Expert Looks Ahead to Promising Liver Cancer Advancements

Before 2017, there were minimal advancements in the treatment field of hepatocellular carcinoma (HCC), with Nexavar (sorafenib) treatment remaining the standard for about a decade.

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

But other therapies are moving steadily through the pipeline, as well. Lenvima (lenvatinib) was compared with Nexavar in the phase 3 Study 304 trial, a noninferiority study that showed no difference between the two agents in the frontline setting. Moreover, the phase 3 CELESTIAL trial exploring Cabometyx (cabozantinib) in patients who previously received Nexavar 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 four tyrosine kinase inhibitors (TKIs); two of them are already approved and two are waiting to be approved,” said Ghassan K. Abou-Alfa, M.D. “In addition to that, we have a checkpoint inhibitor and, of course, there is more to come.”

“More to come,” includes the anticipated phase 3 findings of the Pexa-Vec oncolytic immunotherapy in patients who previously received 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 Summit 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.

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

It has been great to be here for the State of the Science Summit, 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 liver cancer. As we know, liver cancer had only one therapy, Nexavar, 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 Nexavar 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, Stivarga has been proven to show an improvement in survival compared with placebo after the prior exposure to Nexavar. This is FDA approved.

In addition to that, we have seen incredible data on the advent of checkpoint inhibitors or immunotherapy. Opdivo has been evaluated in a phase 2 trial and has shown that the response rate for patients with HCC will be somewhere in the range between 15 percent and 20 percent. Based on that limited phase 2 study, the FDA approved the drug in the second-line setting. Of course, we are awaiting the large phase 3 trial, Checkmate-459, which will look at Opdivo versus Nexavar 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 Lenvima, another TKI, which was evaluated versus Nexavar. It was a quite innovative study and more importantly, the study was positive. There was no difference between Lenvima and Nexavar. If anything, Lenvima 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 three drugs, and the fourth one is Cabometyx, 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 Cabometyx 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 Cabometyx shaking up the paradigm?

Actually, this question is very important. It is not only dependent the Cabometyx data; it is going be dependent on many other data, including Opdivo. 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.

The science of that is going to come into play, and this is one of the biggest challenges that I am working on at the moment — how to line them up. If CheckMate-459 is positive, and there are other studies coming along — including HIMALAYA, which is a large study looking at the combination of anti—PD-1 plus anti–CTLA-4—patients will expect us to attempt checkpoint inhibitors as a first-line therapy. Then from that point on, you go into the second-line setting, which will be based on TKIs.

How are the TKIs going to be lined up? It will probably be dependent on certain guidances. For example, we know that Stivarga [targets] IGF and Lenvima [targets] FGF. These are going to be certain aspects that we might elaborate further. To be fair, the question is a little bit early because we don’t have the data for Cabometyx yet. For Lenvima, we have it only for an abstract form. For Opdivo, we have the data but we don’t have it in a phase III trial. There is lots to be covered still, and we will move forward in that regard.

Will more checkpoint inhibitors be explored down the road?

I would take the question a different way. There will be more checkpoint inhibitors but interestingly, for me, I have already decided that TKIs are great. They have really improved outcomes for patients. Now, [more TKIs] are going to be a variation of the same subject. Checkpoint inhibitors are almost [in the same situation] and we already know the lineup of what is going to happen with them.

Other than Opdivo, we have Keytruda (pembrolizumab) which is being looked at in the second-line setting. We have the Imfinzi (durvalumab) and tremelimumab combination in the first-line setting, which is being looked at in the HIMALAYA study. There is no question that we know the caveat of things. What will the combinations be of? Will it be a combination of TKIs plus checkpoint inhibitors? By all means, it will happen.

However, my mindset is somewhere else. The third phase of that effort is going to be more based on local approaches with systemic therapy or more directed immunotherapy. I am very happy to see, and very proud that I am involved in, the effort with Pexa-Vec, which is being looked at as an intratumoral injection on top of Nexavar. We'll see that phase III trial soon. It is ongoing and we will see where it’s going to take us. It is an impressive effort, but the other thing that will have a lot of potential, though we haven’t seen any data yet, will be CAR T-cell therapy. There is no question that there are questions looking at AFP [alpha-fetoprotein]. The question is, “Is AFP the right antigen that we're going a after, or will there be another antigen?”

Going back to Stivarga, what else could we see with this agent?

There are a lot of potentials over here but, so far, the best understanding we have is [its activity with patients who have] prior exposure to Nexavar. Combinations have been tried with Nexavar, but I don’t think there is going to be anything visible as with Stivarga.

In closing, what do you expect we will be reflecting on at the end of 2018?

One year from now, we will no doubt, [be discussing] CheckMate-459; we will hopefully have enough data with regard to Keytruda. The HIMALAYA study just started, so it will not be ready by then, but we probably will have some gist about that. More importantly, we will see some efforts regarding answers about the sequencing, and I would like to see more activity from the novel components I mentioned, such as the Pexa-Vec virus or CAR T-cell therapy.