Hepatic Arterial Infusion Chemotherapy Combined Lenvatinib and PD-1 Inhibitor Showed Improved Survival for Infiltrative Hepatocellular Carcinoma: A Multicenter Cohort Study

Ruixia Li,1,* Xiaohui Wang,2,* Hui Li,3 Murong Wang,3 Juncheng Wang,4 Wei Wang,5 Qunfang Zhou6 1Department of Thyroid Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China; 2Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Changsha, Hunan Province, People’s Republic of China; 3Department of Minimally Invasive Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People’s Republic of China; 4Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People’s Republic of China; 5Department of General surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, People’s Republic of China; 6Department of Interventional Radiology, 5th Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Wang, Department of General surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, People’s Republic of China, Tel +86-0416-84197693, Email [email protected] Qunfang Zhou, Department of Interventional Radiology, 5th Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China, Tel +86-010-66939123, Email [email protected]: Lenvatinib and programmed cell death protein-1 (PD-1) inhibitor on infiltrative hepatocellular carcinoma (HCC) have obtained demonstrated efficacy and still need improvement. Hepatic arterial infusion chemotherapy (HAIC) has shown promising results for advanced HCC. This study aimed to compare the efficacy of HAIC combined Lenvatinib and PD-1 inhibitor versus Lenvatinib combined PD-1 inhibitor for infiltrative HCC.Patients and Methods: A total of 232 patients were enrolled. There were 114 patients received Lenvatinib combined PD-1 inhibitor (Len+PD-1 group) and 118 patients received HAIC combined Lenvatinib and PD-1 inhibitor (HAIC+Len+PD-1 group). Overall survival (OS), progression-free survival (PFS) and safety of patients were compared between the two groups by propensity score–matching (PSM).Results: The 6-, 12-, and 24-month OS rates were 93.8%, 65.1% and 13.4% in Len+PD-1 group, and 100%, 77.3% and 32.1% in HAIC+Len+PD-1 group, respectively. The 3-, 6-, and 12-month PFS rates were 86.4%, 45.7% and 14.1% in Len+PD-1 group, and 95.1%, 59.3% and 25.9% in HAIC+Len+PD-1 group, respectively. The HAIC+Len+PD-1 group had obviously better survival than the Len+PD-1 group both in OS (P=0.002) and PFS (P=0.004). Subgroup analysis revealed that OS in patients with metastasis was improved with HAIC+Len+PD-1 treatment. Patients with alpha-fetoprotein (AFP) response after treatment showed better survival than the non-response. In addition, HAIC+Len+PD-1 group showed manageable adverse events (AEs).Conclusion: Patient with infiltrative HCC, HAIC+Len+PD-1 treatment had longer OS and PFS than Len+PD-1 treatment. Early AFP response was an effective indicator of better survival and tumor response to therapy.Plain language summary: Infiltrative hepatocellular carcinoma (HCC) is an odd group that is not well adjudicated in the current staging systems, and treatment options for patients with infiltrative HCC are challenging with scant and insufficient clinical evidence. In this multi-center study, we innovatively analyzed the outcome of hepatic arterial infusion chemotherapy (HAIC) combined lenvatinib and PD-1 inhibitor (HAIC+Len+PD-1) was associated longer progression-free survival and overall survival than Lenvatinib plus PD-1 inhibitor combination (Len+PD-1) for patient with infiltrative HCC. In addition, further intragroup analysis revealed that OS of patients with and without metastasis in Len+PD-1 group was significant difference. However, no difference was observed in OS for patients with and without metastasis in HAIC+Len+PD-1 group. Patients with alpha-fetoprotein (AFP) response after treatment showed better survival than the non-response. Our research provides evidence that HAIC combined Lenvatinib and PD-1 inhibitor results in clinically significant improvements in infiltrative HCC. It could be recommended as a first choice for infiltrative HCC therapy.Keywords: infiltrative hepatocellular carcinoma, hepatic arterial infusion chemotherapy, lenvatinib, PD-1 inhibitor, alpha-fetoprotein response