Cabozantinib plus atezolizumab for the treatment of advanced hepatocellular carcinoma: shedding light on the preclinical rationale and clinical trials

ABSTRACT

Introduction

Combining multikinase inhibitors (MKIs) with immune checkpoint inhibitors (ICIs) in advanced hepatocellular carcinoma (HCC) has a strong biological rationale. Among MKIs, cabozantinib seems an ideal partner for ICIs, playing a potentially synergistic role via a spectrum of immunomodulatory actions.

Area covered

This paper discusses the preclinical rationale for combining cabozantinib and atezolizumab in advanced HCC. It examines the mechanism of action of these agents and highlights their synergistic activities in vitro. Other MKI plus ICI combinations under investigation are evaluated. The results of the phase 1b COSMIC-021 study testing cabozantinib plus atezolizumab across numerous tumor types are presented along with the study design and the recent results of the phase 3 COSMIC-312 trial evaluating this combination as a front-line option for advanced HCC.

Expert opinion

The eventual approval of novel combinations for advanced HCC will require careful patient selection and a refinement of study design for future trials. Regarding the search for predictive biomarkers, etiology and extent of disease may predict response to therapy. Moving cabozantinib to first-line, treatment sequencing should consider possible cross-resistance not only to ICIs but also to other MKIs. Finally, the response rates of such combinations may pave the way for their evaluation as peri-operative therapies.

KEYWORDS:

• Angiogenesis
• atezolizumab
• cabozantinib
• HCC
• immune checkpoint inhibitors
• immunotherapy
• MKI
• systemic therapy
• TKI

Article highlights

• A strong preclinical rationale supports the combination of multikinase inhibitors with antiangiogenic action and immune checkpoint inhibitors in advanced hepatocellular carcinoma (HCC)

• Among multikinase inhibitors, cabozantinib represents a key partner for immune checkpoint inhibitors, targeting different pathways involved in tumor-associated immune suppression

• The combination of cabozantinib plus atezolizumab was shown effective and with a manageable safety profile in the phase 1b COSMIC-021 study across a number of solid tumors

• Cabozantinib plus atezolizumab is being tested against sorafenib in the global, randomized phase 3 COSMIC-312 trial in a large cohort of treatment-naïve patients with advanced HCC

• The combination outperformed sorafenib in terms of progression-free survival but not yet in terms of overall survival (OS), meeting one of the dual primary endpoints; the OS data are not yet mature

• The eventual approval of new front-line combination options for advanced HCC, including cabozantinib plus atezolizumab, will highlight the need for reliable biomarkers of response to guide patient selection and treatment sequencing as well as the need for a refinement of clinical trial design.

Acknowledgments

Ipsen and Exelixis provided courtesy review of the manuscript for scientific accuracy and fair balance. The authors were free to accept or decline the feedback.

Declaration of interest

A D’Alessio is supported by grant funding from the European Association for the Study of the Liver (Andrew Burroughs Fellowship). T Pressiani has received consulting fees from Bayer, Ipsen, IQVIA; and institutional research funding from Bayer, Lilly, Roche.

N Personeni has received consulting fees from Amgen, Merck Serono, Servier; lectures fees from AbbVie, Gilead, Lilly, Sanofi; travel expenses from Amgen, ArQule; and institutional research funding from Basilea, Merck Serono, Servier.

L Rimassa has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

One reviewer is an advisor for Eisai Co. Ltd. and one reviewer has received honoraria from Ipsen, Roche, AstraZeneca, Bayer, MSD, BMS, and Beigene. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.