Patient Profile 3: Advanced HCC Treated With Cabozantinib in Second Line


Centering discussion on the final patient profile, panelists consider how they select optimal therapy in the second-line setting of advanced hepatocellular carcinoma.


Josep Llovet, MD: Let’s move to the case in second-line [therapy], Amit, please.

Amit Singal, MD: Of course, thanks, Josep. This is a patient we saw, a 70-year-old male with cryptogenic cirrhosis. He had a good performance status at baseline, ECOG performance status of 0, good liver function, with a Child-Pugh A5 score. He started off presenting with early stage disease, one of the key things we always like to see, and normal AFP [alpha-fetoprotein]. The patient initially presented with a unifocal 5-cm HCC [hepatocellular carcinoma] without vascular invasion. As we discussed before, this is a patient who has good liver function, no portal hypertension, [and] unifocal 5-cm HCC. The patient underwent resection, curative therapy once again, as we should be doing in these cases. Although resection is a great therapy, the issue as you’ve already said is the fact that these patients can have recurrence. This patient, on the resection specimen, was found to have microvascular invasion, a predictor of having recurrence, and was found to have a mesenteric implant shortly thereafter. The patient was treated with lenvatinib as therapy for this; this was prior to [atezolizumab and bevacizumab] being available. Thus, lenvatinib was our preferred therapy in this case.

Then the patient, unfortunately, after a period of 6 months was found to have progression, so was found to have multifocal enlarging liver lesions, despite the lenvatinib at that point. The patient fortunately continued to have a good performance status, good liver function, with a Child-Pugh A class, as you can see there, and AFP remained normal. Once again, this is a patient who initially did well on lenvatinib, but now is breaking through with multifocal enlarging liver lesions. For our patient, we thought through the second-line therapies we have available as you’ve nicely summarized, given the normal AFP, and that he was not treated with sorafenib in the past. Hence, we started cabozantinib as the preferred therapy in this patient. The patient tolerated the treatment well and did well with no notable AEs [adverse events] for 5 months. And [the] most recent imaging shows a partial response to cabozantinib, and the patient remains on cabozantinib at this time.

Josep Llovet, MD: Very nice. I have some questions, but I think the most relevant question at this point could be, A, in patients receiving sorafenib or lenvatinib in frontline [therapy], what is your decision-making in terms of the second line? And B, nowadays if you treat a patient in the front line with[atezolizumab-bevacizumab] or [durvalumab and tremelimumab], what would be your second line? Who wants to start?

Andrea Casadei-Gardini, MD: For sorafenib in the first line, for example, we published [about] it last year. One paper [discussed how] patients with early progression on sorafenib and regorafenib performed less well [with] cabozantinib. The cutoff is 6 months normally if I prescribe regorafenib for the patient to have a longer response in the first line to sorafenib. Or with cabozantinib, the response is lesser, [and] it is not possible to apply this to lenvatinib or [atezolizumab-bevacizumab]; we don’t have data after progression on immunotherapy [IO].

Josep Llovet, MD: Katie.

Katie Kelley, MD: After [atezolizumab-bevacizumab], I tend to use a TKI [tyrosine kinase inhibitor], and I tend to use lenvatinib as moving the lines of therapy, one displaced from prior. That would be my initial stance after progression on [atezolizumab-bevacizumab].

Amit Singal, MD: From an [atezolizumab-bevacizumab] perspective or [durvalumab-tremelimumab] in the front line, if they receive an IO regimen, then we typically do the same thing where we use a T-minus-1 approach. I think this is where you see a split in the absence of data. The 2 different approaches that I’ve at least seen are, do you do a T-minus-1 approach, where you go to the prior first-line therapies, so sorafenib and lenvatinib, and then preserve the old second-line therapies for the third line, particularly cabozantinib, which has data in the third-line setting from the CELESTIAL trial. Or do you use any one of those TKIs? Do you use sorafenib, lenvatinib, regorafenib, cabozantinib, as an all-comer approach in the second-line setting. But at our center, we do very similar. We use sorafenib and lenvatinib, which then allows third-line agents for those patients who continue to progress through that second line.

Joseph Llovet, MD: Arndt.

Arndt Vogel, MD: It’s difficult to say, and we had a lot of discussions about that in the past. As you know, I’m not a friend of this T-minus-1, or however you want to call it, approach, and I think we should use the drugs that are most effective, independent of the time when they have been tested for efficacy. For me, I think cabozantinib was definitely a drug that I considered highly effective when you look at the PFS [progression-free survival]. And even if the overall survival was not very good, when you now look at the COSMIC-312 study, it seems to be superior compared to sorafenib in the first-line setting. Again it’s early, we have to wait for the overall survival data, but I consider cabozantinib an effective drug, and I [have] always considered lenvatinib as an effective drug, and this has been confirmed in the LEAP study. Thus for me it would be either cabozantinib or lenvatinib if I could choose, but I live in Germany and in Germany, only sorafenib is reimbursed, so I only use sorafenib.

Andrea Casadei-Gardini, MD: It’s the same in Italy.

Josep Llovet, MD: I think there are enough data also to say, to be fair, that the sequencing of sorafenib followed by regorafenib also provides good outcomes. Certainly, we don’t know about regorafenib after lenvatinib….

Arndt Vogel, MD: We don’t know….

Joseph Llovet, MD: Exactly. The more trials that are coming in the front line, the more an educated guess will be the election based on evidence because still, I think we have a hierarchy that we have been constructing with 15 years of trials that we are going to say now, this is gone. To your question, and we have 2 minutes, it is true that the guidelines are not unanimous on what to do. I would say that most of the guidelines though—and I’m referring to the EASL [European Association for the Study of the Liver] guidelines, the AASLD [American Association for the Study of Liver Diseases] guidelines that will be published in brief, even ASCO [American Society of Clinical Oncology], if you read it through—said these 5 drugs, TKIs and monoclonal antibodies, including [ramucirumab], are effective, but we respect the hierarchy. This is the message of the 3 guidelines. It is true that ESMO [European Society for Medical Oncology], and we’re in the ESMO [annual] meeting, had discrepancies, and these discrepancies are written in the paper, which is very nice. We voted; it’s very democratic. The decision was, as you mentioned, not to consider the pre-established hierarchy. But I think the physician should be exposed to all the guidelines and then make the decisions, and the multidisciplinary board as well.

Transcript edited for clarity.

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