New Challenges Facing Systemic Therapies of Advanced HCC in the Era of Different First-Line Immunotherapy-Based Combinations

SIMPLE SUMMARY: In this review, we detail the data on a new treatment of hepatocellular carcinoma. A new combination of therapies, based on immunotherapy, has recently emerged as efficacious treatment. While being very interesting for patients, this raises new questions: how should we select the most appropriate treatment for each patient? What treatment can we offer after failure of these new treatments? How can we develop new combinations? ABSTRACT: The standard of care of first-line systemic therapy for advanced hepatocellular carcinoma (HCC) is currently changing with the results of the IMbrave150 trial which are demonstrating superiority of the atezolizumab-bevacizumab combination over sorafenib, modifying this line of treatment for the first time in over 10 years. Recently, other immunotherapy-based combinations (durvalumab-tremelimumab, lenvatinib-pembrolizumab, cabozantinib-atezolizumab, and camrelizumab-rivoceranib) reported results in phase III studies, and might challenge this new standard of care. This revolution will lead to a considerable change in practice, and highlight challenges for future drug development. In this review, we will, firstly, describe results of the different combinations, and discuss the difficulties in selecting the first-line treatment. We will then present the different recommendations about second-line treatment following the first-line immunotherapy-based combination, discussing the rationale for the differences in existing recommendations. We will finally discuss the challenges for future drug development in advanced HCC.