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Targeted Approaches in NSCLC: Lessons from Melanoma

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: Monday, Jan 23, 2017


Transcript:

Roy S. Herbst, MD, PhD:
I’m excited, and I think for community oncologists, it’s important to know that now we have another weapon. When you’re working in the trenches and seeing large number of patients with lung cancer, some of them will have more traditional actionable mutations like EGFR and ALK, and others will have PD-L1-positive mutations and they’ll be getting immunotherapies right off the bat or they’ll certainly get immunotherapy later on. But, for those that have this V600E mutation, we have a combination, trametinib/dabrafenib, that has activity. I think one would expect response rates anywhere in the 30% to 50% range. How durable? The test of time will tell. They’ll need to look for some GI and skin toxicities, but it’s not much different than what we’re used to dealing with some of the other TKIs that we work with. So, my goal for my patients and my hope in precision medicine in lung cancer is that someday everyone will get fully profiled, we’ll have a series of agents, and then we’ll match that agent to the drug. And that’s targeted therapy. This is just one more piece of the puzzle. Of course, now, we have to figure out how to target KRAS, which is 20% to 25% of the patients for whom we really don’t have a combination. Some of that might include the drugs we’re talking about here, either being used with immunotherapy or with PI3 kinase inhibitors. But, for right now, this is a step in the right direction.

I’d expect that if the patient responds, symptoms often times will improve, because I think the response will supersede whatever added toxicity you get through the drug. So, I would say they should expect a response 30% to 40% of the time with some improvement in symptoms, but, again, data are still limited.

Often times, in lung cancer, if you’re going to use a combination, such as trametinib and dabrafenib, you would want to have data preclinically in lung cancer or strong data in another tumor type. Of course, in melanoma, that combination against V600E—which is more common in melanoma—is actually more efficacious and less toxic than using the trametinib by itself; the trametinib, of course, being a MEK inhibitor. It’s just very exciting. I think that extrapolation to lung cancer still needs larger trials and randomized studies, but there’s certainly a sense that this combination can be active in lung cancer as well.

Mark A. Socinski, MD: The metastatic melanoma experience, both from a BRAF point of view as well as an immunotherapy point of view, I think there are a lot of lessons or a lot of themes that run consistent between the two diseases. The combination was first demonstrated in malignant melanoma patients, being more effective than single-agent therapy. I think we don’t have that level of evidence in a randomized fashion yet, but as I said previously, I’m not sure that given what we’ve seen in this, between Cohort A and Cohort B, that I would be enthusiastic about doing a randomized trial. Where in other disease settings, like melanoma, we’ve seen a clear advantage to the combination. In at least in the sequential cohort trial of Cohorts A and B, we’ve seen a clear difference, or a signal, with the combination versus monotherapy. So, I don’t think we should reinvent the wheel there. I think we should proceed with a dual inhibition as our platform to move forward.

Transcript Edited for Clarity
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Transcript:

Roy S. Herbst, MD, PhD:
I’m excited, and I think for community oncologists, it’s important to know that now we have another weapon. When you’re working in the trenches and seeing large number of patients with lung cancer, some of them will have more traditional actionable mutations like EGFR and ALK, and others will have PD-L1-positive mutations and they’ll be getting immunotherapies right off the bat or they’ll certainly get immunotherapy later on. But, for those that have this V600E mutation, we have a combination, trametinib/dabrafenib, that has activity. I think one would expect response rates anywhere in the 30% to 50% range. How durable? The test of time will tell. They’ll need to look for some GI and skin toxicities, but it’s not much different than what we’re used to dealing with some of the other TKIs that we work with. So, my goal for my patients and my hope in precision medicine in lung cancer is that someday everyone will get fully profiled, we’ll have a series of agents, and then we’ll match that agent to the drug. And that’s targeted therapy. This is just one more piece of the puzzle. Of course, now, we have to figure out how to target KRAS, which is 20% to 25% of the patients for whom we really don’t have a combination. Some of that might include the drugs we’re talking about here, either being used with immunotherapy or with PI3 kinase inhibitors. But, for right now, this is a step in the right direction.

I’d expect that if the patient responds, symptoms often times will improve, because I think the response will supersede whatever added toxicity you get through the drug. So, I would say they should expect a response 30% to 40% of the time with some improvement in symptoms, but, again, data are still limited.

Often times, in lung cancer, if you’re going to use a combination, such as trametinib and dabrafenib, you would want to have data preclinically in lung cancer or strong data in another tumor type. Of course, in melanoma, that combination against V600E—which is more common in melanoma—is actually more efficacious and less toxic than using the trametinib by itself; the trametinib, of course, being a MEK inhibitor. It’s just very exciting. I think that extrapolation to lung cancer still needs larger trials and randomized studies, but there’s certainly a sense that this combination can be active in lung cancer as well.

Mark A. Socinski, MD: The metastatic melanoma experience, both from a BRAF point of view as well as an immunotherapy point of view, I think there are a lot of lessons or a lot of themes that run consistent between the two diseases. The combination was first demonstrated in malignant melanoma patients, being more effective than single-agent therapy. I think we don’t have that level of evidence in a randomized fashion yet, but as I said previously, I’m not sure that given what we’ve seen in this, between Cohort A and Cohort B, that I would be enthusiastic about doing a randomized trial. Where in other disease settings, like melanoma, we’ve seen a clear advantage to the combination. In at least in the sequential cohort trial of Cohorts A and B, we’ve seen a clear difference, or a signal, with the combination versus monotherapy. So, I don’t think we should reinvent the wheel there. I think we should proceed with a dual inhibition as our platform to move forward.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
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
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
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