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Dual Targeting of BRAF and MEK in NSCLC

Panelists: Mary Jo Fidler, MD, Rush; Roy S. Herbst, MD, PhD, Yale ; Geoffrey R. Oxnard, MD, Harvard; Naiyer Rizvi, MD, Columbia; Mark A. Socinski, MD,
Published: Tuesday, Sep 15, 2015


Transcript:

Mark A. Socinski, MD: Switching gears a little bit to another data set that we saw, I’m going to ask Dr. Fidler to comment on this, and that’s moving into what I call the 1% club. We’ve seen in adenocarcinoma of the lung, a number of different genotypes that are potentially actionable. This year, well, not this year, we’ve heard about it before, but BRAF and specifically the V600E mutation occurs in maybe 1% to 2% of adenocarcinomas of the lung.

A year ago at ASCO we saw the single-agent dabrafenib data, and this year Dr. Johnson presented the combination of dabrafenib/trametinib in this setting, so a BRAF and MEK inhibitor in this setting. Do you want to give us your thoughts about that?

Mary Jo Fidler, MD: The one thing about BRAF, it is relatively uncommon, but it is one of the driver mutations that we see a little bit more where you have a patient with smoking history, which I think differentiates a little bit from some of these other driver mutations, which are not always, but almost exclusively, in non-smokers.

There were preclinical data and also data in the melanoma world suggesting that it is rational to combine dabrafenib and trametinib in non-small cell lung cancer patients who had the BRAF mutation, and they only selected BRAF V600E, which seems to be the one that really correlates with response with dabrafenib in lung cancer. The earlier trial you mentioned was about 20 patients, a small number. There was a response rate, about 30% or so, and it did seem to be durable.

With the combination, the response rate was higher, and the durability was similar to some other targets that we’ve seen for other driver mutations. You have dabrafenib, which is targeting the BRAF and then trametinib which is targeting MEK, which is a little bit downstream. It’s a two-hit strategy, and it does seem to be working better for these BRAF-positive patients. The patients who were exposed to these agents were more heavily pretreated–one, two, three therapies.

With BRAF being a worse prognosis, I just wonder if we’d see even better results if this combination was applied in the first-line setting.

Mark A. Socinski, MD: That’s ongoing at this point where the previously untreated patients are being treated with this combination. I don’t know how many patients have been treated yet, but that’s certainly attractive.

Naiyer Rizvi, MD: Does everyone test their patients for BRAF mutations?

Mark A. Socinski, MD: We have a set of what we call actionable genotypes that we define as our initial thing before we do the next-generation sequencing. We test for it, I don’t know if other centers routinely test for it.

Roy S. Herbst, MD, PhD: We have different levels of testing, but if you’re going to do some sort of next-generation platform, it should certainly be one of the genes; whether you choose 100, 200, or 300, it’s one of the top 10 so you definitely should do it.

Geoffrey R. Oxnard, MD: But I don’t always have my BRAF results back before I’m starting first-line therapy and I’m not always waiting for it in patients where it’s 1%. While it’s a compelling first-line idea, I think it may end up being a second-line strategy for patients where you’re hunting for the genotype and that takes some time.

Mary Jo Fidler, MD: It’s hard to say, though, what’s going to happen maybe even in the near future because if you add up the cost of individual mutation tests, it may be more expensive than doing a next-generation sequencing for all patients. It could be that we’ll have some of that data more upfront in the future.
Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD: Switching gears a little bit to another data set that we saw, I’m going to ask Dr. Fidler to comment on this, and that’s moving into what I call the 1% club. We’ve seen in adenocarcinoma of the lung, a number of different genotypes that are potentially actionable. This year, well, not this year, we’ve heard about it before, but BRAF and specifically the V600E mutation occurs in maybe 1% to 2% of adenocarcinomas of the lung.

A year ago at ASCO we saw the single-agent dabrafenib data, and this year Dr. Johnson presented the combination of dabrafenib/trametinib in this setting, so a BRAF and MEK inhibitor in this setting. Do you want to give us your thoughts about that?

Mary Jo Fidler, MD: The one thing about BRAF, it is relatively uncommon, but it is one of the driver mutations that we see a little bit more where you have a patient with smoking history, which I think differentiates a little bit from some of these other driver mutations, which are not always, but almost exclusively, in non-smokers.

There were preclinical data and also data in the melanoma world suggesting that it is rational to combine dabrafenib and trametinib in non-small cell lung cancer patients who had the BRAF mutation, and they only selected BRAF V600E, which seems to be the one that really correlates with response with dabrafenib in lung cancer. The earlier trial you mentioned was about 20 patients, a small number. There was a response rate, about 30% or so, and it did seem to be durable.

With the combination, the response rate was higher, and the durability was similar to some other targets that we’ve seen for other driver mutations. You have dabrafenib, which is targeting the BRAF and then trametinib which is targeting MEK, which is a little bit downstream. It’s a two-hit strategy, and it does seem to be working better for these BRAF-positive patients. The patients who were exposed to these agents were more heavily pretreated–one, two, three therapies.

With BRAF being a worse prognosis, I just wonder if we’d see even better results if this combination was applied in the first-line setting.

Mark A. Socinski, MD: That’s ongoing at this point where the previously untreated patients are being treated with this combination. I don’t know how many patients have been treated yet, but that’s certainly attractive.

Naiyer Rizvi, MD: Does everyone test their patients for BRAF mutations?

Mark A. Socinski, MD: We have a set of what we call actionable genotypes that we define as our initial thing before we do the next-generation sequencing. We test for it, I don’t know if other centers routinely test for it.

Roy S. Herbst, MD, PhD: We have different levels of testing, but if you’re going to do some sort of next-generation platform, it should certainly be one of the genes; whether you choose 100, 200, or 300, it’s one of the top 10 so you definitely should do it.

Geoffrey R. Oxnard, MD: But I don’t always have my BRAF results back before I’m starting first-line therapy and I’m not always waiting for it in patients where it’s 1%. While it’s a compelling first-line idea, I think it may end up being a second-line strategy for patients where you’re hunting for the genotype and that takes some time.

Mary Jo Fidler, MD: It’s hard to say, though, what’s going to happen maybe even in the near future because if you add up the cost of individual mutation tests, it may be more expensive than doing a next-generation sequencing for all patients. It could be that we’ll have some of that data more upfront in the future.
Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 18th Annual International Lung Cancer Congress®Oct 31, 20181.5
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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