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Molecular Testing in Melanoma: BRAF and PD-L1

Panelists: Jeffrey S. Weber, MD, PhD, Laura and Isaac Perlmutter Cancer Center; Robert Andtbacka, MD, CM, Huntsman Cancer Institute; Omid Hamid, MD, The Angeles Clinic and Research Institute ; Jason J. Luke, MD, FACP, University of Chicago; Michael A. Postow, MD, Memorial Sloan Kettering Cancer Center; Hussein Tawbi, MD, PhD, UT MD Anderson Cancer Center
Published: Friday, Jul 27, 2018



Transcript: 

Jeffrey S. Weber, MD, PhD: Once they have stage III disease, do you all always get BRAF and PD-L1 testing? Omid, if you have a stage III patient that’s in front of you, whom Robert has already operated on, are you going to then see the patient and get BRAF testing?

Omid Hamid, MD: We now try to do it on the majority of patients because of the decisions to be made in the adjuvant setting. In the community, sometimes they’re referred without the tissue available. We would like to have that data in order to know and not delay if there is a metastatic recurrence. With the patient, we discuss that most of the data will be used in the case of metastatic disease, but we do get that data. Ultimately, some of the other mutational analysis that’s done can help us with phase I and other therapies down the line.

Jeffrey S. Weber, MD, PhD: OK. It sounds like you’re going to get it, but it may not impact your immediate management…? It may help you somewhere down the road, if they do progress…? What about PD-L1? Does anyone routinely get PD-L1, Hussein?

Hussein Tawbi, MD, PhD: Not really. One of the challenges of testing for the BRAF gene in those stage 3 patients, especially stage 3a patients, is that they may have some primaries in only microscopic diseases in the sentinel lymph nodes. So, the availability of tissue is a very important aspect. But I completely agree with testing for BRAF and knowing that as early as possible in the patient’s history.

From the PD-L1 perspective, PD-L1 positivity is associated with higher response rates, but PD-L1–negative patients still respond. We really don’t use that to make determinations of whether we should treat our patients or not. If a patient was on a clinical trial, we make a point of testing PD-L1 in that setting, but we don’t use it for clinical decision making, especially not in the adjuvant setting.

Jeffrey S. Weber, MD, PhD: Michael, tell me about the practice-changing trials. There have been 3 trials that are large, randomized trials, that I think have been practice changing. They have matured within the last year, which is pretty remarkable in melanoma. Tell me about the data from these 3 trials.

Michael A. Postow, MD: It’s been great. There have been 3 positive phase III studies. One study looked at BRAF-mutant patients. It tested the combination of dabrafenib plus trametinib versus observation in stage 3a, 3b, and 3c-resected melanoma. That study was very, very positive for its primary endpoint of recurrence-free survival. It also looked like the overall survival was improved, although the statistics were a bit of an early look. So, it’s hard to definitively say that the overall survival was improved, but I think there was clearly a very significant recurrence-free survival advantage in BRAF-mutant patients getting dabrafenib/trametinib over observation. That was the first phase III study.

The other 2 phase III studies that were positive were both PD-1 trials. One study tested the PD-1 inhibitor nivolumab versus the CTLA-4 inhibitor ipilimumab, demonstrating that nivolumab was better than ipilimumab—not just better in terms of improving recurrence-free survival but also better at reducing toxicities. So, if you’re deciding on adjuvant ipilimumab or nivolumab for a patient, I think the answer is now clear—we should choose nivolumab because of the higher recurrence-free survival benefit and lower toxicity rate.

The third phase III study that came out tested adjuvant pembrolizumab versus observation. That study included stage 3a, 3b, and 3c melanoma patients. That was also positive for improvements in recurrence-free survival. So, we now have a win for pembrolizumab over observation, a win for nivolumab over ipilimumab, and a win for dabrafenib and trametinib over observation, alone. There were slightly different populations in some of these trials. The nivolumab study had resected stage 4 patients and no stage 3a patients. There have been many discussions and thoughts about interchangeability between these different agents.

I think the bottom line summary is, it’s impossible to really tell the difference between nivolumab and pembrolizumab in the adjuvant setting, in terms of efficacy. We don’t really have head-to-head data, so it’s really hard to say whether dabrafenib and trametinib is better than PD-1 in the adjuvant setting either. Some of those conversations are really tough. What do you choose for a BRAF-mutant patient—BRAF/MEK or PD-1 inhibitors? If you have a BRAF-mutant wild-type patient, your only choice is PD-1, at least over ipilimumab and observation, if you want to improve recurrence-free survival. We’re still waiting on overall survival data, of course.

Jeffrey S. Weber, MD, PhD: There was actually a fourth trial, the BRIM8 trial, which we waited quite a while to see the results of. Is there anything that you can glean from those data that would either inform practice or help you to conceive over the next trial?

Michael A. Postow, MD: The BRIM8 trial was another phase III study testing vemurafenib as a monotherapy BRAF inhibitor versus observation. That trial was interesting. It looked at a slightly different patient population than the other studies did. The vemurafenib did show a biologic effect. It did look like it was better to have vemurafenib. But the way that the statistics were designed, it was technically not a positive study. It did not improve recurrence-free survival in the stage 3c-resected group of patients, which was the first cohort that needed to be analyzed. But the most important takeaway from that, for me, is that there was some activity with BRAF monotherapy. However, if you’re choosing BRAF-directed treatment in the adjuvant setting, you’d go with BRAF and MEK—dabrafenib and trametinib.

But also, interestingly, it included patients with stage 2c-resected melanoma. These were patients who did not have a sentinel lymph node involved with disease. It’s a reminder that this is a high-risk group of patients—2c, ulcerated primaries, in many cases. That tells us that we need to test some of these drugs in stage 2 patients. In fact, we have upcoming adjuvant studies of PD-1 drugs like pembrolizumab in higher-risk stage 2 patients that could really impact how the disease is managed. A lot of the patients who recurred, who had stage 4 disease, did not previously have stage 3 disease. They had stage 2, high-risk disease, or even stage 1. That stage 2 trial was a very important study.

Jason J. Luke, MD, FACP: The thing that comes up in my practice—that started coming up as soon as the data became available—is, do we know whether or not the patient has a BRAF mutation at the time that we’re making the decision surrounding adjuvant therapy? There’s all of this great data from BRAF and MEK and now with PD-1. But if you don’t know whether or not the patient has a BRAF mutation, you really can’t make that decision. That’s something in which our community needs to sort of reach back with our pathology and our surgery groups, to expedite getting that information. It’s understandable that patients come in who are obviously concerned. You have to tell them, “You have to go away and come back.”

Now, certainly, that’s a reasonable thing to do. This is a big decision. There are toxicities associated with these treatments, and it’s not something we want to rush into. But certainly, I would advocate that having all of the information at the beginning is better than not having it.

And to the point about stage 2 trials, I completely agree. I think that there is a high-risk population of patients, actually bigger than the stage 3 population, who potentially could benefit from some of these therapies—albeit we have to consider the toxicities and the number needed to treat here. We really have to have a big impact there, otherwise we’re potentially exposing a lot of patients to toxicities.

Transcript Edited for Clarity 

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Transcript: 

Jeffrey S. Weber, MD, PhD: Once they have stage III disease, do you all always get BRAF and PD-L1 testing? Omid, if you have a stage III patient that’s in front of you, whom Robert has already operated on, are you going to then see the patient and get BRAF testing?

Omid Hamid, MD: We now try to do it on the majority of patients because of the decisions to be made in the adjuvant setting. In the community, sometimes they’re referred without the tissue available. We would like to have that data in order to know and not delay if there is a metastatic recurrence. With the patient, we discuss that most of the data will be used in the case of metastatic disease, but we do get that data. Ultimately, some of the other mutational analysis that’s done can help us with phase I and other therapies down the line.

Jeffrey S. Weber, MD, PhD: OK. It sounds like you’re going to get it, but it may not impact your immediate management…? It may help you somewhere down the road, if they do progress…? What about PD-L1? Does anyone routinely get PD-L1, Hussein?

Hussein Tawbi, MD, PhD: Not really. One of the challenges of testing for the BRAF gene in those stage 3 patients, especially stage 3a patients, is that they may have some primaries in only microscopic diseases in the sentinel lymph nodes. So, the availability of tissue is a very important aspect. But I completely agree with testing for BRAF and knowing that as early as possible in the patient’s history.

From the PD-L1 perspective, PD-L1 positivity is associated with higher response rates, but PD-L1–negative patients still respond. We really don’t use that to make determinations of whether we should treat our patients or not. If a patient was on a clinical trial, we make a point of testing PD-L1 in that setting, but we don’t use it for clinical decision making, especially not in the adjuvant setting.

Jeffrey S. Weber, MD, PhD: Michael, tell me about the practice-changing trials. There have been 3 trials that are large, randomized trials, that I think have been practice changing. They have matured within the last year, which is pretty remarkable in melanoma. Tell me about the data from these 3 trials.

Michael A. Postow, MD: It’s been great. There have been 3 positive phase III studies. One study looked at BRAF-mutant patients. It tested the combination of dabrafenib plus trametinib versus observation in stage 3a, 3b, and 3c-resected melanoma. That study was very, very positive for its primary endpoint of recurrence-free survival. It also looked like the overall survival was improved, although the statistics were a bit of an early look. So, it’s hard to definitively say that the overall survival was improved, but I think there was clearly a very significant recurrence-free survival advantage in BRAF-mutant patients getting dabrafenib/trametinib over observation. That was the first phase III study.

The other 2 phase III studies that were positive were both PD-1 trials. One study tested the PD-1 inhibitor nivolumab versus the CTLA-4 inhibitor ipilimumab, demonstrating that nivolumab was better than ipilimumab—not just better in terms of improving recurrence-free survival but also better at reducing toxicities. So, if you’re deciding on adjuvant ipilimumab or nivolumab for a patient, I think the answer is now clear—we should choose nivolumab because of the higher recurrence-free survival benefit and lower toxicity rate.

The third phase III study that came out tested adjuvant pembrolizumab versus observation. That study included stage 3a, 3b, and 3c melanoma patients. That was also positive for improvements in recurrence-free survival. So, we now have a win for pembrolizumab over observation, a win for nivolumab over ipilimumab, and a win for dabrafenib and trametinib over observation, alone. There were slightly different populations in some of these trials. The nivolumab study had resected stage 4 patients and no stage 3a patients. There have been many discussions and thoughts about interchangeability between these different agents.

I think the bottom line summary is, it’s impossible to really tell the difference between nivolumab and pembrolizumab in the adjuvant setting, in terms of efficacy. We don’t really have head-to-head data, so it’s really hard to say whether dabrafenib and trametinib is better than PD-1 in the adjuvant setting either. Some of those conversations are really tough. What do you choose for a BRAF-mutant patient—BRAF/MEK or PD-1 inhibitors? If you have a BRAF-mutant wild-type patient, your only choice is PD-1, at least over ipilimumab and observation, if you want to improve recurrence-free survival. We’re still waiting on overall survival data, of course.

Jeffrey S. Weber, MD, PhD: There was actually a fourth trial, the BRIM8 trial, which we waited quite a while to see the results of. Is there anything that you can glean from those data that would either inform practice or help you to conceive over the next trial?

Michael A. Postow, MD: The BRIM8 trial was another phase III study testing vemurafenib as a monotherapy BRAF inhibitor versus observation. That trial was interesting. It looked at a slightly different patient population than the other studies did. The vemurafenib did show a biologic effect. It did look like it was better to have vemurafenib. But the way that the statistics were designed, it was technically not a positive study. It did not improve recurrence-free survival in the stage 3c-resected group of patients, which was the first cohort that needed to be analyzed. But the most important takeaway from that, for me, is that there was some activity with BRAF monotherapy. However, if you’re choosing BRAF-directed treatment in the adjuvant setting, you’d go with BRAF and MEK—dabrafenib and trametinib.

But also, interestingly, it included patients with stage 2c-resected melanoma. These were patients who did not have a sentinel lymph node involved with disease. It’s a reminder that this is a high-risk group of patients—2c, ulcerated primaries, in many cases. That tells us that we need to test some of these drugs in stage 2 patients. In fact, we have upcoming adjuvant studies of PD-1 drugs like pembrolizumab in higher-risk stage 2 patients that could really impact how the disease is managed. A lot of the patients who recurred, who had stage 4 disease, did not previously have stage 3 disease. They had stage 2, high-risk disease, or even stage 1. That stage 2 trial was a very important study.

Jason J. Luke, MD, FACP: The thing that comes up in my practice—that started coming up as soon as the data became available—is, do we know whether or not the patient has a BRAF mutation at the time that we’re making the decision surrounding adjuvant therapy? There’s all of this great data from BRAF and MEK and now with PD-1. But if you don’t know whether or not the patient has a BRAF mutation, you really can’t make that decision. That’s something in which our community needs to sort of reach back with our pathology and our surgery groups, to expedite getting that information. It’s understandable that patients come in who are obviously concerned. You have to tell them, “You have to go away and come back.”

Now, certainly, that’s a reasonable thing to do. This is a big decision. There are toxicities associated with these treatments, and it’s not something we want to rush into. But certainly, I would advocate that having all of the information at the beginning is better than not having it.

And to the point about stage 2 trials, I completely agree. I think that there is a high-risk population of patients, actually bigger than the stage 3 population, who potentially could benefit from some of these therapies—albeit we have to consider the toxicities and the number needed to treat here. We really have to have a big impact there, otherwise we’re potentially exposing a lot of patients to toxicities.

Transcript Edited for Clarity 
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TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
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