The Role of Cabozantinib as a Therapeutic Option for Hepatocellular Carcinoma: Current Landscape and Future Challenges.

The systemic treatment of advanced hepatocellular carcinoma (HCC) has significantly changed over the last years, with the introduction of two new standard-of-care first-line treatments (lenvatinib and the combination of atezolizumab and bevacizumab) and the success of several new agents in second line. In particular, after the approval of regorafenib, ramucirumab and cabozantinib, the landscape of second-line treatment has become notably complex, providing a serious challenge in clinical practice. In this review, we focus on cabozantinib, a multikinase inhibitor which was proven effective in improving overall and progression-free survival of patients previously treated with sorafenib in the randomized Phase III CELESTIAL trial. CELESTIAL is the only phase III study to have included patients in the third-line setting and cabozantinib efficacy was confirmed in several post hoc analyses, irrespective of alpha-fetoprotein levels, albumin-bilirubin score, age, and duration of previous sorafenib treatment. The safety profile of cabozantinib in the CELESTIAL trial was comparable with other multikinase inhibitors used for HCC and the most frequent grade ≥3 adverse events were diarrhea, palmar-plantar erythrodysesthesia, fatigue, hypertension, and aspartate aminotransferase increase. Tolerability did not differ between younger and older patients and quality of life was significantly improved compared to placebo during the treatment. In this review, we also make a particular mention to the use of cabozantinib in populations which are normally excluded from clinical trials, such as older patients and Child-Pugh B patients. Finally, we present the new treatment strategies in which cabozantinib is being tested, most notably the combination of cabozantinib and atezolizumab in the first-line setting in the phase III COSMIC-312 trial and the use of cabozantinib after progression on immune-checkpoint inhibitors.

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© 2021 D’Alessio et al.

Déclaration de conflit d'intérêts

NP 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. LR 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, 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 apart from those disclosed.