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Checkpoint Inhibitors, TKIs, and Novel Agents Poised to Enter Liver Cancer Treatment Paradigm

Gina Columbus @ginacolumbusonc
Published: Tuesday, Dec 19, 2017

Dr Ghassan Abou-Alfa
Ghassan Abou-Alfa, MD
Prior to 2017, the hepatocellular carcinoma (HCC) space had little movement in therapeutic advancements beyond standard sorafenib (Nexavar).

Two more agents have since been added to the treatment landscape: regorafenib (Stivarga) in April and nivolumab (Opdivo) in September, both of which can be administered in patients following treatment with sorafenib.

But other therapies are moving steadily through the pipeline, as well. Lenvatinib (Lenvima) was compared with sorafenib in the phase III Study 304 trial, a noninferiority study that showed no difference between the 2 agents in the frontline setting. Moreover, the phase III CELESTIAL trial exploring cabozantinib (Cabometyx) in patients who previously received sorafenib was announced to have met the primary endpoint of overall survival. Data are likely to be presented at the 2018 Gastrointestinal Cancers Symposium.

“We have a total 4 tyrosine kinase inhibitors (TKIs); 2 of them are already approved and 2 are waiting to be approved,” said Ghassan K. Abou-Alfa, MD. “In addition to that, we have a checkpoint inhibitor and, of course, there is more to come.”

“More to come,” includes the anticipated phase III findings of the Pexa-Vec oncolytic immunotherapy in patients who previously received sorafenib (Nexavar), as well as the early studies starting to explore chimeric antigen receptor (CAR) T-cell therapy in liver cancer.

In an interview during the 2017 OncLive® State of the Science SummitTM on Gastrointestinal Cancers, Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed what he sees coming down the pike in HCC with regard to novel agents, including CAR T-cell therapy, and the burgeoning questions with optimal sequencing of these treatments.

OncLive®: A lot has been happening in this field as of late. What would you like to highlight?

Abou-Alfa: It has been great to be here tonight for the State of the Science SummitTM, and it was a great honor to talk about primary liver cancer, especially this year. This has been an incredible year and positive time regarding our therapies for [patients with] liver cancer. As we both know, liver cancer had only one therapy, sorafenib, that was approved by the FDA almost 10 years ago. If anything, we have been trying for the past 10 years to see how we can improve on the outcome of sorafenib either by trying different things—by going into combination therapies, or even looking at second-line therapy.

Many great efforts have been done and, unfortunately, all of them have been negative. However, this year has been quite impressive. Now, in the second-line setting, regorafenib has been proven to show an improvement in survival compared with placebo after the prior exposure to sorafenib. This is FDA approved.

In addition to that, we have seen incredible data on the advent of checkpoint inhibitors or immunotherapy. Nivolumab has been evaluated in a phase II trial and has shown that the response rate for patients with HCC will be somewhere in the range between 15% and 20%. Based on that limited phase II study, the FDA approved the drug in the second-line setting. Of course, we are awaiting the large phase III trial, Checkmate-459, which will look at nivolumab versus sorafenib in the first-line setting. We'll see where this will take us.

Then, interestingly, the story does not stop there. We have heard about the noninferiority study of lenvatinib, another TKI, which was evaluated versus sorafenib. It was a quite innovative study and more importantly, the study was positive. There was no difference between lenvatinib and sorafenib. If anything, lenvatinib was shown to have other important aspects that are positive regarding response and tolerance. I, personally, would not be surprised if it was FDA approved.

We have talked about 3 drugs, and the fourth one is cabozantinib, a c-MET inhibitor. Our prior experience with c-MET inhibitors, with tivantinib was a negative study and it did not show an improvement in outcomes versus placebo in c-MET–positive patients.

But this time, we took a different perspective with cabozantinib where we allowed all patients to enroll and the trial is positive. We don’t have data yet but, as already announced in the public releases, we expect to present the data at the 2018 Gastrointestinal Cancers Symposium. That is, in brief, where things stand.

Though it is early, how do you foresee an FDA approval of cabozantinib shaking up the paradigm?

Actually, this question is very important. It is not only dependent the cabozantinib data; it is going be dependent on many other data, including nivolumab. In other words, how are we going to line up those therapies? [Do you decide by saying things] like, “I like this drug. I’m used to that drug” or “Is [this drug] more tolerated?” There is more to the story.

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