Yijie Zhang,1,2,* Jin Lei,3,* Huaxing Ma,3 Shi Zuo2 

1Department of General Surgery, Medical College of Soochow University, Suzhou, People’s Republic of China; 2Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 3School of Basic Medical Sciences, Guizhou Medical University, Guiyang, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Shi Zuo, Email drzuoshi@gmc.edu.cn

Background: Lenvatinib is the first-line treatment option for patients with advanced hepatocellular carcinoma (HCC); however, the impact of lenvatinib resistance on patient prognosis is unknown.
Methods: We recruited all patients with advanced HCC who received first-line lenvatinib treatment between February 2019 and February 2023 at two medical centers in China, according to the selection criteria. The patients were divided into primary and secondary resistance groups based on tumor progression within 3 months. The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS). Logistic regression and Cox proportional hazards models were used to explore factors influencing drug resistance and prognosis. The study end points were drug resistance, PFS, and OS.
Results: A total of 531 patients met the study criteria, with 169 (31.8%) and 362 (68.2%) patients in the primary and secondary groups, respectively. An alpha-fetoprotein (AFP) concentration > 400 ng/mL was an independent risk factor for primary drug resistance. Patients in the primary group had a significantly shorter median OS (11.0 vs 31.0 months, P< 0.001) than those in the secondary group. The 1-, 2- and 3-year cumulative survival rates in the primary group were 46.3%, 22.2%, and 10.1%, while those in the secondary group were 82.3%, 59.1% and 44.9%, respectively. Compared to tyrosine kinase inhibitor (TKI) monotherapy, longer median PFS (4.0 vs 7.0 months, P=0.008) and OS (11.0 vs 23.0 months, P=0.024) were achieved with the combination of a TKI plus a PD-1 inhibitor as a second-line therapy after lenvatinib resistance.
Conclusion: There is a high rate of primary resistance to lenvatinib in patients with HCC and the prognosis for those with primary resistance is poor. TKI combined with PD-1 inhibitors should be preferentially recommended for lenvatinib-resistant patients.

Keywords: hepatocellular carcinoma, resistance, lenvatinib, programmed cell death protein-1 inhibitor, tyrosine kinase inhibitor, second-line