1. Maxwell, Sarah
  2. Goodwin, Peter

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BARCELONA-Oral cabozantinib "significantly improved" overall survival (OS) and progression-free survival (PFS) compared to placebo in patients with advanced hepatocellular carcinoma (HCC) whose disease had progressed despite sorafenib therapy in the phase III CELESTIAL trial reported to the ESMO World Congress on Gastrointestinal Cancer 2018 (Abstract O-011).

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"This is a new oral drug [that's] very easy for the patient to take at home. And it works for some patients. When it works, it can work very well. It can prolong life-and with very good responses in some patients in terms of tumor necrosis, tumor shrinkage, and tumor de-vascularization. It's well-tolerated and it's a new tool to fight against cancer," said study co-author Philippe Merle, MD, PhD, Hepato-Gastro Oncologist and Medical Oncologist at the Hospice Civile de Lyon University Hospital in Lyon, France.


He acknowledged that cabozantinib-an inhibitor of tyrosine kinase c-MET and of vascular endothelial growth factor receptor 2 (VEGFR2)-had not been able to cure all patients with HCC. "But in combination with other drugs, and with immune therapy, I think it will make a great step forward to improve the prognosis of this very poor-prognosis disease."


Study Details

The double-blind CELESTIAL trial randomized (2 to 1) 707 patients who had advanced HCC of mixed etiology (including hepatitis B and C virus infection and alcoholic cirrhosis) to receive oral therapy with cabozantinib or placebo after they had disease progression following treatment with up to two lines of prior systemic therapy including sorafenib. The primary endpoint was OS. Secondary endpoints were investigator-assessed PFS and objective response rate (ORR).


The study met the primary endpoint at the second interim analysis (after 75% of the planned 621 events) with a median OS of 10.2 months among patients receiving the active drug compared with 8.0 months for those treated with placebo-a hazard ratio (HR) of 0.76 with a "p" value of 0.0049. The median PFS was 5.2 months for cabozantinib-treated patients and 1.9 months for those given placebo-an HR of 0.44 with a "p" value of less than 0.001. There was an order of magnitude difference in ORR: a median of 4 percent of patients responded to cabozantinib compared with only 0.4 percent of patients taking the placebo (with a "p" value of 0.0086).


The was a higher incidence of grade 3 or 4 adverse events (mostly grade 3) in the active treatment arm-including hand-foot skin reaction (17% with cabozantinib compared with 0% in patients taking the placebo), hypertension (16% compared with 2%), increased aspartate aminotransferase (12% compared with 7%), fatigue (10% compared with 4%), and diarrhea (10% compared with 2%).


Merle described this tolerance profile as being similar to profiles with other drugs used in HCC. "The drug [was as] well-tolerated as regorafenib in second-line therapy." He said side effects were "a little bit better" than with sorafenib and, although there were more side effects than with IV therapy (such as with ramucirumab), he noted cabozantinib was "not so badly tolerated" and that toxicities were easy to manage. "It's very easy to stop the disease and prolong the life of patients with a rather good quality of life."


Further Investigation

While sorafenib was "a good drug," Merle said that because it did not always work it was necessary for around two-thirds of patients to move on to further therapy after progression on sorafenib. "And now we have a choice between regorafenib or cabozantinib. But we don't know how to make [the] choice," he explained. "It's very difficult, because we have no study to prove what kind of drug to choose. We have no biomarker. With alpha-fetoprotein we have a biomarker for ramucirumab. But for cabozantinib we have no biomarker."


Merle suggested that using immunohistochemistry to detect tyrosine kinase c-MET expression could have helped as a step towards providing a potential biomarker. But this had not been performed in the CELESTIAL study. "So we don't know whether c-MET was associated with better response to the drug or not," he noted. Though he acknowledged that tracking all of the potential pathways for c-MET was a complex challenge.


Although the study had shown cabozantinib was potentially "very good for patients," there was more to be done, Merle acknowledged. "Now we have a lot of work to do to find the right sequence between sorafenib, regorafenib, cabozantinib-in what order we have to prescribe these drugs." Merle also said the sequence would need to be revised soon to reflect emerging data from studies of immunotherapies for HCC that were also looking promising.


Sarah Maxwell and Peter Goodwin are contributing writers.