Expert Roundtable: Clinical Significance of the HCC REACH/ REACH-2 Trials

In a discussion panel hosted by Ghassan K. Abou-Alfa, MD, at the ESMO World Congress on Gastrointestinal Cancer 2019, Arndt Vogel, MD, PhD, and Chris Verslype, MD, PhD, FACP, discussed the clinical significance of the REACH and REACH-2 clinical trials, in which the efficacy of ramucirumab therapy was evaluated for patients with advanced hepatocellular carcinoma (HCC).

Transcript:

Dr. Ghassan Abou-Alfa:  We're here at the World GI Cancer Congress in Barcelona. Today, we had great data that we heard about REACH and REACH-2 data in HCC liver cancer of ramucirumab. I'm Ghassan Abou-Alfa from Memorial Sloan Kettering Cancer Center in New York City in the US.

I'm joined by Dr. Arndt Vogel from the University of Hanover in Germany and Dr. Chris Verslype from the University of Leuven in Belgium. We're here to discuss what we heard about and reflect on the data. With this said, I would like to ask Dr. Vogel maybe to start by telling us. What was the REACH and REACH-2 data about? What's the purpose of those studies?

Dr. Arndt Vogel:  I think in HCC, we know that we have a hyper vascularized tumor and we can diagnose the tumor just by imaging because it's so characteristic. We do know that HCC is a very chemo-resistant tumor. The first drug that was approved was sorafenib, more than 10 years ago, and it was a multi tyrase and kinase inhibitor, which has the strong efficacy against the VEGF receptor pathway, and we do think that the efficacy of sorafenib depends both on the direct effect on the tumor and also on it's anti-angiogenic efficacy.

There was clearly a rationale to specifically focus more on the VEGF receptor pathway and ramucirumab was a drug, which has a high activity. It's approved in other GI cancers. Ramucirumab has been tested before. It never really made it to a positive Phase 3 study. There were some indications that hitting this pathway could have an effect in HCC.

We also have learned that there are many angiogenic sectors like VEGF, VEGFR2, FGF19, which also have a strong prognostic role. I think there were plenty of reasons to test this drug in HCC, and Lilly did this with the REACH study, which actually was negative, but they realized that there's efficacy in the patients with high AFP levels. Then, they did the REACH-2 study, which was specifically focused on patients with a high AFP level and a poor prognosis.

Luckily, the study was positive.

Dr. Abou-Alfa:No, that's very important. I think you bring a very important point, which is that anti-angiogenic therapy is probably a critical component or a player with regard to the treatment of HCC despite general attempts from beforehand that did not necessarily work as we just heard, for example, the bevacizumab, but then the REACH followed by the REACH-2 came out with rather more intriguing data.

Chris, the REACH was negative, but REACH-2 was positive. I think the focus, as we just heard from Arndt, was the AFP of more than 400. Tell us first, before we dissect that further, please tell us a little bit more about the data of the REACH-2 so we can try to put it in perspective.

Dr.Chris Verslype:  First, to summarize REACH-2, it's really focused on second line HCC following sorafenib progression or sorafenib intolerance. This is an important population, and especially those patients with the high alpha-fetoprotein, and it was already touched by Arndt, that it is really a population with a poor prognosis. They have about a median survival of maximum five months, patients with good liver function, high alpha-fetoprotein, and intolerant or resistant to sorafenib.

This population, when they are exposed to ramucirumab, what we see, we see a prolongation of overall survival of about three months. That's what we see in most of these trials on HCC, that is survival advantage lies in the range of treatments that patients got extra with a hazard ratio of about 0.7. This is quite consistent. These are the main results of the REACH-2.

Of course, it was associated also with the gain of progression-free survival. These data are very strong, very valid, and very relevant also for clinical practice. What's the presentation of today, here at the ESMO World Conference, it focused on a post-hoc analysis of a group of patients that were either were not treated with TACE prior in their history. It seems that whether you get TACE or not, even with a longer diagnosis of HCC, it made absolutely no difference in this patient population.

This is an interesting finding that, for this subgroup, there is an equal benefit when you give them ramucirumab. The third aspect is that the safety is excellent in these patients. The side effects of ramucirumab are mainly related to hypertension. In more than 10 percent of patients, you have a grade 3 hypertension, which can be managed very good in clinical practice and you don't have the side effects of angiogenics like TKI, sorafenib, rego, and so on. They don't have these cumbersome side effects for patients.

It's a different safety profile, it's manageable, and you have a nice benefit.

Dr. Abou-Alfa: Well, we're hearing a lot of data over here but it's quite fascinating. If anything, the REACH despite, as we heard from both Arndt and Chris, was negative but there was a pre-planned analyses with regard to the patients with high alfa-fetoprotein more than 400 that was really the trigger to do the REACH-2 study, which, as we heard also from Chris, was positive with the improvement in survival of 8.5 months for the patients with the ramucirumab versus 7.3 for the placebo.

Then, we heard a nice collection of the two studies together that was presented not that long ago by Dr. Levett at the ASCO meeting in Chicago where pretty much the improvement in survival went up to more than 10 months versus about 6 months for the placebo arm. No doubt, this kind of like brings in a little bit of very important perspective, one of them I think we're totally comfortable with, which is that this is definitely an anti-angiogenic effect that's needed for the tumors to be controlled on.

I have to admit that many of us are still perplexed with the alpha-fetoprotein story. I'll go back to Arndt. That alpha-fetoprotein, what do you make out of it?

Dr. Vogel:I mean, it's really difficult to understand, and we can't explain it at the moment I guess. What Lilly at the moment is doing is doing all these subgroup analyses, and I think this is a very good idea because now, we really need to learn and understand what is the best sequence, how do we use the drugs, when do we use the drugs. I think we are learning really a lot at the moment.

I can't really answer your question, but in respect to what we have learned today about TACE, I think it's good to see that pre-treatment with TACE has no effect on the efficacy of ramucirumab. When we talk about HCC, we always need to keep in mind that we are talking about two diseases, the chronic liver disease, impaired liver function, and the tumor. There always needs to be a balance between we need to protect the liver and we need to be effective against the tumor.

TACE is, I think, a highly effective treatment, and I like it a lot, but we need to be careful that we do not over treat our patients with TACE because this can have an effect on liver function. Why I am saying this is because there was also an interesting subgroup analysis at EACR where they looked at the efficacy of ramucirumab in respect to liver function. They used the IB score and Child-Pugh A 5A6 subgroup. I think specifically in this high AFP group, liver function has also a very important prognostic role.

When we think Child-Pugh A, these are our best patients because they're candidates for clinical trial. When you think Child-Pugh A, it's Child-Pugh A, but it's not that simple. When we looked specifically in A5 and A6, or AB-grade 1 versus 2, so minor differences in liver function, it has a high impact on prognostic impact. Median survival in the AB-1 in the Child-Pugh A group was around 10 months, but in the AB-2 and Child-Pugh A7, uhh, A6 group, it was only around 6 months. So clear prognostic impact on liver function in this Child-Pugh A group.

When we look at efficacy, the efficacy in the AB-1 Child-Pugh A-5 group had a hazard ratio of around 0.6. In the AB-2 and Child-Pugh A-6 group, it was 0.8. It's just retrospective, but you could argue that liver function might be both prognostic and also predictive for our systemic treatments.

Having said that, we need really to look at the use of TACE. I think there needs to be this balance. If TACE is effective, of course, we should use TACE. When we see that we do not really get the deep response, just stable disease with TACE, I think we really should, using systemic therapy, switch early so that we have patients with good liver function because liver function will affect the efficacy of our systemic treatment.

Dr. Abou-Alfa:I like very much what you said. If anything, Arndt, I totally agree. This is very important is that with the advent of the several therapies that can be used in systemic disease, the idea to try to hold off the patients in regard to local therapy like, for example, transarterial chemoembolization or TACE forever is not probably the right thing to do.

This is data that, today, as we just nicely heard from Chris, is suggestive again, most importantly is to move the patients into systemic disease and systemic therapy setting when appropriate rather than push the argument all the way to push as much TACE as we can. That's really the critical component of that discussion.

I would like to go back one more time to the alpha-fetoprotein. I'd like to ask Chris, the alpha-fetoprotein...I'll give you the scenario. If a patient has hepatitis-B and related HCC, they have alpha-fetoprotein of like half a million, it doesn't mean much to me because it's hepatitis-B. On the other hand, the hepatitis-C, it was like a normal alpha-fetoprotein, it also doesn't mean much to me.

We understand that to be related possibly to some of the disease, but here for the first time, it's being looked at as being an indicator for response to certain therapy. Tell us a little bit more.

Dr. Verslype:Yeah, the story of alpha-fetoprotein, this is for hepatologists, of course, we have a hate and love relation with alpha-fetoprotein. For screening, we know it has been said not to use it because of false-positives, but really, there are some arguments that it's a prognostic parameter. It is in association with vascular invasion, more aggressive the disease. There is a relation to stem cell features in certain classifications. It's, for sure, a more aggressive course.

We know in Asia, more hepatitis-B, more advanced disease, more metastasis, it's a different population than the classic alcoholic or the NASH population. Alpha-fetoprotein, the subgroup is a prognostically poor group and it seems that you can rescue this high alpha-fetoprotein group with this new drug, with ramucirumab and that you can offer survival perspective to these patients.

For me, it's a marker of aggressiveness. The question is this cut-off of 400 is very intriguing. What will you do with a patient of 350? We know in the REACH-2 trial that investigators have rated and followed the patients for a while to get this 400 mark. Then, the question is how will we do and use this in clinical practice?

The main message would be it's a marker of progressiveness. We have this drug. We know in these high levels of alpha-fetoprotein of half a million, as you say, then I would propose if the patient has a good liver function, of course, and you have to treat the hypertension, you have to be aware of the side effects. It stays a good option.

Dr. Abou-Alfa:Yeah, please Arndt, go ahead.

Dr. Vogel:One point, I agree and I like your comment on hepatitis-B because it was quite obvious. We have this cut-off of 400, and I completely agree it's kind of a marker for more aggressiveness. When we look at the subgroups for the Asian population, they had significantly higher AFP median than compared to the non-Asian patients. It was maybe like three times as high and a lot of hepatitis-B as Chris said.

When you look at the efficacy and the survival data, they both are very similar so indicating more AFP does not necessarily mean worse prognosis. It's more like we have this cut-off, high AFP, then it's a poor prognosis, but it's not really that you can say, yeah, as I said, higher AFP, worse prognosis. It's not that simple. It's kind of complicated.

Dr. Abou-Alfa: No, no, if anything, I would challenge you, all of us, and I would probably ask both of you or whoever would like to answer...Most of the other drugs including cabozantinib, for example, as just an example, how sure of that the AFP relationship is there as well? Are we just happen to be taking a snapshot, picture of the patients with the high alpha-fetoprotein in that ramucirumab study a little bit at a later time or is it really a very special different population that ramucirumab would be probably more beneficial for that population because of the high AFP?

Dr. Vogel: The only thing I can say is that for ramucirumab, it has been looked at in a prospective way in a clinical trial specifically targeted. For cabo, it's separate analysis again but it seems that the message is that the signal is going there. It's there somewhere, but at least, it has been best prospectively studied in the ramucirumab trials.

That's the reason I have to congratulate the investigators and all the supporting staff and everything of this trial because this is a major undertaking. It's, in fact, the only good predictive marker as such for the kind of therapy that we have in HCC.

Dr. Abou-Alfa:I hear you, and I agree with you. Arndt, what we're going to do tomorrow...Tomorrow is Sunday, but on Monday morning, patients come to you. Where are you going to place ramucirumab in regard to sequence of therapy and how much differing is there going to be by the AFP level?

Dr. Vogel: It depends. Actually, so far, we do not really have clear data what is the best sequence. What we know is that we have a lot of drugs available and we can choose which is good. Then, I think we really need to look at the course of the disease in first line.

If somebody has a really long response to sorafenib and we have the data for the rego sequence, which is also very nice, so I think there's also an argument to use if somebody tolerates sorafenib, has a median treatment regimen in the rego trial of seven months. If you have long response to sorafenib, I think we have a good argument to continue with regorafenib and not switch to TKI.

On the other hand, I mean, most of our patients do not tolerate these TKIs so well. Having an antibody available in our options I think is really great because then we can really tailor it more to the patient. If they do not tolerate it, if they have diarrhea, if they have fatigue and stuff like that, it's kind of a TKI holiday, which is also nice.

I would make it really dependent on the liver function, as I said before, on tolerability of sorafenib or lenvatanib in first line, and of course, you have to take into account ramucirumab and, as Chris said, if somebody has an AFP level of 350, 450, if he tolerates sorafenib well, I think we could also go for rego.

If he does not tolerate sorafenib well, I would also use ramucirumab with an AFP of 350. I think this cut-off is a little bit arbitrary and we can't really say that it's a strong and very hard cut-off. I think it's not an easy task, and we need really to see how we sequence best. What I really would like to see is, and there are more and more data coming out, how these drugs affect liver function because what I said before, we talked a lot about liver function with local therapy, how it deteriorates. We are seeing from the lenvatanib trial that liver function also declines on systemic therapy.

I think this is something we really need to look very closely at. We need to measure liver function during systemic treatment, and we need to see it. I hope we will get these data even if they are just post-hoc in another disease. We need to see how these drugs affect liver function.

We have placebo as a control so we do see that liver function also declines in patients treated with placebo just due to the progression of disease. It's always a combination of progressive tumor and maybe side effects of the drugs. We need to see this data. Personally, I think we have only a small window of opportunity for systemic treatment.

If we do see one drug preserves liver function better than the other drug, then this would be my choice in second line. There's more data we need to see, really.

Dr. Abou-Alfa:I totally agree. If anything, however, it has been an incredible couple of years as we just heard from Dr. Vogel. Now, we have in first line, sorafenib, which actually started the race almost more than 10 years ago now. We have now in second, correction, in first line also, lenvatanib, quite impressive data comparability to sorafenib with regard to survival outcome but also with improvement in regard to PFS and in regard to response rate.

In second line, we have regorafenib, beautiful data, especially in connection with prior sorafenib exposure. We have cabozantinib. Interestingly here, despite that, yes, we don't like side effects but data that have shown that cabozantinib actually can help improve on the outcome of patients if the side effects are there. This has been shown with different drugs among which, regorafenib, sorafenib, etc.

Of course, we have also the ramucirumab as we just nicely presented, especially in the setting of the high alpha-fetoprotein. These are literally five TKIs, but we can't of course wrap up the discussion without at least bringing in checkpoint inhibitors. A lot of has went on in regards to checkpoint inhibitors.

Maybe I'll ask, Chris, your thoughts on the data on the immunotherapy.

Dr. Verslype:For me, the overall results of the trials are very disappointing, but as a clinician-- and I have seen some powerful effects in individual patients so there is, for sure, a subgroup of about 15 to 20 percent of patients that really have a benefit. But, the studies fail to identify these patients, and this is a very important issue that should stimulate us, in fact, to continue on the research track and find these patients.

Of course, the way to go is the combination of anti-angiogenic therapy and really, immune checkpoint inhibitors are other ways like we see in other fields. This is really the way to go forward. For me, these drugs are there and TKIs and anti-angiogenic agents are more than ever alive now because of the major studies on immune checkpoint inhibitors. They, in fact, failed their primary endpoint, but still there is a big way to go in research terms.

Dr. Abou-Alfa:Well, what Dr. Verslype is talking about here is quite important outcome data in regard to the use of pembrolizumab versus placebo in second line setting that was negative, as was reported at ASCO in a press release, that reported that nivolumab versus sorafenib in first line is also negative.

Let me just wrap it up by asking Dr. Vogel, are you surprised, not surprised?

Dr. Vogel:First of all, I would like to ask are they really negative? If you look at the keynote data when you compare the Phase 2 study and the Phase 3 study, the results exactly match. Usually, we have...In the Phase 2, we have a lot of hopes, very long survival, and then in the Phase 3, it drops a lot. In this case, it was almost exactly the same.

The overall survival was even one month longer than in the Phase 2 study. When we look at the statistics of overall survival of 0.02, PFS of 0.0002, I mean in the path, it was a positive trial. I still have to struggle a little bit to understand the statistics here. And tt's clinically meaningful. It's statistically, in my old-fashioned view, a positive study. When we look at the nivo data you just mentioned, we also have a hazard ratio of 0.85 and a P value of 0.007 I think.

It's also a very close cut. We, of course, need to see the data. I agree with Chris. It's a subgroup of patients. We have hyper-progressives. We have non-responders. We have responders. It's a mixed bag, but we all have seen these great responders without any side effects, complete responders.

Is it over? No, it's not. It can't be over because, I mean...I think we have to view these checkpoint inhibitors in a different way. I don't know how, but if I would have HCC, I would be treated with a checkpoint inhibitor because you have this chance of having a great response, a long duration of response.

For the authorities, it's a struggle because so many of these studies are negative. From a clinical point of view, yeah, we need to find biomarkers, which will be extremely difficult and we need to find a way on how we can integrate these drugs, in my view, in the treatment. Usually, we see the responses very early on so maybe we start and we stop when we do not see a response. I don't know.

But to say it's over, no, I think that would be also not the right way to go.

Dr. Abou-Alfa:I totally agree. If anything, this is quite fascinating. What we heard here is really an update on the checkpoint inhibitor data, as we mentioned, pembrolizumab versus placebo in second line setting, nivolumab versus sorafenib in first line setting are reported as negative. However, I totally agree with Chris that there is no doubt that these drugs work, but however, they work in very specific settings for specific patients.

It's a matter of a job that we really identify those patients and really make sure that we give them the appropriate therapy when needed. On the other hand, it's really a tour de force in regard to literally five TKIs already approved as we, again, summarize, sorafenib, lenvatanib, regorafenib, cabozantinib, and ramucirumab.

Ramucirumab is the one we spent quite a bit of time talking about in regard to this perplexing point, with regard to the alpha-fetoprotein more or less than 400 as being a director in regard to if the drug works or not. 

All in all, seven drugs in HCC within literally the span of no more than two years is probably most valuable and important for our patients.

It's a really great honor to really work on and try to help advance the disease. Again, on behalf of Dr. Vogel and Dr. Verslype, I thank you very much for joining us. Thank you.