The Role of Cabozantinib as Second-Line Therapy in mHCC

Transcript: Ghassan K. Abou-Alfa, MD: It’s quite interesting because specifically the patients who tolerated sorafenib but ultimately progressed on sorafenib, when you give them regorafenib—this was not a planned part of the study—they went ahead and looked retrospectively at the survival from the start of sorafenib until progression or until death after getting regorafenib, which, interestingly, was about 26 months. No question there is a story there that could be explained biologically. However, interestingly, the field did not really take a break at that and say, “OK, now we have a second-line,” because in no time another drug came on that really was quite impressive, called cabozantinib. Farshid, tell us.

Farshid Dayyani, MD: Cabozantinib is a tyrosine kinase inhibitor [TKI] that affects the VEGF pathways, VEGF receptor 1, 2, 3 but also AXL and MET, which are 2 important drivers of metastases invasion within tumors. The idea was to develop a molecule that comes with a 2-pronged approach, to effect the microenvironment, the immune milieu, but also the primary tumor. And the space cabozantinib was tested in in HCC [hepatocellular carcinoma] initially is the CELESTIAL trial, randomized phase III 2-to-1 in second-line setting. And I think now that we have 5 drugs approved in the second-line setting, for our colleagues it’s important to realize the devil is in the detail and data are not all the same. The way we derive to these FDA approvals are different.

Ghassan K. Abou-Alfa, MD: Fair enough. Katie, I like what Farshid said. But at the same time, why would I like that? In full disclosure, you and I were heavily involved in regard to that work. But we hear about tivantinib. Why was tivantinib in a phase III trial negative and cabozantinib was positive?

Katie Kelley, MD: Right. Tivantinib was another purported MET inhibitor, though the mechanism of MET inhibition was different and perhaps not an activated MET inhibitor necessarily. And it also had some microtubulin activity and so some cytotoxic effects that could confound the results by causing low platelets and other toxicity along the way. Tivantinib unfortunately was a negative study in the METIV-HCC randomized phase III trial, selecting patients with high MET expression. I think again there’s a lot of potential reasons for that not working, one being that perhaps MET alone is not a sufficient target to really change the behavior of a tumor. Whereas, a drug like cabozantinib, which is a multi-kinase inhibitor, including MET, but also ongoing, hitting the VEGF antiangiogenic approach in parallel, complementary inhibition may be more successful. And then tivantinib itself may not have been as good of a MET inhibitor as was needed. I think the exact reasons for the success of cabozantinib versus the failure of tivantinib are probably multi-pronged.

But suffice it to say, I think one of the key points about the CELESTIAL trial and cabozantinib is that it included not just second-line but also a population of third-line. It was agnostic really to what was the immediate prior therapy. And so all patients had to have had prior sorafenib, but patients could have had another line in between or preceding that. And so it’s reassuring to see the efficacy of the drug holding true, regardless of duration of prior sorafenib, regardless of what were the immediate prior therapy, regardless of the tolerability. The subanalyses showed it maintained benefit across all those conditions.

Ghassan K. Abou-Alfa, MD: I totally agree with you. Actually, when we were about to start working on the cabozantinib, we made it a point and our recommendation was that the drug should be available for all patients. Because remember, same like in breast cancer, we don’t really measure how much ER/PR [estrogen receptor/progesterone receptor] positivity we have. Even a whiff of ER/PR-positive, it was still useful therapy. Same thing over here, we don’t know how much MET is needed, and this is again a multi-tyrosine kinase inhibitor. It has to be understood from that perspective. Again, the data were positive, really solid, including third-line therapy that was given to certain patients with prior exposure to sorafenib, but it was not necessarily in any specific delineation. In other words this could happen with something in between—and still, however, it came with quite robust positive data. Another thing that is intriguing though about cabozantinib, and I’ll go back to Amit, are the adverse events [AEs].

Amit Singal, MD: I think that when you take a look at the CELESTIAL trial and you take a look at the AE profile with cabozantinib, it’s similar to the other TKIs. It’s the same AEs that you’re used to seeing with sorafenib, same AEs that you see with lenvatinib or regorafenib. But overall, I would say that it’s very well tolerated. There were no unexpected AEs. These are the same AEs that we we’re all used to seeing and all used to managing very well in our practice.

Ghassan K. Abou-Alfa, MD: I would say that it’s manageable.

Amit Singal, MD: Yes.

Ghassan K. Abou-Alfa, MD: Fair enough. What’s your dose for that, Katie?

Katie Kelley, MD: Over half the patients did require dose reduction from the 60 mg starting dose down to 40 mg. And so I’m quick to do that in practice or even if I’m uncertain about a patient’s likelihood of toleration of the dose based on perhaps other comorbidities or, being a particularly small person, I sometimes will start with a 40 mg dose, playing the odds from the data.

Ghassan K. Abou-Alfa, MD: Yes. Were there any particularities about who will respond better or it didn’t matter, everyone did well?

Katie Kelley, MD: We saw a benefit across all the relevant clinical prognostic factors to date. Analyses based on tumor MET status are pending.

Ghassan K. Abou-Alfa, MD: Fair enough. Farshid, for whatever reason, we spoke a little bit in the beginning about the different risk factors for HCC. Would you weigh in and say, “I would choose this drug for that specific patient because of the risk factor,” or you are agnostic from that perspective?

Farshid Dayyani, MD: The totality of data favors cabozantinib over placebo with a very robust hazard ratio. If you look at the forest plots of subsets, and now you have to realize that the numbers get smaller, it seems for overall survival [OS], not for progression-free survival [PFS], the HCV [hepatitis C virus] population might have derived smaller relative benefit. But again, if you look at the PFS hazard ratio, it’s very robust, meaning drug activity. So at this time, I’m not ready to say based on viral background I would choose drugs, even though that’s something to look into, the reasons why we might have seen that in the CELESTIAL trial.

Ghassan K. Abou-Alfa, MD: I totally agree. If anything, at this point, despite all that we discussed, and this is very important, we really need to know what the risk factor for a patient is because this might be information that can guide how to manage the liver cirrhosis component, make sure that we control, for example, the hepatitis. And no doubt ultimately we’ll find a little bit better information, but for now cabozantinib is definitely applicable for all patients, like lenvatinib was.

Transcript Edited for Clarity