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Combination Therapy in BRAF-Mutant NSCLC

Panelists: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Lyudmila A. Bazhenova, MD, University of California San Diego; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; Zofia Piotrowska, MD, Massachusetts General Hospital Cancer Center; Jonathan W. Riess, MD, MS, UC Davis Comprehensive Cancer Center
Published: Thursday, Sep 13, 2018



Transcript:

Benjamin P. Levy, MD: Let’s move on to BRAF. This is yet another mutation—BRAF V600E—and it is potentially actionable. Lyudmila, do you want to walk us through some of the work with BRAF? How do you manage a patient with a BRAF V600E mutation?

Lyudmila A. Bazhenova, MD: As an oncologist, you probably have heard about BRAF mutations in melanoma. In lung cancer, BRAF mutations can also happen, but they’re much less frequent than in melanoma. The overall incidence of BRAF mutations in lung cancer is about 1.4%. Also, a majority of the BRAF mutations in melanoma are V600E. In lung cancer, only half of the BRAF mutations are V600E. In the lung setting, we were following the footsteps of our melanoma colleagues, where they showed that the dual combination of dabrafenib and trametinib is better than dabrafenib alone.

So, the same studies were done in lung cancer. It was actually a 3-cohort study. Cohort 1 was just dabrafenib. Cohort 2 was dabrafenib plus trametinib in chemotherapy-pretreated patients. Cohort 3 was dabrafenib plus trametinib in treatment-naïve patients. The treatment-naïve patient results are actually quite striking. We saw a response rate of approximately 70%, and the progression-free survival was about 10 months. So, currently, dabrafenib/trametinib is an FDA-approved combination for V600E-positive lung cancer. That adds 1 more molecular marker to the list that we need to test for, in addition to EGFR, ALK, and ROS.

Benjamin P. Levy, MD: Just to make this distinction, it is for V600E, not for non-V600E?

Lyudmila A. Bazhenova, MD: Exactly.

Benjamin P. Levy, MD: The devil is in the details when you’re looking at these molecular interrogations…But for a non–BRAF V600E patient, we would not consider using this combination…

Lyudmila A. Bazhenova, MD: Not at this point.

Jonathan W. Riess, MD, MS: I think this also has activity against V600K? We’ve had some others. There are some other uncommon ones, such as V600X. Technically, it doesn’t meet the approved indication. But both V600E and V600K can respond.

Alexander Drilon, MD: I agree. If it’s a V600 substitution, there’s a reasonable chance that the standard therapeutic combination will work. But in lung cancer, the majority of the non-V600 pie is made up of non-V600 alterations. The punch line is that the standard single-agent vemurafenib or dabrafenib or the combination doesn’t seem very poised to work for those patients.

Jonathan W. Riess, MD, MS: And then I would just ask the question of: V600E—chemotherapy first or dabrafenib/trametinib?

Benjamin P. Levy, MD: You stole my thunder. It’s good. I was going to ask…

Zofia Piotrowska, MD: Or chemoimmunotherapy for...

Benjamin P. Levy, MD: Exactly. I think I would feel comfortable going with a targeted agent up front, but I don’t know what other people’s thoughts are.

Jonathan W. Riess, MD, MS: I agree. The response rate of 60%, meeting a progression-free survival of about 10 months—I think I usually do dabrafenib/trametinib.

Lyudmila A. Bazhenova, MD: When you compare, remember that cohort B was post chemotherapy and that the response rate was very similar. It really doesn’t seem to be beneficial for us to give them chemotherapy first. I would agree—just targeted therapy, right up front.

Jonathan W. Riess, MD, MS: Would this be a chemoimmunotherapy patient after progression on dabrafenib/trametinib, as opposed to ALK or EGFR?

Benjamin P. Levy, MD: I think we’re trying to learn more about this. We learned about this at one of the sessions at the ASCO Annual Meeting—the role of immunotherapy in specific genotypes and trying to gain an understanding of where these fit in. When do they fit in? Where? Is it a smoking patient? Is it a nonsmoking patient? All these clinical factors have to be weighed in, in terms of the decision making. It’s a very omplicated world out there.

Zofia Piotrowska, MD: PD-L1 seems to not be enough, at least on its own, for a lot of these situations.

Benjamin P. Levy, MD: Yes. Who would have thought that we would have so many choices just 5, 10 years ago?

Transcript Edited for Clarity 

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Transcript:

Benjamin P. Levy, MD: Let’s move on to BRAF. This is yet another mutation—BRAF V600E—and it is potentially actionable. Lyudmila, do you want to walk us through some of the work with BRAF? How do you manage a patient with a BRAF V600E mutation?

Lyudmila A. Bazhenova, MD: As an oncologist, you probably have heard about BRAF mutations in melanoma. In lung cancer, BRAF mutations can also happen, but they’re much less frequent than in melanoma. The overall incidence of BRAF mutations in lung cancer is about 1.4%. Also, a majority of the BRAF mutations in melanoma are V600E. In lung cancer, only half of the BRAF mutations are V600E. In the lung setting, we were following the footsteps of our melanoma colleagues, where they showed that the dual combination of dabrafenib and trametinib is better than dabrafenib alone.

So, the same studies were done in lung cancer. It was actually a 3-cohort study. Cohort 1 was just dabrafenib. Cohort 2 was dabrafenib plus trametinib in chemotherapy-pretreated patients. Cohort 3 was dabrafenib plus trametinib in treatment-naïve patients. The treatment-naïve patient results are actually quite striking. We saw a response rate of approximately 70%, and the progression-free survival was about 10 months. So, currently, dabrafenib/trametinib is an FDA-approved combination for V600E-positive lung cancer. That adds 1 more molecular marker to the list that we need to test for, in addition to EGFR, ALK, and ROS.

Benjamin P. Levy, MD: Just to make this distinction, it is for V600E, not for non-V600E?

Lyudmila A. Bazhenova, MD: Exactly.

Benjamin P. Levy, MD: The devil is in the details when you’re looking at these molecular interrogations…But for a non–BRAF V600E patient, we would not consider using this combination…

Lyudmila A. Bazhenova, MD: Not at this point.

Jonathan W. Riess, MD, MS: I think this also has activity against V600K? We’ve had some others. There are some other uncommon ones, such as V600X. Technically, it doesn’t meet the approved indication. But both V600E and V600K can respond.

Alexander Drilon, MD: I agree. If it’s a V600 substitution, there’s a reasonable chance that the standard therapeutic combination will work. But in lung cancer, the majority of the non-V600 pie is made up of non-V600 alterations. The punch line is that the standard single-agent vemurafenib or dabrafenib or the combination doesn’t seem very poised to work for those patients.

Jonathan W. Riess, MD, MS: And then I would just ask the question of: V600E—chemotherapy first or dabrafenib/trametinib?

Benjamin P. Levy, MD: You stole my thunder. It’s good. I was going to ask…

Zofia Piotrowska, MD: Or chemoimmunotherapy for...

Benjamin P. Levy, MD: Exactly. I think I would feel comfortable going with a targeted agent up front, but I don’t know what other people’s thoughts are.

Jonathan W. Riess, MD, MS: I agree. The response rate of 60%, meeting a progression-free survival of about 10 months—I think I usually do dabrafenib/trametinib.

Lyudmila A. Bazhenova, MD: When you compare, remember that cohort B was post chemotherapy and that the response rate was very similar. It really doesn’t seem to be beneficial for us to give them chemotherapy first. I would agree—just targeted therapy, right up front.

Jonathan W. Riess, MD, MS: Would this be a chemoimmunotherapy patient after progression on dabrafenib/trametinib, as opposed to ALK or EGFR?

Benjamin P. Levy, MD: I think we’re trying to learn more about this. We learned about this at one of the sessions at the ASCO Annual Meeting—the role of immunotherapy in specific genotypes and trying to gain an understanding of where these fit in. When do they fit in? Where? Is it a smoking patient? Is it a nonsmoking patient? All these clinical factors have to be weighed in, in terms of the decision making. It’s a very omplicated world out there.

Zofia Piotrowska, MD: PD-L1 seems to not be enough, at least on its own, for a lot of these situations.

Benjamin P. Levy, MD: Yes. Who would have thought that we would have so many choices just 5, 10 years ago?

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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