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Changing Treatment Paradigm for BRAF-Mutant NSCLC

Panelists: Suresh S. Ramalingam, MD, Emory University School of Medicine; Benjamin Besse, MD, PhD, Gustave Roussy; Marina Garassino, MD National Cancer Institute; Giorgio Scagliotti, MD, PhD, University of Turin
Published Online: Friday, Dec 01, 2017



Transcript: 

Suresh S. Ramalingam, MD: I’m going to switch gears and talk about another target where targeted therapy is now appropriate, and that is for patients with BRAF mutations in lung cancer: 2 to 3% of patients with lung adenocarcinoma seem to have this. Some of them do not have a V600E mutation, but if you do have a V600E mutation, it seems like the BRAF inhibition strategy is a factor. We’ve seen this in melanoma, where for patients with BRAF V600E mutation, which is very common there, using the combination of dabrafenib and trametinib is standard strategy and approach. For lung cancer, in the United States, the FDA recently approved a combination of dabrafenib and trametinib.

I personally have treated a patient with BRAF mutation, a lady in her 60s who had diffuse lymphangitic carcinomatosis in the lung. About a year and a half ago, even before the combination was approved, we started her on it based on her being able to access the drugs through a program. She is tolerating the drugs well, and her disease is almost in a near complete remission, which represents the power of using a targeted approach for a patient with BRAF mutation-positive disease. Benjamin, your colleagues in France have been leading some of these trials. Talk to us about the data with dabrafenib/trametinib and your experiences with that combination.

Benjamin Besse, MD, PhD: Dabrafenib and trametinib have been approved in Europe in pretreated patients. As you said, it’s only 1% of the patients, but the activity of the drug is really in line with what you see in EGFR and EGFR inhibitors, ALK and ALK inhibitors. This is really the same figure. The response rate in pretreated patients—meaning post-chemotherapy—is 67%, and the PFS is 10 months. My colleague is presenting at ESMO data from the frontline setting, and the figures are exactly the same: a response rate of roughly 60% and 10 months of PFS, maybe a bit better in fact. So, it is completely paradigm changing. It gives at least 1 year of disease control, and we have treated some of these patients with BRAF inhibitors in the trial. One of our latest patients has been treated for 5 years, and she is still in very good shape with disease control. It’s a very potent combination.

The very nice thing here is that each drug alone is quite toxic, but both combined are less toxic, meaning the toxicity profile is not an addition of the 2. It’s less toxic, and you have just to deal with a few fever peaks, some skin issues, and sometimes fatigue. You might have to decrease the dose, because all of this toxicity is dose dependent, but the tolerability of the combination is very, very good. I think it’s really a standard of care. Giving chemotherapy is not a bad thing for these patients, but at one point, they have to receive the combination.

Suresh S. Ramalingam, MD: To follow up on that, if you had a patient positive for a BRAF mutation, would you give the combination as first-line therapy? Or would you still give them platinum-based chemotherapy?

Benjamin Besse, MD, PhD: If it’s available, I would definitely offer the combination up front. There is no discussion that in the area of EGFR and ALK, a TKI is the preferred choice up front. It’s exactly the same here.

Suresh S. Ramalingam, MD: That brings us to the issue of testing. We are used to testing for EGFR and ALK, and now ROS1 is obviously part of the mix given that crizotinib is an approved option. Is BRAF testing part of the standard testing platform at your institution? Share your thoughts on what are standard.

Marina Garassino, MD: I work in a cancer center, so we have an NGS panel for all patients, but I think that this can’t be the clinical routine practice for all centers. At least in Italy, the combination is not yet available. So, I think that it must be considered a routine test when the drug will be available for everybody.

Suresh S. Ramalingam, MD: Giorgio?

Giorgio Scagliotti, MD, PhD: It’s already part of 7-gene panels. We are doing the 7-gene panel in clinical practice for nonsquamous non–small cell lung cancer. And we are moving to a 50-gene panel in a few weeks that we would like to offer systematically to all patients with non–small cell lung cancer. I agree with Benjamin about the fact that we need to offer this treatment possibility. It is true that it’s only 1% of patients, probably less than 1%, but it’s important to understand. It is the same story as the exon 14 skipping mutation. No one thought that crizotinib was working in the exon 14 skipping population of the MET gene. But we have another opportunity with these patients, most likely less than 1% of the population. We are probably moving in the right direction.

The issue is that in these educational activities, we are used to talking about thoracic oncology. We are not trying to be cross-contaminated with experience from other types of tumors. But at this meeting, for instance, attending a session on melanoma, I saw that our melanoma friends are moving in a new direction. I know that lung is not melanoma, I agree with you. But they are moving away from targeted therapies. They are using combinations, as we are using in this case, and they are also considering immunotherapy. But they are considering it in a late stage because, obviously, the combination of trametinib and cobimetinib and the BRAF inhibitor and immunotherapy is pretty toxic. Again, they are planning studies in which the 2 approaches—with immunotherapy, there is no way that it is effective in melanoma—are assessed in a sequential treatment.

It is true that we said before that EGFR is not the right setting for immunotherapy, but it’s not true for all. In this case, I’m still considering that we probably need to look to the sequential approach. It is not easy to do studies. David Planchard did the study with a limited number of patients, because he had to screen a lot of patients for a BRAF mutation. But regarding this experience with the BRAF inhibitors in combination with the MEK inhibitors, the next stage, at least for me, could be to consider a study of immunotherapy in this field.

Benjamin Besse, MD, PhD: Regarding screening, the tricky thing here is that in EGFR-mutant or ALK-rearranged disease, it’s light- or never-smokers, so you screen EGFR, then ALK, and then ROS1.

Giorgio Scagliotti, MD, PhD: That isn’t the case.

Benjamin Besse, MD, PhD: It’s not the case for BRAF, so there is no patient phenotype. Half are heavy smokers, half are never-smokers. The only thing is that it’s mutually exclusive with other mutations like EGFR or KRAS. If it’s not in the initial panel, I think it’s really something to be looked at indeed, for example, in KRAS or EGFR wild-type patients.

Suresh S. Ramalingam, MD: Clearly, we now have at least 4 driver mutations that we should look for in patients with nonsquamous disease: EGFR, ALK, ROS1, and BRAF. And, of course, an NGS panel will get you all of this information. But whatever panel your institution is using, make sure that you have these 4 genes covered for non–small cell lung cancer patients, because they have a direct implication within the United States for FDA-approved therapies.

Transcript Edited for Clarity 

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Transcript: 

Suresh S. Ramalingam, MD: I’m going to switch gears and talk about another target where targeted therapy is now appropriate, and that is for patients with BRAF mutations in lung cancer: 2 to 3% of patients with lung adenocarcinoma seem to have this. Some of them do not have a V600E mutation, but if you do have a V600E mutation, it seems like the BRAF inhibition strategy is a factor. We’ve seen this in melanoma, where for patients with BRAF V600E mutation, which is very common there, using the combination of dabrafenib and trametinib is standard strategy and approach. For lung cancer, in the United States, the FDA recently approved a combination of dabrafenib and trametinib.

I personally have treated a patient with BRAF mutation, a lady in her 60s who had diffuse lymphangitic carcinomatosis in the lung. About a year and a half ago, even before the combination was approved, we started her on it based on her being able to access the drugs through a program. She is tolerating the drugs well, and her disease is almost in a near complete remission, which represents the power of using a targeted approach for a patient with BRAF mutation-positive disease. Benjamin, your colleagues in France have been leading some of these trials. Talk to us about the data with dabrafenib/trametinib and your experiences with that combination.

Benjamin Besse, MD, PhD: Dabrafenib and trametinib have been approved in Europe in pretreated patients. As you said, it’s only 1% of the patients, but the activity of the drug is really in line with what you see in EGFR and EGFR inhibitors, ALK and ALK inhibitors. This is really the same figure. The response rate in pretreated patients—meaning post-chemotherapy—is 67%, and the PFS is 10 months. My colleague is presenting at ESMO data from the frontline setting, and the figures are exactly the same: a response rate of roughly 60% and 10 months of PFS, maybe a bit better in fact. So, it is completely paradigm changing. It gives at least 1 year of disease control, and we have treated some of these patients with BRAF inhibitors in the trial. One of our latest patients has been treated for 5 years, and she is still in very good shape with disease control. It’s a very potent combination.

The very nice thing here is that each drug alone is quite toxic, but both combined are less toxic, meaning the toxicity profile is not an addition of the 2. It’s less toxic, and you have just to deal with a few fever peaks, some skin issues, and sometimes fatigue. You might have to decrease the dose, because all of this toxicity is dose dependent, but the tolerability of the combination is very, very good. I think it’s really a standard of care. Giving chemotherapy is not a bad thing for these patients, but at one point, they have to receive the combination.

Suresh S. Ramalingam, MD: To follow up on that, if you had a patient positive for a BRAF mutation, would you give the combination as first-line therapy? Or would you still give them platinum-based chemotherapy?

Benjamin Besse, MD, PhD: If it’s available, I would definitely offer the combination up front. There is no discussion that in the area of EGFR and ALK, a TKI is the preferred choice up front. It’s exactly the same here.

Suresh S. Ramalingam, MD: That brings us to the issue of testing. We are used to testing for EGFR and ALK, and now ROS1 is obviously part of the mix given that crizotinib is an approved option. Is BRAF testing part of the standard testing platform at your institution? Share your thoughts on what are standard.

Marina Garassino, MD: I work in a cancer center, so we have an NGS panel for all patients, but I think that this can’t be the clinical routine practice for all centers. At least in Italy, the combination is not yet available. So, I think that it must be considered a routine test when the drug will be available for everybody.

Suresh S. Ramalingam, MD: Giorgio?

Giorgio Scagliotti, MD, PhD: It’s already part of 7-gene panels. We are doing the 7-gene panel in clinical practice for nonsquamous non–small cell lung cancer. And we are moving to a 50-gene panel in a few weeks that we would like to offer systematically to all patients with non–small cell lung cancer. I agree with Benjamin about the fact that we need to offer this treatment possibility. It is true that it’s only 1% of patients, probably less than 1%, but it’s important to understand. It is the same story as the exon 14 skipping mutation. No one thought that crizotinib was working in the exon 14 skipping population of the MET gene. But we have another opportunity with these patients, most likely less than 1% of the population. We are probably moving in the right direction.

The issue is that in these educational activities, we are used to talking about thoracic oncology. We are not trying to be cross-contaminated with experience from other types of tumors. But at this meeting, for instance, attending a session on melanoma, I saw that our melanoma friends are moving in a new direction. I know that lung is not melanoma, I agree with you. But they are moving away from targeted therapies. They are using combinations, as we are using in this case, and they are also considering immunotherapy. But they are considering it in a late stage because, obviously, the combination of trametinib and cobimetinib and the BRAF inhibitor and immunotherapy is pretty toxic. Again, they are planning studies in which the 2 approaches—with immunotherapy, there is no way that it is effective in melanoma—are assessed in a sequential treatment.

It is true that we said before that EGFR is not the right setting for immunotherapy, but it’s not true for all. In this case, I’m still considering that we probably need to look to the sequential approach. It is not easy to do studies. David Planchard did the study with a limited number of patients, because he had to screen a lot of patients for a BRAF mutation. But regarding this experience with the BRAF inhibitors in combination with the MEK inhibitors, the next stage, at least for me, could be to consider a study of immunotherapy in this field.

Benjamin Besse, MD, PhD: Regarding screening, the tricky thing here is that in EGFR-mutant or ALK-rearranged disease, it’s light- or never-smokers, so you screen EGFR, then ALK, and then ROS1.

Giorgio Scagliotti, MD, PhD: That isn’t the case.

Benjamin Besse, MD, PhD: It’s not the case for BRAF, so there is no patient phenotype. Half are heavy smokers, half are never-smokers. The only thing is that it’s mutually exclusive with other mutations like EGFR or KRAS. If it’s not in the initial panel, I think it’s really something to be looked at indeed, for example, in KRAS or EGFR wild-type patients.

Suresh S. Ramalingam, MD: Clearly, we now have at least 4 driver mutations that we should look for in patients with nonsquamous disease: EGFR, ALK, ROS1, and BRAF. And, of course, an NGS panel will get you all of this information. But whatever panel your institution is using, make sure that you have these 4 genes covered for non–small cell lung cancer patients, because they have a direct implication within the United States for FDA-approved therapies.

Transcript Edited for Clarity 
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