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The Current Understanding of Biomarkers in Melanoma

Panelists: Robert H.I. Andtbacka, MD, CM, Huntsman Cancer Institute; Michael A. Davies, MD, PhD, MD Anderson Cancer Center; Antoni Ribas, MD, PhD, University of California Los Angeles; Georgina Long, MD, Melanoma Institute of Australia; Michael Postow, MD, Memorial Sloan Kettering Cancer Center
Published: Friday, Dec 09, 2016


Transcript:

Robert H.I. Andtbacka, MD, CM:
Hello, and thank you for joining this OncLive Peer Exchange® titled, “Practical Management of Advanced Melanoma: A Case-Based Discussion.” Despite the availability of an increasing number of treatment options in advanced melanoma, many clinical scenarios remain where there is no clear-cut course of action. Through a case-based discussion, this OncLive Peer Exchange® among a panel of international melanoma experts will focus on areas still open for debate. It will include discussions on the latest evidence and drill down on what is impacting clinical practice today.

I am Dr. Robert Andtbacka, and I am an associate professor of surgical oncology in the Department of Surgery at University of Utah. I’m also the co-director of the Melanoma Program and co-director of the Melanoma Clinical Research Program at the Huntsman Cancer Institute in Salt Lake City, Utah. Participating today on our distinguished panel are: Dr. Michael Davies, associate professor and deputy chair for the Department of Melanoma Medical Oncology, Department of Systems Biology, and Department of Translational Molecular Pathology at the University of Texas MD Anderson Cancer Center in Houston, Texas; Dr. Georgina Long, professor of melanoma medical oncology and translational research for the Melanoma Institute of Australia, the University of Sydney, and the Royal North Shore Hospital in Sydney, Australia; Dr. Michael Postow, medical oncologist at the Memorial Sloan Kettering Cancer Center in New York City, New York; and Dr. Antoni Ribas, professor of medicine, professor of surgery, and professor of molecular and medical pharmacology at the University of California Los Angeles, director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center, and chair of the Melanoma Committee for the South West Oncology Group.

Let’s begin with our first patient. This is a 75-year-old female who has been diagnosed with metastatic melanoma. The melanoma is found to be BRAF wild-type. The patient has a low-tumor burden with lung and subcutaneous metastases. The ECOG performance status is 0. Mike, for this patient, if the patient came to your center, is there any additional testing you would do on the tumor in addition to testing for BRAF?

Michael A. Davies, MD, PhD: Routinely, we do our molecular testing in patients with melanoma using a panel-based approach that looks at several different genes at the same time. For a patient who is BRAF wild-type, meaning they don’t have a V600 mutation in the BRAF gene, there are probably two other genes we would be interested in the mutational status. The first is NRAS, which is the second most common oncogenic mutation we see in cutaneous melanoma patients. In part, it’s because the NRAS mutations and BRAF V600 mutations are mutually exclusive. So, seeing an NRAS mutation does increase our confidence in the specificity and accuracy of a wild-type BRAF test. And we do have clinical trials available for patients with an NRAS mutation. The other mutation we would consider testing for is for the c-Kit oncogene, as there is clinical evidence that melanoma patients with c-Kit mutations can benefit from treatment with c-Kit inhibitors.

Robert H.I. Andtbacka, MD, CM: And does the site of melanoma also differ for the testing you do, whether this is a cutaneous melanoma versus a mucosal melanoma?

Michael A. Davies, MD, PhD: Absolutely. So, we know that the prevalence of the different oncogenic mutations that are detected in melanoma varies based on the site of the primary tumor. Again, for cutaneous melanomas, the most common mutations are in BRAF and in NRAS. Kit mutations are quite rare, but can occur. In contrast, patients who have mucosal melanomas have a much lower rate of BRAF mutations and actually a higher rate of the Kit mutations.

Robert H.I. Andtbacka, MD, CM: Anti-PD-1 therapy has truly changed the way we treat patients with metastatic melanoma, but there’s still quite a bit of controversy whether we should test for the anti-PD-L1 on the tumor tissue. At your center, do you routinely test for anti-PD-L1?

Michael A. Davies, MD, PhD: It’s a really good question. And, certainly, one of the things that complicates this question is the fact that we know that the different PD-L1 antibody tests can actually give very different results. So, we consider this to be an area of active research and investigation at this point, but we do not consider PD-L1 testing to be standard for all of our patients at this point.

Robert H.I. Andtbacka, MD, CM: Tony, what about at UCLA, do you routinely test for anti-PD-L1 for patients with metastatic melanoma?

Antoni Ribas, MD, PhD: Actually, we do not, Robert. In this patient, we would not test more than BRAF for routine clinical care. Our only standard test is testing for BRAF V600 E or K mutation, which is a companion diagnostic for therapies with BRAF and MEK inhibitors—dabrafenib/trametinib or vemurafenib/cobimetinib. The approvals of anti-PD-1 for melanoma, both nivolumab and pembrolizumab, do not require testing the tumor and having a PD-L1-positive tumor. But, that doesn’t mean I don’t want to do it. I wish I could do it in all of the patients. In the future we’re not going to be testing for one mutation, we’re going to be testing for as many mutations as possible, and the techniques are there. It’s just the standardization of them and who pays for them that is what’s limiting us using it on a routine basis. The same goes for protein assays that would allow us to select what’s the more appropriate immunotherapy for a patient. We know that the biology tells us that if there is PD-L1 and there are T-cells, the patient may be more likely to respond because the T-cells are more likely being turned off by PD-L1. But, turning that from a research experiment into the clinic, it’s a different thing because then you have to standardize the assay in ways that go way beyond when you’re doing research. Then we also need to know the sampling and what’s the error rate for not getting the right part of the tumor. Where does the tumor come from, tumor heterogeneity, a whole bunch of questions that make it hard right now to make a decision on patient care with assays that we know are not the best possible ones.

Robert H.I. Andtbacka, MD, CM: What about in Australia, Georgina? Would you routinely test for PD-L1 in Australia?

Georgina Long, MD: Just like Tony and Mike, it’s really a research tool at this stage. And, as Tony highlighted, we know that the PD-L1 expression is associated with response, but it’s not a mutually exclusive thing. So, people who have no expression can respond to anti-PD-1 therapy. In fact, we’ve done a pooled analysis, for example, across the nivolumab program. And, when you look at the ROC, receiver operator curve, there is actually no optimal cutoff. The test is not sensitive, and it’s not specific to predict response and progression-free survival. Not only for nivolumab alone, but also for nivolumab and ipilimumab, it’s not a sensitive and specific test. So, we use it in research just as Tony said. It’s open to interpretation. You need a really good pathologist who knows what they’re doing, and you need to look at the full tumor in the microenvironment, so we use it for research.

Robert H.I. Andtbacka, MD, CM: If I understand this correctly then, there’s no percentage of expression that is really a true cutoff for this in terms of response, in terms of progression-free survival?

Georgina Long, MD: Progression-free survival, no. For either of those outcomes, there is no optimal cutoff for PD-L1 expression.

 
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Transcript:

Robert H.I. Andtbacka, MD, CM:
Hello, and thank you for joining this OncLive Peer Exchange® titled, “Practical Management of Advanced Melanoma: A Case-Based Discussion.” Despite the availability of an increasing number of treatment options in advanced melanoma, many clinical scenarios remain where there is no clear-cut course of action. Through a case-based discussion, this OncLive Peer Exchange® among a panel of international melanoma experts will focus on areas still open for debate. It will include discussions on the latest evidence and drill down on what is impacting clinical practice today.

I am Dr. Robert Andtbacka, and I am an associate professor of surgical oncology in the Department of Surgery at University of Utah. I’m also the co-director of the Melanoma Program and co-director of the Melanoma Clinical Research Program at the Huntsman Cancer Institute in Salt Lake City, Utah. Participating today on our distinguished panel are: Dr. Michael Davies, associate professor and deputy chair for the Department of Melanoma Medical Oncology, Department of Systems Biology, and Department of Translational Molecular Pathology at the University of Texas MD Anderson Cancer Center in Houston, Texas; Dr. Georgina Long, professor of melanoma medical oncology and translational research for the Melanoma Institute of Australia, the University of Sydney, and the Royal North Shore Hospital in Sydney, Australia; Dr. Michael Postow, medical oncologist at the Memorial Sloan Kettering Cancer Center in New York City, New York; and Dr. Antoni Ribas, professor of medicine, professor of surgery, and professor of molecular and medical pharmacology at the University of California Los Angeles, director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center, and chair of the Melanoma Committee for the South West Oncology Group.

Let’s begin with our first patient. This is a 75-year-old female who has been diagnosed with metastatic melanoma. The melanoma is found to be BRAF wild-type. The patient has a low-tumor burden with lung and subcutaneous metastases. The ECOG performance status is 0. Mike, for this patient, if the patient came to your center, is there any additional testing you would do on the tumor in addition to testing for BRAF?

Michael A. Davies, MD, PhD: Routinely, we do our molecular testing in patients with melanoma using a panel-based approach that looks at several different genes at the same time. For a patient who is BRAF wild-type, meaning they don’t have a V600 mutation in the BRAF gene, there are probably two other genes we would be interested in the mutational status. The first is NRAS, which is the second most common oncogenic mutation we see in cutaneous melanoma patients. In part, it’s because the NRAS mutations and BRAF V600 mutations are mutually exclusive. So, seeing an NRAS mutation does increase our confidence in the specificity and accuracy of a wild-type BRAF test. And we do have clinical trials available for patients with an NRAS mutation. The other mutation we would consider testing for is for the c-Kit oncogene, as there is clinical evidence that melanoma patients with c-Kit mutations can benefit from treatment with c-Kit inhibitors.

Robert H.I. Andtbacka, MD, CM: And does the site of melanoma also differ for the testing you do, whether this is a cutaneous melanoma versus a mucosal melanoma?

Michael A. Davies, MD, PhD: Absolutely. So, we know that the prevalence of the different oncogenic mutations that are detected in melanoma varies based on the site of the primary tumor. Again, for cutaneous melanomas, the most common mutations are in BRAF and in NRAS. Kit mutations are quite rare, but can occur. In contrast, patients who have mucosal melanomas have a much lower rate of BRAF mutations and actually a higher rate of the Kit mutations.

Robert H.I. Andtbacka, MD, CM: Anti-PD-1 therapy has truly changed the way we treat patients with metastatic melanoma, but there’s still quite a bit of controversy whether we should test for the anti-PD-L1 on the tumor tissue. At your center, do you routinely test for anti-PD-L1?

Michael A. Davies, MD, PhD: It’s a really good question. And, certainly, one of the things that complicates this question is the fact that we know that the different PD-L1 antibody tests can actually give very different results. So, we consider this to be an area of active research and investigation at this point, but we do not consider PD-L1 testing to be standard for all of our patients at this point.

Robert H.I. Andtbacka, MD, CM: Tony, what about at UCLA, do you routinely test for anti-PD-L1 for patients with metastatic melanoma?

Antoni Ribas, MD, PhD: Actually, we do not, Robert. In this patient, we would not test more than BRAF for routine clinical care. Our only standard test is testing for BRAF V600 E or K mutation, which is a companion diagnostic for therapies with BRAF and MEK inhibitors—dabrafenib/trametinib or vemurafenib/cobimetinib. The approvals of anti-PD-1 for melanoma, both nivolumab and pembrolizumab, do not require testing the tumor and having a PD-L1-positive tumor. But, that doesn’t mean I don’t want to do it. I wish I could do it in all of the patients. In the future we’re not going to be testing for one mutation, we’re going to be testing for as many mutations as possible, and the techniques are there. It’s just the standardization of them and who pays for them that is what’s limiting us using it on a routine basis. The same goes for protein assays that would allow us to select what’s the more appropriate immunotherapy for a patient. We know that the biology tells us that if there is PD-L1 and there are T-cells, the patient may be more likely to respond because the T-cells are more likely being turned off by PD-L1. But, turning that from a research experiment into the clinic, it’s a different thing because then you have to standardize the assay in ways that go way beyond when you’re doing research. Then we also need to know the sampling and what’s the error rate for not getting the right part of the tumor. Where does the tumor come from, tumor heterogeneity, a whole bunch of questions that make it hard right now to make a decision on patient care with assays that we know are not the best possible ones.

Robert H.I. Andtbacka, MD, CM: What about in Australia, Georgina? Would you routinely test for PD-L1 in Australia?

Georgina Long, MD: Just like Tony and Mike, it’s really a research tool at this stage. And, as Tony highlighted, we know that the PD-L1 expression is associated with response, but it’s not a mutually exclusive thing. So, people who have no expression can respond to anti-PD-1 therapy. In fact, we’ve done a pooled analysis, for example, across the nivolumab program. And, when you look at the ROC, receiver operator curve, there is actually no optimal cutoff. The test is not sensitive, and it’s not specific to predict response and progression-free survival. Not only for nivolumab alone, but also for nivolumab and ipilimumab, it’s not a sensitive and specific test. So, we use it in research just as Tony said. It’s open to interpretation. You need a really good pathologist who knows what they’re doing, and you need to look at the full tumor in the microenvironment, so we use it for research.

Robert H.I. Andtbacka, MD, CM: If I understand this correctly then, there’s no percentage of expression that is really a true cutoff for this in terms of response, in terms of progression-free survival?

Georgina Long, MD: Progression-free survival, no. For either of those outcomes, there is no optimal cutoff for PD-L1 expression.

 
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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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