疗相关死亡。 结论：三药联合治疗（HAIC-TKI-PD-1）在伴有PVTT的HCC患者中显示出优于HAIC-TKI双药治疗的疗效，在ORR、mOS和mPFS方面取得了显著改善，且安全性可接受。然而，PD-1抑制剂在60岁以上或有肝外转移的患者中显示出最小的生存获益。
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