Evolution of Clinical Trials of Systemic Therapies for Hepatocellular Carcinoma Between 2005 and 2024: Based on ClinicalTrials.gov

This study aimed to evaluate the fundamental characteristics of clinical trials and changes over time in clinical trials of systemic therapies for hepatocellular carcinoma (HCC). Interventional clinical trials of systemic therapies registered at ClinicalTrials.gov from January 2005 to December 2024 were downloaded. Data on recruitment status, clinical phase, therapy type, trial design, outcome indicators, and other relevant factors were evaluated. A total of 1233 trials were included, of which 363(29.4%) were registered from 2005 to 2014 and 870 (70.6%) were registered from 2015 to 2024, reflecting the growing body of research on HCC. Regarding the intervention model type, single-group designs were employed in 679 (55.1%) trials, and parallel designs were employed in 489 (39.7%). A total of 209 trials were Phase 1 (17.0%), 152 (12.3%) were phase 1|phase 2, 560 were phase 2 (45.4%), 41 (3.4%) were phase 2|phase 3, 162 (13.1%) were phase 3, and 32 (2.6%) were phase 4. Small-molecule targeted agents, immune monotherapies, and targeted agent and immunotherapy combinations were the primary interventions, being used in 364 (29.5%), 434 (35.2%), and 287 (23.3) studies, respectively. Immune checkpoint inhibitors, particularly programmed death receptor 1 or programmed death ligand 1 antibodies, were the most studied immunotherapies. The development of systemic therapies for HCC have made significant progress in the past 2 decades, especially in the areas of immunotherapy and targeted therapy. The results of this study provide an important reference for the development of new HCC therapies and optimization of clinical trial design and treatment strategies.