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The Future of Driver Mutations in NSCLC

Insights From: Roy S. Herbst, MD, PhD, Yale Cancer Center; Bruce E. Johnson, MD, Dana-Farber Cancer Institute; Mark A. Socinski, MD, Florida Hospital Cancer Institute
Published: Tuesday, Jan 31, 2017


Transcript:

Bruce E. Johnson, MD:
The future of the patients with V600E-mutant non–small cell lung cancer looks a bit better in that they now have an additional treatment option as we go forward. One of the things that has happened to our patients, who have these oncogenic drivers for which we have effective therapies, is that we see a rather dramatic difference in their outcome. We looked at our patients, for instance, who have EGFR-mutant non–small cell lung cancer and we published a study from our own institution where we’ve had targeted agents that have been available now, with the mutation testing, for about 12 years. For the subset of 137 patients who we followed for more than 5 years, we have about 14% of them alive at 5 years. That’s still too small, but it’s dramatically different than the 2% to 5% we see in the typical populations.

Now that we’ve identified an effective therapy for the patients with V600E-mutant non–small cell lung cancer, we can expect this population, with this effective portion of the therapy, to begin to see not only a difference in progression-free survival, but also hopefully begin to see their survival extend out beyond what would be expected. As I mentioned before, we have a substantial history of the outcomes of the patients with V600E-mutant non–small cell lung cancer who have been treated with chemotherapy in the past, and we know that it’s the typical approximately 12-month survival. So, as we follow these patients and see their outcomes, we can compare their outcomes to what we’ve seen in the past, and it will give us additional confidence that we will actually make a difference in the outcomes of these patients with this subset. As we gradually expand the number of patients who can be effectively treated with different oncogenic drivers, we hope to see this continue to expand so an increasing portion can have effective targeted therapies and begin to change the paradigm of the outcomes of these patients.

The next steps for research in the patients with V600E non–small cell lung cancer will include the development of more effective and more potent inhibitors of the BRAF-mutant non–small cell lung cancer, as well as MEK inhibition. We hope to see more effective drugs targeting not only BRAF, but also its other RAF partners, where we may be able to see some more effective therapy and also more tolerable MEK inhibitors.

The other part where we’d like to see some increased efforts is targeting the non-V600Es. In most of these, it appears that the pathway is activated, and we need to have an ongoing assessment of the efficacy both of the MEK inhibitors as well as other RAF inhibitors of these mutants. And there are techniques that are currently ongoing. There are publications in August 2016 taking a look at activation of the pathway based on the non-V600E mutations in BRAF and other lung cancers. And also, there are ongoing preclinical studies assessing the efficacy of combined BRAF and MEK inhibition in the non-V600Es. If we’re successful in being able to target this patient population, it would double the numbers of patients we could give targeted therapies to who had mutant BRAF, because the V600Es are only 50% of all the BRAF mutations that we see in non–small cell lung cancer.

Roy S. Herbst, MD, PhD: Lung cancer is a big disease, so there are many targets. There are 25,000 genes that code for proteins that could be potentially mutated in this disease. We’re casting a wide net. I’d say, of course, there’s immunotherapy, agents that target checkpoints and novel checkpoints, and then all the immune-regulatory molecules. But as far as targeted therapy goes in lung cancer right now, we’re continuing to look for ways to target RAS. I’d say KRAS is a big one in that there are some specific drugs that will directly target RAS. There will be drugs that target RAS farnesylation and bind to the cell membrane. There are going to be drugs that are looking to target resistance. Don’t forget, with EGFR and ALK inhibitors, as good as those agents are, no one is cured. What we need to do is target resistance, and resistance will emerge to every agent that we use. So, there’s a lot of work to still do.

Mark A. Socinski, MD: The reality of our lung cancer population is that only a minority of patients currently have identifiable driver mutations where we have the ability to take action in used targeted approaches. There are still a substantial chunk of patients in which we don’t identify a driver mutation. That shouldn’t discourage doctors from testing, because even if you find that 1% or 2% that have something, you can make a major difference in their overall experience.

We have a lot of unanswered questions. Are there other driver mutations yet to be described in this population? What’s the role of immunotherapy in these patients? What’s the role of standard chemotherapy or those combinations in this population of patients? What’s the role of integrating immunotherapy into the BRAF population? This is mostly a smoking population, as we’ve discussed, and that’s where immunotherapy seems to have greater benefit. So, I think there are many unanswered questions in this population, but I’m optimistic that we’re going to continue to make gains for the BRAF V600E patients.

Transcript Edited for Clarity
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Transcript:

Bruce E. Johnson, MD:
The future of the patients with V600E-mutant non–small cell lung cancer looks a bit better in that they now have an additional treatment option as we go forward. One of the things that has happened to our patients, who have these oncogenic drivers for which we have effective therapies, is that we see a rather dramatic difference in their outcome. We looked at our patients, for instance, who have EGFR-mutant non–small cell lung cancer and we published a study from our own institution where we’ve had targeted agents that have been available now, with the mutation testing, for about 12 years. For the subset of 137 patients who we followed for more than 5 years, we have about 14% of them alive at 5 years. That’s still too small, but it’s dramatically different than the 2% to 5% we see in the typical populations.

Now that we’ve identified an effective therapy for the patients with V600E-mutant non–small cell lung cancer, we can expect this population, with this effective portion of the therapy, to begin to see not only a difference in progression-free survival, but also hopefully begin to see their survival extend out beyond what would be expected. As I mentioned before, we have a substantial history of the outcomes of the patients with V600E-mutant non–small cell lung cancer who have been treated with chemotherapy in the past, and we know that it’s the typical approximately 12-month survival. So, as we follow these patients and see their outcomes, we can compare their outcomes to what we’ve seen in the past, and it will give us additional confidence that we will actually make a difference in the outcomes of these patients with this subset. As we gradually expand the number of patients who can be effectively treated with different oncogenic drivers, we hope to see this continue to expand so an increasing portion can have effective targeted therapies and begin to change the paradigm of the outcomes of these patients.

The next steps for research in the patients with V600E non–small cell lung cancer will include the development of more effective and more potent inhibitors of the BRAF-mutant non–small cell lung cancer, as well as MEK inhibition. We hope to see more effective drugs targeting not only BRAF, but also its other RAF partners, where we may be able to see some more effective therapy and also more tolerable MEK inhibitors.

The other part where we’d like to see some increased efforts is targeting the non-V600Es. In most of these, it appears that the pathway is activated, and we need to have an ongoing assessment of the efficacy both of the MEK inhibitors as well as other RAF inhibitors of these mutants. And there are techniques that are currently ongoing. There are publications in August 2016 taking a look at activation of the pathway based on the non-V600E mutations in BRAF and other lung cancers. And also, there are ongoing preclinical studies assessing the efficacy of combined BRAF and MEK inhibition in the non-V600Es. If we’re successful in being able to target this patient population, it would double the numbers of patients we could give targeted therapies to who had mutant BRAF, because the V600Es are only 50% of all the BRAF mutations that we see in non–small cell lung cancer.

Roy S. Herbst, MD, PhD: Lung cancer is a big disease, so there are many targets. There are 25,000 genes that code for proteins that could be potentially mutated in this disease. We’re casting a wide net. I’d say, of course, there’s immunotherapy, agents that target checkpoints and novel checkpoints, and then all the immune-regulatory molecules. But as far as targeted therapy goes in lung cancer right now, we’re continuing to look for ways to target RAS. I’d say KRAS is a big one in that there are some specific drugs that will directly target RAS. There will be drugs that target RAS farnesylation and bind to the cell membrane. There are going to be drugs that are looking to target resistance. Don’t forget, with EGFR and ALK inhibitors, as good as those agents are, no one is cured. What we need to do is target resistance, and resistance will emerge to every agent that we use. So, there’s a lot of work to still do.

Mark A. Socinski, MD: The reality of our lung cancer population is that only a minority of patients currently have identifiable driver mutations where we have the ability to take action in used targeted approaches. There are still a substantial chunk of patients in which we don’t identify a driver mutation. That shouldn’t discourage doctors from testing, because even if you find that 1% or 2% that have something, you can make a major difference in their overall experience.

We have a lot of unanswered questions. Are there other driver mutations yet to be described in this population? What’s the role of immunotherapy in these patients? What’s the role of standard chemotherapy or those combinations in this population of patients? What’s the role of integrating immunotherapy into the BRAF population? This is mostly a smoking population, as we’ve discussed, and that’s where immunotherapy seems to have greater benefit. So, I think there are many unanswered questions in this population, but I’m optimistic that we’re going to continue to make gains for the BRAF V600E patients.

Transcript Edited for Clarity
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