Cabozantinib in Second-Line Treatment of Advanced Hepatocellular Carcinoma

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Ghassan Abou-Alfa, MD

Ghassan Abou-Alfa, MD

E. Gabriela Chiorean, MD

E. Gabriela Chiorean, MD

Compared with placebo, cabozantinib (Cabometyx) significantly improved overall survival and progression-free survival in patients with advanced hepatocellular carcinoma who were previously treated with sorafenib (Nexavar), with no new safety signals, according to data from the phase III CELESTIAL trial. These results were originally presented as an oral presentation at the 2018 ASCO GI Cancers Symposium and in a poster at the 2018 ASCO Annual Meeting by Ghassan Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, and colleagues.1 The study was later discussed at Best of ASCO Chicago by E. Gabriela Chiorean, MD, along with other top selected abstracts in noncolorectal gastrointestinal cancer,2 and was published in The New England Journal of Medicine.3

“Cabozantinib is effective and works irrespective of prior benefit from sorafenib. Additionally, toxicity can be managed with dose reductions,” said Dr. Chiorean, Clinical and Research Director of Gastrointestinal Medical Oncology at the University of Washington and Seattle Cancer Care Alliance. “Cabozantinib should be a new second-line treatment option in hepato-cellular carcinoma,” she said.

Study Design

Cabozantinib is an inhibitor of MET, vascular endothelial growth factor receptor (VEGFR), and AXL. 

The double-blind global trial randomized a total of 707 patients 2:1 to receive 60 mg of cabozantinib once daily or placebo. Participants were stratified by etiology, geographic region, and the presence of extrahepatic spread and/or macrovascular invasion. 

Cabozantinib is effective [in advanced hepatocellular carcinoma] and works irrespective of prior benefit from sorafenib. Additionally, toxicity can be managed with dose reductions.
— E. Gabriela Chiorean, MD

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The study population was 82% male, with a median age of 64 years. About 38% of patients had hepatitis B, 24% had hepatitis C, 85% had extrahepatic spread and/or macrovascular invasion, 27% had received 2 prior systemic regimens for advanced hepatocellular carcinoma, and 25% were enrolled in Asia. 

Eligible patients had a pathologic diagnosis of hepatocellular carcinoma, Child-Pugh score A (ie, mild liver impairment), and Eastern Cooperative Oncology Group performance status ≤ 1. Patients must have received prior sorafenib, could have received up to two lines of prior systemic therapy, and must have had disease progression following at least one. The primary endpoint was overall survival; participants underwent imaging every 8 weeks and were treated until disease progression or unacceptable toxicity. 

Significant Improvements in Survival 

At the second planned interim analysis, the investigators observed almost a 25% improvement in overall survival and nearly 60% improvement in progression-free survival, though response rates were low. Median overall survival was 10.2 months with cabozantinib vs 8.0 months for placebo (P = .0049), median progression-free survival was 5.2 months for cabozantinib compared to 1.9 months for placebo (P < .0001), and objective response rate was 4% vs 0.4% (P = .0086). 

It’s outstanding to see the progress we’re making in hepatocellular carcinoma.
— E. Gabriela Chiorean, MD

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There was a higher incidence of grade 3/4 adverse events (predominantly grade 3) in the cabozantinib arm, including palmar-plantar erythrodysesthesia, or hand-foot skin reaction (17% vs 0), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%). 

“As is expected with cabozantinib, hand-foot skin reaction was responsible for most treatment discontinuation and dose reductions,” she said. “In fact, in this study, the starting dose was 60 mg, but the majority of patients ended up having a cabozantinib dose of about 40 mg.” 

According to Dr. Chiorean, these results change the current standard of care for the second-line treatment of hepatocellular carcinoma. She maintains that cabozantinib should now be considered as a second-line option. 

Implications for the Future 

However, she noted that in the second line, deciding between cabozantinib, regorafenib (Stivarga), ramucirumab (Cyramza), and nivolumab (Opdivo) should be dependent on the individual patient. “Likely the order of what to use in the second line will change depending on what we use in the first line,” she said. “[Results from] CheckMate 459 comparing nivolumab to sorafenib will be presented at the European Society for Medical Oncology 2018 Congress in October, and that will potentially change practice.” 


  • Compared to placebo, cabozantinib improved overall survival by almost 25% and progression-free survival by almost 60% in patients with advanced hepatocellular carcinoma who received prior sorafenib.
  • Grade 3/4 hand-foot skin reaction was common in patients who received cabozantinib, but severity can be managed with dose reductions.
  • Cabozantinib should now be considered a second-line option in these patients after treatment with sorafenib. 

The high incidence of hand-foot skin reaction remains a barrier to using cabozantinib. If a patient had severe hand-foot skin reaction from sorafenib in the first line, consider nivolumab for second-line treatment, she advised. Second-line nivolumab after sorafenib may even be a better treatment option, with U.S. Food and Drug Administration approval and an overall survival of about 15 months, she added. “But again, if we [move] nivolumab to the first line after October, cabozantinib will remain a good second-line option.” 

“It’s outstanding to see the progress we’re making in hepatocellular carcinoma,” she added. “The Celestial study is practice-changing. This is actually the highest delta we’ve seen in progression-free survival (3.3 months) and overall survival (2.2. months) vs placebo when compared with other second-line therapy options.” 

She said future research should focus on determining how to sequence programmed cell death protein 1 (PD-1) inhibitors and VEGFR tyrosine kinase inhibitors and should evaluate whether combined PD-1/VEGFR–targeted therapies in the first line are superior to sequential first- and second-line treatments for hepatocellular carcinoma. ■

DISCLOSURE: Dr. Chiorean has received (institutional) research funding from Celgene, Boehringer Ingelheim, Incyte, Ignyta, Stemline Therapeutics, Lilly, and Merck; is a consultant/advisor to Celgene, Five Prime Therapeutics, Halozyme, Vicus Therapeutics, Genentech/Roche, Ipsen, AstraZeneca, and Exelixis; and has received travel/accommodation expenses from Genentech/Roche, Celgene, and AstraZeneca.


1. Abou-Alfa GK, Meyer T, Cheng A, et al: Cabozantinib versus placebo in patients with advanced hepatocellular carcinoma who have received prior sorafenib: Results from the randomized phase 3 CELESTIAL trial. 2018 ASCO Annual Meeting. Abstract 4019. Presented June 3, 2018.

2. Chiorean G: Gastrointestinal (noncolorectal) cancer. 2018 Best of ASCO Chicago. Presented August 11, 2018.

3. Abou-Alfa GK, Meyer T, Cheng A: Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 379:54-63, 2018.