Novel Approaches to Treatment of Hepatocellular Carcinoma - Episode 7
Richard Finn, MD: Let’s transition from oral drugs to intravenous drugs. And we’ve touched on the I-Os [immune-oncology agents]. The other intravenous drug that has positive phase III data is ramucirumab, a monoclonal antibody to the VEGF receptor. It’s currently approved in several indications: lung cancer, I think gastric cancer. Can you comment on the development of ramucirumab in liver cancer and where it is today?
Anthony El-Khoueiry, MD: Sure. The VEGF receptor is thought to be a valid target in liver cancer. So there was an initial study that was done second-line post-sorafenib comparing ramucirumab to best supportive care, called the REACH trial, which was negative. On a subgroup analysis, an exploratory analysis retrospectively done, showed that there seemed to be a benefit in the patient with elevated AFP [alpha-fetoprotein] above 400 ng/mL. So, based on that data, the REACH-2 study was done, which limited eligibility to patients who had progressed on sorafenib, had an AFP at 400 or higher, and with preserved liver function. And that was a positive trial showing improvement in overall survival with ramucirumab compared to best supportive care. Now, one could look at this and say the magnitude of the benefit may have been a bit smaller compared to the other second-line studies, I think about 1.5 months or so. There was a combined analysis done of both REACH trials, REACH-1 and REACH-2, and taking patients with an AFP over 400. And when that analysis is done, then the magnitude of the benefit is more comparable to what we see in the other sorafenib studies, around 3 months or so.
Richard Finn, MD: This is the first time that we have a biomarker to guide treatment in liver cancer. We were just talking about PD-1 [programmed cell death protein 1] biomarker, biomarkers for the TKIs [tyrosine kinase inhibitors]. So now we have a drug that’s very specific. It’s a monoclonal antibody. We see that it improves survival in this selected group. Where do you see this drug falling into the paradigm now of I-O, TKIs, ramucirumab?
Anthony El-Khoueiry, MD: It’s difficult to guess where it will fall. But it’s another option. It’s another tool we have. I think the safety profile is certainly different than the TKIs, which is a distinguishing factor. The traditional problems of hand-foot skin reaction and diarrhea are not necessarily there. Of course, hypertension is still there. There was slightly more frequent ascites with ramucirumab, for example. But generally, the safety profile may be a distinguishing factor as far as an option other than I-O for this patient population.
Richard Finn, MD: Yes. And, as we talked about the other phase III studies, it met its primary endpoint, and secondary endpoints were also improved with ramucirumab, doubling of PFS [progression-free survival] and tumor control rates. How do you think of high AFP, even from your frontline population? Do you start thinking about that right away as a different type of liver cancer?
Anthony El-Khoueiry, MD: Absolutely.
Richard Finn, MD: And I’m sorry to interrupt, Anthony. And when I say high AFP, what is high AFP out of the normal range? We know in REACH it was 400 as a cutoff. What about 200s, what about 10,000?
Anthony El-Khoueiry, MD: Sure. I think generally it is accepted in HCC [hepatocellular carcinoma] in both patients who undergo locoregional therapy or systemic therapy that AFP is a prognostic marker. So higher AFP tends to entail worse prognosis generally. Now, what the magic cutoff is, it’s difficult. Most studies have been using 400 as their cutoff.
Some studies have used 200. But with anybody who’s above 200, and certainly above 400, I start thinking that I may be facing a poorer prognosis. And does that change my treatment paradigm? Not necessarily, but I’m a bit more vigilant about switching lines of therapy, about palliating these patients a bit more aggressively, potentially. As far as how it relates to ramucirumab usage, certainly it was an eligibility criterion. But, when we look at the other agents, many of them have had analyses to see where there is benefit in high AFP and low AFP.
Richard Finn, MD: Specifically lenvatinib looked at that, regorafenib looked at that. In second-line, regorafenib, cabozantinib.
Anthony El-Khoueiry, MD: Exactly. All of these agents have looked at that and even with nivolumab. The benefit seems to be whether there’s elevated AFP or not.
Richard Finn, MD: I was going to ask you, in the PD-1, have you presented those data that the response rate is comparable?
Anthony El-Khoueiry, MD: Correct, in abstract form. I think the benefit tends to be there whether the AFP was high or not. So I think we’re going to need a little bit more information to know whether AFP will really change our selection of agents.
Richard Finn, MD: Yes, very interesting. I think at this meeting there is going to be some data presented about how patients who have a drop in their AFP with ramucirumab tend to have a better outcome as well.
Transcript Edited for Clarity