Screening Candidates for Conversion Therapy in Unresectable Hepatocellular Carcinoma Patients After Tyrosine Kinase Inhibitor Plus PD-1/PD-L1 Antibody Therapy: A Multicenter Retrospective Study

Abstract

Zhe Jin,1,&ast; Xueyan Li,2,&ast; Ling Lv,3,&ast; Bin Zhang,1 Xiao Ma,1 Siqin Chen,1 Jingjing You,1 Xuewei Wu,1 Liaoyuan Wang,1 Xin Liu,1 Fei Wang,1 Xiaoming Chen,4 Lijuan Yu,2 Shuixing Zhang,1 Lu Zhang1 1Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Nuclear Medicine, Hainan Cancer Hospital, Haikou, Hainan, People’s Republic of China; 3Department of Radiology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China; 4Department of Minimally Invasive Intervention, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuixing Zhang, Department of Radiology, The First Affiliated Hospital of Jinan University, No. 613 Huangpu West Road, Tianhe District, Guangzhou, Guangdong, 510627, People’s Republic of China, Tel [phone], Email [email protected] Lu Zhang, Department of Radiology, The First Affiliated Hospital of Jinan University, No. 613 Huangpu West Road, Tianhe District, Guangzhou, Guangdong, 510627, People’s Republic of China, Tel +86 020 18009032439, Email [email protected]: Conversion therapies after immune checkpoint inhibitors (ICIs) plus tyrosine-kinase inhibitors (TKIs) provide curative surgery chance and prolong survival for unresectable hepatocellular carcinoma (uHCC). However, only some patients have the opportunity to receive conversion therapies. To this end, we aimed to develop and validate a machine-learning model to identify patients who may have the chance to undergo conversion therapy.Methods: This retrospective cohort study included 443 patients with uHCC who received ICIs and TKIs from four centers. Variables were analyzed using univariate and multivariate logistic regression to identify independent indicators of conversion therapy. The Gradient Boosting Machine (GBM) algorithm was used to develop and validate model, and the Shapley additive explanation algorithm was used to mechanically explain the prediction of the model.Results: Overall, 84 (19%) patients underwent conversion therapy, and their prognosis were significantly longer than those did not (P < 0.05). CA125 level, pre-TKI therapy, pre-antiviral therapy, lymph node metastasis status, and number of intrahepatic lesions were identified as indicators of conversion therapy. The GBM-based combined model outperformed the BCLC classification (P < 0.05), yielding an AUC of 0.76 and 0.74 in the training and external validation cohorts, respectively. Survival analyses indicated that patients who underwent surgery as conversion therapy had a better prognosis than those who underwent ablation therapy (P < 0.05).Conclusion: The GBM-based combined model could identify patients who may benefit from conversion therapy for uHCC treated with ICIs and TKIs. Surgical resection as curative conversion therapy may provide better survival benefits than ablation therapy.Plain Language Summary: Combining tyrosine kinase inhibitors (TKIs) with anti-programmed cell death protein 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) antibodies has significantly improved treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC). Consequently, some patients may become eligible for curative conversion. However, identifying patients suitable for curative conversion therapy remains a critical challenge. This study identifies validated clinical predictors and develops an interpretable machine learning model for the potential of conversion therapy following TKI and anti-PD-1/PD-L1 combination therapy. Additionally, it provides a comparative analysis of the survival benefits associated with different conversion therapy regimens. These findings may offer preliminary insights that could inform clinical consideration for uHCC patients.Keywords: hepatocellular carcinoma, immune checkpoint inhibitor, tyrosine kinase inhibitor, curative conversion therapy, machine learning

Keywords

• Hepatocellular carcinoma
• Immune checkpoint inhibitor
• Tyrosine kinase inhibitor
• Curative conversion therapy
• Machine learning