Cabozantinib for the treatment of hepatocellular carcinoma

ABSTRACT

Introduction: The randomized, placebo-controlled, phase III CELESTIAL trial demonstrated statistically and clinically significant improvement in overall survival with cabozantinib in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. Most frequently reported adverse events included palmar-plantar erythrodysesthesia, hypertension, increased aspartate aminotransferase, fatigue, and diarrhea.

Areas covered: In this review we analyze and discuss preclinical and clinical data of cabozantinib. We summarize efficacy and safety results of phase II and III trials of cabozantinib in the treatment of patients with advanced HCC and we present ongoing trials of cabozantinib in combination with checkpoint inhibitors.

Expert opinion: Cabozantinib is a new second-line and the only third-line treatment for patients with advanced HCC, nevertheless some data are still missing to better inform clinical decisions on how to treat specific patient populations. Next trials designs will have to incorporate heavy efforts in terms of translational research to maximize the benefits of such treatments.

KEYWORDS:

• Hepatocellular carcinoma
• cabozantinib
• angiogenesis
• MET
• AXL

Article highlights

• Cabozantinib is an oral inhibitor of multiple receptor tyrosine kinases including MET, VEGFR 1, 2 and 3, AXL, and RET

• Cabozantinib has statistically significantly improved overall survival in patients with advanced HCC previously treated with sorafenib

• In the phase III CELESTIAL trial median OS was 10.2 months on cabozantinib vs 8.0 months on placebo, with a HR of 0.76 and a p value of 0.005; cabozantinib was superior to placebo in all the efficacy endpoints and in all subgroups of patients

• In the same phase III CELESTIAL trial cabozantinib showed an acceptable safety profile, confirmed in all subgroups of patients, and a benefit in quality of life; most commonly observed grade 3–4 AEs were PPE, hypertension, increased AST, fatigue, and diarrhea

• Cabozantinib (Cabometyx®) is approved by the EMA and the FDA for the treatment of patients with HCC previously treated with sorafenib at the dose of 60 mg orally daily (tablet formulation)

• Cabozantinib is a new option as second-line treatment and the only one as third-line treatment for patients with advanced HCC

• The phase III COSMIC-312 trial is testing the combination of cabozantinib and atezolizumab as first-line therapy in patients with advanced HCC

Declaration of interest

Nicola Personeni has received lecture fees from AbbVie and Gilead, and travel fees from ArQule. Lorenza Rimassa has received consulting fees from Lilly, Bayer, Sirtex Medical, ArQule, Exelixis, Ipsen, Celgene, Eisai, Hengrui Therapeutics, MSD, Baxter, Amgen, Italfarmaco, Sanofi, and Incyte; lecture fees from AstraZeneca, AbbVie, Gilead, and Roche; travel fees from ArQule and Ipsen. Armando Santoro has received consulting fees from BMS, Servier, Gilead, Pfizer, Eisai, Bayer, MSD, Arqule; lecture fees for Takeda, BMS, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, Astra-Zeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, MSD. 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.