Trial Designs for Integrating Novel Therapeutics into the Management of Intermediate-Stage Hepatocellular Carcinoma

Abstract

Yung-Yeh Su,1– 3,* Yi-Sheng Liu,4,* Chin-Fu Hsiao,5 Chiun Hsu,6– 8 Li-Tzong Chen1,2,9,10 1National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; 2Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Department of Medical Imaging, National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University, Tainan, Taiwan; 5Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan; 6Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; 7Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan; 8National Taiwan University Cancer Center, Taipei, Taiwan; 9Department of Internal Medicine, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 10Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan*These authors contributed equally to this workCorrespondence: Li-Tzong Chen, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100 Tzyou 1 st Road, Kaohsiung, 80756, Taiwan, Tel [phone] ext 7451, Fax [phone], Email [email protected] Chiun Hsu, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan, Tel [phone] ext. 62859, Fax [phone], Email [email protected]: Intermediate-stage hepatocellular carcinoma (HCC) consists of heterogeneous groups of patients in terms of tumor burden and organ function reserves. Although liver-directed therapy (LDT), including trans-catheter arterial chemoembolization, radiofrequency ablation or even surgical resection, is the recommended frontline treatment modality, intrahepatic and distant failures are common. The recent advances in systemic treatment, notably the introduction of immune checkpoint inhibitor (ICI)-based therapy, have significantly improved the objective tumor response rate, quality of response and overall survival in patients with recurrent and advanced HCC. Whether the combination of systemic treatment and LDT can further improve the outcome of patients with intermediate-stage HCC is currently being extensively evaluated. In this article, the recent clinical trials incorporating different ICI-based combinations with different LDT for intermediate-stage HCC were reviewed focusing on trial design issues, including patient selection, endpoint definition, and biomarker development. The strength and caveats of different combination strategies and novel biomarker development were discussed.Keywords: immunotherapy, liver-directed therapy, biomarker

Keywords

• immunotherapy
• liver-directed therapy
• biomarker