2016 ASCO Annual Meeting Research Round Up – Melanoma, with Ryan J. Sullivan, MD

September 22, 2016
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In today’s podcast, Cancer.Net Associate Editor Dr. Ryan Sullivan discusses some of the research on melanoma presented at the 2016 ASCO Annual Meeting. 



ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology known as ASCO - the world's leading professional organization for doctors who care for people with cancer.

In today's podcast, Cancer.Net Associate Editor Dr. Ryan Sullivan discusses some of the research on melanoma presented at the 2016 ASCO Annual Meeting. Dr. Sullivan is a medical oncologist at the Massachusetts General Hospital Cancer Center. The ASCO Annual Meeting is the premier educational and scientific event where physicians, researchers, and other healthcare professionals gather to discuss the latest in cancer care and treatment. This Cancer.Net podcast helps put new research findings into context and explains what they mean for patients. ASCO would like to thank Dr. Sullivan for summarizing this research.

Dr. Sullivan: Hello. My name is Ryan Sullivan. I'm a medical oncologist at Massachusetts General Hospital Cancer Center in Boston. And I'm here today to discuss some of the exciting developments in the field of melanoma oncology that occurred at the 2016 ASCO Annual Meeting. The first topic I'm going to discuss is to describe some of the details that were presented about a phase III trial of a drug called binimetinib versus a drug called dacarbazine in patients with NRAS-mutant melanoma of the skin. And this trial went by the moniker NEMO.

This is a trial that enrolled patients with NRAS-mutant melanoma. The background about this trial is that between 20 and 30% of patients with melanoma have a tumor which is mutated for a gene called NRAS. NRAS is a very important gene in the pathway called the MAPK pathway. And in this pathway are other genes such as RAF, and MEK, and ERK, which when activated can drive the tumor to grow, to spread, and to even suppress the immune system. The important part about this pathway is that there are a number of proteins that are potentially druggable, and those include the ones I just mentioned: RAF, MEK, and ERK. And in the NEMO study the idea behind randomizing patients to the drug called binimetinib is that this drug is a MEK inhibitor - and that's spelled M-E-K. And MEK inhibitors have been shown to be effective in BRAF-mutated melanoma, which is present in about 50% of patients. And in fact, two MEK inhibitors, one called trametinib and the other called cobimetinib are approved to treat patients with BRAF-mutant melanoma.

But there is also a phase II trial - so, an earlier stage trial - that was published two to three years ago that showed that this drug binimetinib MEK inhibitor was associated with response in about 20 or 25% of patients, which would be predicted to be higher than patients who might be treated with a chemotherapy. So, this trial was a randomized trial, which means that patients either received treatment with binimetinib, or received treatment with dacarbazine, which is a chemotherapy. And they were chosen to go onto one of the two arms based on random selection, so it wasn't by choice of the investigator. And in the trial, 402 patients were randomized in what's called a two-to-one fashion, which means two patients out of three were randomized to receive the MEK inhibitor, binimetinib, and one out of three patients was randomized to receive the chemotherapy. This was not a blinded study, meaning that everybody knew what they were getting when they were being treated.

The important point of this trial is that they were looking to see how long the disease would remain without progression, meaning that the disease would not grow. And that was the primary endpoint, was the time to progression of disease - something called PFS. Other important endpoints included whether patients were alive or not, or more likely to be alive if they received one therapy or another, the disease control rate, and the response rate. Patients who enrolled on this study were allowed to have had prior therapy as long as that therapy was an immune therapy, but they were not allowed to have received a prior MEK inhibitor or a prior chemotherapy.

The data from this trial are as follows. Of the patients who enrolled there was very similar types of NRAS mutations, very similar age, gender, functional level, and prior therapy, when we compare patients who went on the therapy versus patients who were not on the therapy. The primary endpoint, which again was this endpoint called progression-free survival, which is essentially measuring and comparing the time of progression in patients who received the MEK inhibitor versus a chemotherapy, was actually improved for the patients who received the MEK inhibitor binimetinib. And when you compare the two groups, patients were about 38% less likely to progress at any time that they received binimetinib than if they received chemotherapy. And this finding was statistically significant.

It didn't appear that there was any one group that was substantially superior than another when you looked at what we call the subgroup analysis, with one exception. And that was patients who received prior immune therapy seemed to actually do better with the binimetinib, and were significantly improved when the binimetinib versus the dacarbazine group than when you compared the groups and patients who had not received prior immune therapy.

The other pieces of data that were generated from this trial were the response rates. And in fact, patients who received binimetinib had a significantly higher response rate. 15% of patients had responses compared to 7% of patients who received the chemotherapy. When we talk about disease control rate, we're talking about whether or not the disease got smaller or whether the disease didn't grow. And when you looked at that percentage, 58% of patients had control of the disease that lasted at least four months compared to 25% of patients who received dacarbazine.

In a preliminary analysis comparing whether patients were more likely to be alive if they received binimetinib versus dacarbazine - and I should say that we actually commend the authors of this study for presenting this data because it was premature, but they felt that they really wanted to show this - it didn't appear that there was any advantage to binimetinib compared to dacarbazine. Again, meaning that patients who received binimetinib were no more likely to be alive than patients who received dacarbazine at any time point - 3 months, 6 months, 12 months, 15 months, et cetera.

The side effect comparison of the two treatments were very interesting. As expected, the chemotherapy was associated with more side effects in terms of causing reduction in blood counts. But, binimetinib, which is a therapy that often causes skin side effects, was much more likely to cause skin side effects than dacarbazine. There were also a few blood tests which were more likely to be abnormal if patients received binimetinib compared to dacarbazine, and side effects like diarrhea, nausea, and vomiting were more likely to be seen with binimetinib, particularly diarrhea. Vomiting was perhaps a little bit more common as well. Some other side effects from binimetinib that were more likely to be seen included swelling of the feet, which happens in about 30% of patients who receive that drug. But, the levels of fatigue seem to be similar, or perhaps even a little bit better in the binimetinib group compared to the dacarbazine group. Otherwise, the treatments seemed to be associated with similar side effects.

The conclusions of this study were as follows. Binimetinib did indeed meet its so-called primary endpoint, which was that patients were more likely to have their disease remain free of growing than patients who received the chemotherapy dacarbazine. The improvement in this outcome was modest, and namely the progression-free survival hit a median, meaning half of patients were likely to progress about three months in to binimetinib and about a month and half in to dacarbazine. This benefit was seen in patients who had not received prior therapy, but also in patients who had received prior immune therapy. And in fact, when you looked at specifically the patients who had received prior immune therapy, it looked that there may be even more benefit of binimetinib compared to chemotherapy and those folks.

Ramifications of these data are-- is that it's possible that binimetinib could be approved by the FDA based on this data, and if it were, it could potentially offer another therapy for the treatment of melanoma in a new subgroup of patients. Because the majority of patients don't appear to have responses, and most patients who receive this therapy will have growth of their disease within a few months speaks to the need for better therapies for, one, melanoma in general, but two, this specific subgroup of patients with melanoma NRAS-mutated patients. And in fact, there are now trials that are underway looking at combinations of this MEK inhibitor called binimetinib with other therapies, and hopefully we will have more definitive data on those types of treatments in the near future.

The second trial that I'd like to talk about is an interesting study that looked at the long-term outcomes of patients with BRAF-mutated melanoma who were treated, again, on a phase III trial, and the study was called the COMBI-d trial. This was a trial of a BRAF inhibitor called dabrafenib, plus a MEK inhibitor called trametinib compared to patients receiving just the BRAF inhibitor dabrafenib. Again, this was a randomized phase three trial, and the rationale for this study is that about 50% of patients have a mutation in the gene called BRAF. These mutations lead to activation of a pathway called the MAPK pathway, and this leads to highly active proteins in this pathway which drive tumor growth, tumor cell survival, metastasis, and suppression of the immune system.

The proteins that are susceptible to being blocked by drugs include BRAF and MEK. And to date, there are two BRAF inhibitors, dabrafenib and vemurafenib, and two MEK inhibitors, trametinib and cobimetinib, which are approved for the treatment of patients with BRAF-mutated melanoma. Importantly, there are three randomized phase III trials, which compare BRAF and MEK inhibitor therapy versus single-agent BRAF inhibitor therapy. One is the COMBI-d trial, which I'll be talking about today. One is the COMBI-v trial, which is looking at the combination of dabrafenib plus trametinib versus vemurafenib. And one is called the coBRIM trial, which is looking at the combination of vemurafenib plus cobimetinib compared to patients who received single-agent vemurafenib.

What has been previously presented at past ASCOs and has been published in peer-reviewed publications, all three of these trials showed superiority of the combination of a BRAF and MEK inhibitor compared with a single-agent BRAF inhibitor. And specifically, patients were less likely to have their disease grow and more likely to be alive if they received the BRAF and MEK inhibitor combination versus receiving just the BRAF inhibitor. These trials led to the approval of two combinations of therapy, both dabrafenib and trametinib and vemurafenib and cobimetinib for patients with BRAF-mutated melanoma, and in fact, have led to the change in standard of care that when patients are to receive a BRAF inhibitor therapy for their BRAF-mutated melanoma, the standard of care is now to receive two drugs instead of one.

The trial that was presented at ASCO was an update of this COMBI-d trial. And again, the COMBI-d trial, it enrolled 424 patients and compared the combination of dabrafenib, trametinib versus dabrafenib plus a placebo, which is a sugar pill that's given in combination with the dabrafenib so that nobody who's on the study, and none of the doctors who are treating people on the study know whether the patient received trametinib or received the placebo. The goals of this trial were to see whether patients did better if they received dabrafenib and trametinib versus dabrafenib. And by defining what better is, that patients were less likely to have the disease grow, more likely to be alive, and more likely to have a shrinkage of their tumor, so-called response.

As I said, over 420 patients were enrolled on this trial. This was a one-to-one randomized trial, which means that patients had a 50/50 chance of being enrolled to the combination, or enrolled to the singulation of dabrafenib plus the placebo. The interesting part of this study is that this is an analysis looking to see whether or not there were factors that could be identified from when you start a patient on therapy that might predict whether or not they were going to be alive and remaining on therapy many years later. And in fact, this was an update of the so-called overall survival analysis, which was the final analysis performed a year before this meeting, and was really looking to see what was going on three years after patients started the therapy.

When we looked at-- or rather, when the presenter looked at the difference between the two populations, they were very similar - pre-treatment versus the combination, received therapy versus those who received single-agent therapy. The long-term outcomes are quite interesting. Three years, and again, this trial closed over two years ago, so the three-year numbers are quite important. The, what we call, progression-free survival, which is whether patients' disease grew on therapy, was 22% in the patients who received combination therapy, meaning that almost a quarter of patients who were initially treated with the combination, remained on the combination, and without any evidence of the disease growing, three years after starting therapy. Compared to patients who received just dabrafenib therapy, that number was about 12%. When we looked at whether patients were likely to be alive, just a little under half of patients were alive at three years if they received a combination of therapy as opposed to about a third of patients who received the single-agent therapy. This is very mature data, and to date is one of the longest follow-ups showing that a substantial minority of patients are having long-term survival, who were diagnosed with melanoma. Obviously, in this scenario, those patients received two therapies for their BRAF-mutated melanoma.

When looking at some of the factors that might predict whether patients were likely to be alive and likely to be without progression of the disease, there were a few that really stuck out. One is whether when patients start therapy they have an elevated blood test called LDH. LDH is a substance that's released by tumor cells and normal cells alike. LDH has been well known to be a predictor of outcome in patients with melanoma. And patients who have a high level are those patients who do worse, and patients who have a low level, those patients do better. And in fact, this trial showed that held up quite well that patients who had a normal LDH lived longer and lived longer without needing another therapy.

However, there were a few other interesting numbers to be taken from this. And patients whose LDH was normal and who had less than three sites of disease, meaning a site of disease could be the liver. A site of the disease could be the lungs. A site of the disease could be the skin or lymph nodes. Of the patients who had less than three sites of disease, over a majority of patients were alive at three years, and nearly 40% of patients didn't need another therapy. They remained on treatment without their disease growing at three years. That's a really staggering number.

The investigators of this study also looked to see whether or not there were any findings in the tumors that might predict outcome. I think it's best to say that there were some interesting data that was shown, and that there may be some findings in the tumor in addition to a BRAF-mutation that might predict a better or worse outcome. But, right now we don't know whether approaching those patients with different types of therapy, including, perhaps, drugs that might block pathways, that new mutations might be activating, whether that strategy is either safe or effective in patients with BRAF-mutated melanoma. But at least it does suggest that there are some hypotheses, some thoughts, about how we might make this type of therapy better.

In the end, I think the most exciting part about this presentation was the fact that almost half of our patients are alive, based on a trial that started several years ago, when they received BRAF MEK inhibitor therapy for BRAF-mutated melanoma. This is unprecedented survival data. I think it's also important for us to understand when we see this data, that this is not us declaring victory, but rather us understanding and appreciating where we stand right now, and then trying to gain a better understanding of how it might be better. And the authors of this presentation do, in fact, begin to describe, first, ways we might be able to select patients just on how they are - what does their blood look like, how well are they when they start the therapy - and then also, what else is going on in their tumor that might predict that they are going to do great with this therapy, or that maybe they need a third drug or a different combination of therapy. But, in the end, I think this specific presentation really highlights how effective the targeted therapies for melanoma, which were developed over the past five to ten years, are translating into clinical benefit in patients with this disease.

The third topic I'd like to talk about is a similar study to the one that was presented about BRAF-mutated patients and looking at what we call the three-year follow-up. So this study was presenting data from patients who received a therapy called pembrolizumab, which is an anti-PD-1 antibody. It's approved by the FDA to treat patients with melanoma. It is an immune therapy and it had been studied in a number of different trials, including phase I trials, phase II trials, and phase III trials, and it has shown to be superior to chemotherapy after patients had received a drug called ipilimumab. It's been shown to be superior to ipilimumab when patients have previously been untreated, and it is - along with a PD-1 therapy called nivolumab - one of the standard first-line therapies for the treatment of patients with melanoma.

The data that was presented in this meeting was the data from 655 patients who all had melanoma, who were treated on the first trial of pembrolizumab. The data was really to look at the long-term outcomes of patients. When looking at the results of this trial, it's important to note that the 655 patients who were treated looked very similar, when we compare their baseline characteristics to patients who were treated with other types of therapies. These are a fairly representative group of melanoma patients, meaning that when we're looking at long-term outcomes, and we would rightly be able to compare the long-term outcomes that we're seeing in this patient population to other patient populations previously looked at for melanoma.

In this data set, about half of patients had previously received ipilimumab, about a third of the patients had received previous chemotherapy, and almost 20% of patients had received previous BRAF targeted therapy. The majority of patients tolerated therapy well, and in this data set the severe and life-threatening side effect rate was in the 14 to 17% range. The most common immune-related side effects, which are side effects that are driven by a patient's immune system in response to these therapies, the most common was inflammation of the thyroid, which is largely either increased or decreased function of the thyroid gland. That happened over 10% of the time. Inflammation of the lungs, which happened about 4.5% of the time. Inflammation of the colon, which happened a little over 3% of the time. And inflammation of the liver, which happened approximately 1% of the time.

When looking at the long-term outcomes, previously what had been shown is that at about two years, half of patients were alive who received treatment as part of this group of patients, and at the three-year mark is about 40%. Similar to the data that was presented at this meeting with BRAF and MEK Inhibitor therapy, this is unprecedented data. We've never had these types of outcomes in patients with melanoma before. And though we certainly need to do better than having only 40% of our patients alive three years after starting treatment, what I think is important to state is that this is far better than we've ever done before. And it gives us hope that these types of therapies and perhaps more effective therapies down the road can in fact increase that number dramatically higher.

When we look at some of the subgroups, it appears that the dose of the treatment didn't make a difference. Patients were a little bit more likely to do well if they'd not been treated previously than if they'd received previous treatment. And I think what was also very interesting was that if patients hadn't received treatment before at three years, about a fifth of them were likely not to have had their disease grow. And if we looked at patients who hadn't been treated before, almost a third of those patients at three years had their disease remain under control without any growth. And when we look at how long responses last, it appears that most people who respond will maintain their response, and of the patients who did respond, about three quarters of them remained in response two years after treatment, and about 60% of the number of patients who had responded and were being followed far out as three years was pretty low, but somewhere probably between 50 and 60% of patients remained in response.

So I think the take home message there is if you have a response to pembrolizumab and probably to the drug nivolumab, that's likely to be maintained for a long time. And the data that was presented here, which is very exciting, suggested that would be maintained for years in the majority of patients. About 10% of patients who are in this group of patients had what we call a complete response, which means their disease went away. And in those patients, and there is 95 such patients who are identified as having a complete response, the majority of these patients stop therapy. In fact, all but 19%, which is 18 patients, stopped therapy. Now, some patients stopped because they have side effects, and that was about 15% to 16% of patients. But most patients stopped because they were having a great response and their doctor talked to them, and they said, "Maybe we should stop therapy and see what happens." So 61 of the 95 patients fell into that category.

And what's really, really cool is that almost all of these patients who stopped therapy remained in response with two years or more of follow-up. And that is really exciting, and it's really exciting because that is the first bit of data that suggests that if patients have an amazing response to these drugs, that it may not be necessary to have further therapy, and those patients potentially may never need therapy again. And the numbers that we have is that 59 of the 61 patients who had a complete response and came off therapy because the decision was made with their doctor to come off therapy, maintain a response at a rate of 97%, and follow-up was at least two years in all but a couple of these patients.

So I think the biggest take-home points from this study are two-fold. One, the long-term survival in patients who received this therapy is as good as with any other therapy we've seen before, and by long term, I mean three years of follow-up. And that patients who have responses, those responses are likely to last, and they're likely to last for years. And finally, if patients have a complete response, their providers can confidently say that, if we stop this therapy, you are very, very, very, very, very likely, greater than 95% likely to have this response maintained. And that changes the way we approach patients. It changes the way we think about these therapies and how long we should be giving these therapies to our patients.

ASCO: Thank you, Dr. Sullivan. To learn more about the science presented at the 2016 ASCO Annual Meeting, visit www.cancer.net/ASCOannualmeeting. If you have questions about whether new research may affect your care, be sure to talk with your doctor.

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