Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is a challenging condition to treat, with reported five-year survival rates ranging from 30% to 50%. Recently, the FDA approved cabozantinib (Cabometyx®, Exelixis, Inc.) as second-line treatment for patients with HCC previously treated with sorafenib. Thomas A. Abrams, MD, Assistant Professor of Medicine at Harvard Medical School, spoke with i3 Health about cabozantinib's approval and about the various options now available for second- and third-line treatment of HCC.
Can you comment on the significance of cabozantinib's approval as second-line treatment for HCC?
Thomas A. Abrams, MD: I'm excited by it because it provides another treatment avenue for our patients with HCC who previously would have run out of options rather quickly. Over the last year and a half, there's been a spate of drugs approved. These have really given so much greater treatment flexibility, which I think is terrific. I think that the specific excitement over cabozantinib is that it's not quite the same as some of the other tyrosine kinase inhibitors (TKIs). This drug hits some different targets.
The CELESTIAL study wasn't as carefully selected as other trials. Some patients on the study were intolerant of sorafenib rather than just having progressed on the drug. Other patients had even received anti–PD-1 (anti-programmed cell death protein 1) therapies, so you have data not only in the second line after sorafenib failure, but you also have data in the third line. I think that really helps because now that you have multiple options, drug sequencing becomes a major concern. While it's far from worked out how to best sequence them, it is reassuring to know there are data supporting use of cabozantinib in the third-line.
How does cabozantinib compare with other HCC therapies?
Dr. Abrams: It's similar to other TKIs. In terms of the side effect profile, it certainly has side effects such as diarrhea and fatigue. It probably doesn't have quite as much in the way of hand-foot syndrome and maybe not quite as much hypertension, but certainly it's in the same ballpark as many of the other TKIs, like sorafenib, regorafenib, and lenvatinib. We just have to really use all of the medicines. We have to try and deal with those side effects and intervene early so patients can maintain dose efficacy and maintain their time on the drug.
Do I think it's much different in efficacy? Probably not, although, as I said, it does hit some different targets, so that speaks to the possibility that it may have differential effect. However, when you look at the survival data, they're kind of similar to those of the other drugs. If patients really were doing great on sorafenib, they could slot right into regorafenib. If they weren't doing very well on it, then I think that cabozantinib might be another option because it hits some different targets.
In addition, the data for ramucirumab are pretty good for patients with alpha-fetoprotein (AFP) greater than 400. Although that has also been tested in the refractory setting, I think for a patient with a very high AFP titer whose performance status is marginal or whose liver function is poor, ramucirumab should be something to consider in the first line as well as TKIs can be difficult to give it those situations.
Then, of course, you have the immunotherapies that are also approved—nivolumab and pembrolizumab, the PD-1 inhibitors—and you've got to figure out a way to put them into the mix as well.
I think it's a challenge right now as we don't really know what the most efficacious sequence is, and it's probably going to depend on the patient. As we learn more about the tumor microenvironment, genomics, and all of those hot topics, I think we might be able to better individualize treatment.
What would you advise doctors to consider in balancing cabozantinib against these other options, both in the second line and also, as you mentioned, in third-line treatment?
Dr. Abrams: You consider side effects, first and foremost. You look at what are the most common side effects and try to ascertain where patients are going to be most comfortable, and then you try also to use at least whatever scant information we have to try and anticipate efficacy. If they did really well on sorafenib for a long period of time, then another TKI makes sense, but if they really just blew through sorafenib or tolerated it poorly, then I think patients would probably be better served trying something totally new and different, like a PD-1 inhibitor. That's kind of where my practice heads. I wish we had more data-driven answers, but I think as it stands right now, we just have to go by side effects and perceived efficacy.
What do you think are some of the most significant challenges in treating patients with treatment-resistant HCC?
Dr. Abrams: I think the biggest one is that many patients don't do very well, and they don't live very long. Their liver function may deteriorate quickly, and they won't get to second or third-line therapy. It's hard to keep patients not only alive but alive and well enough to get beyond sorafenib. I think that is probably the greatest challenge. A lot of patients that you meet are really not sorafenib candidates when you first meet them; they're really only candidates for a PD-1 or nothing. There are a lot of patients whom you would really love to be treating with a PD-1 upfront, even though the indication is for the second line.
Do you have any advice for community oncologists treating patients with HCC?
Dr. Abrams: I think that they're really going to have to get more familiar with this disease because they are going to see it more and more. Right now, I think it's treated chiefly in academic settings, mainly because of its multidisciplinary aspects; a lot of patients are getting liver-directed therapies and even surgery and being evaluated for transplantation. However, I think community oncologists are going to see more and more of the advanced patients, and my advice is don't necessarily refer them out immediately. Try to gain some familiarity with the unique challenges of treating these patients. I think that's important because not all patients do poorly. A lot of patients are going to live a reasonably long time with advanced disease, and it's going to be a rewarding experience.
How do you see HCC treatment evolving?
Dr. Abrams: I think that this is the dawn of a new era. We have a lot more drugs at our disposal and certainly a lot more understanding of the drivers of the disease. I think that we are going to continue to see better outcomes, not just because of better drugs but also because we can take care of these patients better. That's a good thing.
About Dr. Abrams
Thomas A. Abrams, MD, is an Assistant Professor of Medicine at Harvard Medical School. He is a Senior Physician at Dana-Farber Cancer Institute and an Associate Physician at Brigham & Women's Hospital.
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Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily represent the views of i3 Health.