Combining VEGF and PD-1/PD-L1 inhibition in advanced hepatocellular carcinoma: clinical trials, real-world evidence, and future directions

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with most of patients diagnosed at advanced stage. Thus, systemic therapy remains a cornerstone of treatment. In recent years, immunotherapy has changed therapeutic scenario, being investigated also in combination with anti-vascular endothelial growth factor (VEGF) agents. This approach has demonstrated safety and efficacy in several trials, paving the way for their investigation in earlier disease stages and in different settings. A structured literature review was conducted using PubMed and ClinicalTrials.gov to identify published evidence supporting safety and efficacy of anti-programmed death-1/programmed death-ligand-1(PD-1/PD-L1) and anti-VEGF agents in different therapeutic settings and identifying ongoing clinical trials and key research directions. Combination of anti-PD-1/PD-L1 and anti-VEGF agents has demonstrated safety and efficacy as a first-line treatment for advanced HCC, supported by results from phase 3 trials. These results suggest that further investigation is warranted to optimize first-line efficacy, second-line choice, and potential application in earlier disease stages. The clinical benefit of anti-PD-1/PD-L1 and anti-VEGF agents have also opened the door to a new clinical paradigm, where transitioning from systemic therapy to locoregional therapies, resection or even liver transplantation could be a feasible treatment strategy.