Simultaneous and Sequential Use of Molecular Targeted Agents Plus Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Real-World Practice in China

Jing Li,1,2,* Liang Huang,1,* Chao Ge,3,* Xingwu Zhu,1 Maixuan Qiu,1 Chaopan Chen,3 Shaohua Wei,2 Yiqun Yan1 1Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China; 2Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 3Department of General Surgery, Ningbo Development Zone Hospital, Ningbo, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yiqun Yan, Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, No. 700 North Moyu Road, Shanghai, 201805, People’s Republic of China, Email ehbhyyq@163.com Shaohua Wei, Department of General Surgery, The Second Affiliated Hospital of Soochow University, No. 1055 Shanxiang Road, Suzhou, 215004, People’s Republic of China, Email shaohuawei2010@sina.comPurpose: Molecular targeted agents (MTAs) plus immune checkpoint inhibitors (ICIs) treatment for advanced hepatocellular carcinoma (HCC) has shown an exciting prospect. This study aimed to report the efficacy of the Simultaneous and Sequential use of them in a real-world practice.Patients and Methods: From April 2019 to December 2020, patients with advanced HCC in three Chinese medical centers receiving MTAs and ICIs as their initial systemic therapy were enrolled. Participants were classified into the Simultaneous group (treated with them simultaneously) and the Sequential group (treated with MTAs initially and added ICIs after tumor progression). Toxicity, tumor response, survival outcomes and prognostic factors were investigated.Results: One hundred and ten consecutive patients participated in the study (64 in the Simultaneous group and 46 in the Sequential group). A total of 93 (84.5%) patients experienced treatment-related adverse events (AEs), of which 55 (85.9%) in the Simultaneous group and 38 (82.6%) in the Sequential group (P=0.19). Grade 3/4 AEs were observed in 9 (8.2%) patients. Patients in the Simultaneous group achieved a higher objective response rate than those in the Sequential group (25.0% vs 4.3%, p=0.04). The median overall survival (OS) of the entire cohort was 14.8 [95% confidence interval (CI): 4.6– 25.5] months and the OS rates at 6 and 12 months were 80.6% and 60.9%, respectively. Patients in the Simultaneous group achieved better survival outcomes than those in the Sequential group, but without statistically significant differences. Child-Pugh 6 scores (HR: 2.97, 95% CI: 1.33– 6.61, P=0.008), tumor number ≤ 3 (HR: 0.18, 95% CI: 0.04– 0.78, P=0.022), extrahepatic metastasis (HR: 3.05, 95% CI: 1.35– 6.87, P=0.007) were independent prognostic factors for survival.Conclusion: The combined treatment of MTAs and ICIs shows good tumor response and survival outcomes with acceptable toxicity for advanced HCC in the real-world practice, in particular when they are applied simultaneously.Keywords: hepatocellular carcinoma, systemic therapy, molecular targeted agents, immune checkpoint inhibitors