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

First-Line Treatment for Advanced Hepatocellular Carcinoma: A Three-Armed Real-World Comparison

“…Given the inherent limitations of a retrospective study in comparison to other study designs, more evidence-based therapy decisions for the individual and the potential of further immunotherapies, such as tremelimumab and durvalumab, are required for the evolving landscape of HCC treatment. 31 …”

The prognostic role of tumour progression and liver function at progression under immunotherapy for hepatocellular carcinoma

“…1 Despite the application of surveillance programs, 2,3 many patients have disease that is not amenable to curative treatments at presentation, and for this reason, they undergo treatments such as transarterial chemoembolization (TACE), radioembolization (also known as selective internal radiation therapy, or SIRT) and systemic treatment. At advanced stage, the advent of immune checkpoint inhibitors (ICIs) has drastically changed the landscape of HCC treatment, 4,5 and ICIs are currently tested in earlier lines of therapy.…”

“…Recently, the durvalumab–tremelimumab and camrelizumab–rivoceranib combinations also demonstrated improved OS and ORR as compared to sorafenib and are likely to be added in the options of first‐line therapy 7,8 . The choice of first‐line ICI‐based combination will become a new question for the clinician in the near future 4 . However, there are no data from phase III trials to support second‐ or third‐line drug sequences after this combination, and the best sequential first‐ and second‐line systemic treatment remains elusive.…”

“…7,8 The choice of first-line ICI-based combination will become a new question for the clinician in the near future. 4 However, there are no data from phase III trials to support second-or third-line drug sequences after this combination, and the best sequential firstand second-line systemic treatment remains elusive. Indeed, the advent of ICI combinations in HCC leads to major changes in practices, and novel treatment strategies might emerge in the future.…”

“…Indeed, the advent of ICI combinations in HCC leads to major changes in practices, and novel treatment strategies might emerge in the future. 4 Recently, a Markovian simulation study 9 that compared the efficacy and safety of five targeted agents (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) after atezolizumab plus bevacizumab therapy suggested that lenvatinib is the most effective treatment, whereas sorafenib has the best safety profile, but robust data from randomized controlled trials and from prospective clinical practice studies are still lacking. Furthermore, the continuation of ICI beyond progression has been proposed as a potential strategy in HCC and was included in the design of the phase III trials.…”