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CELESTIAL Trial: Second-Line Cabozantinib's Value in HCC

Insights From: Josep Llovet, MD, Mount Sinai School of Medicine; Riccardo Lencioni, MD, University of Miami Miller School of Medicine
Published: Wednesday, Feb 21, 2018



Transcript: 

Riccardo Lencioni, MD: The CELESTIAL trial, presented by Ghassan Abou-Alfa, was a randomized placebo-controlled trial of cabozantinib versus placebo in the second-line setting. The patient population is the same as in other studies, so a patient who had prior sorafenib still with compensated cirrhosis and the same performance status. Overall, the study met the primary endpoint of improving overall survival, from 8 months in the placebo arm up to 10.2 months in the cabozantinib arm. This is very important, because now we have 2 drugs and both have shown positive data in the second line.

This is, this is very interesting, because we now have potential for multiple strategies and multiple options. It would be very important to understand, of course, the best strategy for each patient, but we definitely now have plans in place for patients with advanced HCC, even those who progress after first-line therapy.

Josep Llovet, MD: The importance of the cabozantinib trial relies on the fact that the 3 drugs that are in the field so far—sorafenib, regorafenib and lenvatinib—are, in the lingo of the FDA, called “dirty molecules.” They are very promiscuous; they target 40 kinases or so. Cabozantinib, despite that it targets several kinases, is more selective. It’s blocking VEGF, c-Met, and AXL. This is relevant in the sense that we know VEGF is an important prognostic factor and probably relative in HCC. c-Met signaling is also important; it’s activated in 50% of the tumors at that stage. The fact that this drug has a narrower spectrum of targets and is also achieving clinical relevant outcomes is important in my mind.

The results of the trial were, in summary, that the drug is able to expand survival around 2 months, from 8 months to 10.2 months, in second-line patients progressing on sorafenib without any remarkable adverse events. There’s the usual hypertension, hand-foot skin reaction, and so on, but nothing that is not manageable. The objective response by RECIST was 4% with cabozantinib, but modified RECIST hasn’t reported. I think that it’s an additional effective drug that is certainly needed for all of these patients.

Transcript Edited for Clarity 
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Transcript: 

Riccardo Lencioni, MD: The CELESTIAL trial, presented by Ghassan Abou-Alfa, was a randomized placebo-controlled trial of cabozantinib versus placebo in the second-line setting. The patient population is the same as in other studies, so a patient who had prior sorafenib still with compensated cirrhosis and the same performance status. Overall, the study met the primary endpoint of improving overall survival, from 8 months in the placebo arm up to 10.2 months in the cabozantinib arm. This is very important, because now we have 2 drugs and both have shown positive data in the second line.

This is, this is very interesting, because we now have potential for multiple strategies and multiple options. It would be very important to understand, of course, the best strategy for each patient, but we definitely now have plans in place for patients with advanced HCC, even those who progress after first-line therapy.

Josep Llovet, MD: The importance of the cabozantinib trial relies on the fact that the 3 drugs that are in the field so far—sorafenib, regorafenib and lenvatinib—are, in the lingo of the FDA, called “dirty molecules.” They are very promiscuous; they target 40 kinases or so. Cabozantinib, despite that it targets several kinases, is more selective. It’s blocking VEGF, c-Met, and AXL. This is relevant in the sense that we know VEGF is an important prognostic factor and probably relative in HCC. c-Met signaling is also important; it’s activated in 50% of the tumors at that stage. The fact that this drug has a narrower spectrum of targets and is also achieving clinical relevant outcomes is important in my mind.

The results of the trial were, in summary, that the drug is able to expand survival around 2 months, from 8 months to 10.2 months, in second-line patients progressing on sorafenib without any remarkable adverse events. There’s the usual hypertension, hand-foot skin reaction, and so on, but nothing that is not manageable. The objective response by RECIST was 4% with cabozantinib, but modified RECIST hasn’t reported. I think that it’s an additional effective drug that is certainly needed for all of these patients.

Transcript Edited for Clarity 
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