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BRAF/MEK Efficacy in BRAF-mutant 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 Online: Monday, Jan 09, 2017



Transcript:

Roy S. Herbst, MD, PhD:
It’s very exciting now that we can actually find mutations and also then match them to specific drug or drug combinations. In lung cancer, V600E, a BRAF mutation, is present in 3% to 5% of patients, probably closer to 3%. But lung cancer is the most common cause of cancer death, and there are 200,000 or more cases alone in the United States. So, there are still a good number of cases. Data initially were based on using trametinib alone in this setting. Now, trametinib plus dabrafenib in a single-arm trial has been quite impressive. I believe the response rates were upward of 30% to 40%. That’s certainly a combination that’s being looked at. It was presented at one of the recent meetings, and people are excited about that combination now for patients with a V600E mutation.

Bruce E. Johnson, MD: The design of the trials that have studied dabrafenib and trametinib for BRAF-mutant lung cancer were written to assess the activity of the drugs individually and together, and both in previously treated patients as well as previously untreated patients. When we designed the trial, we decided to write the trial to assess the activity of dabrafenib by itself as a monotherapy. And at the time, we knew the response of dabrafenib in BRAF-mutant melanoma was approximately 50% while the responses were less than 10% in BRAF-mutant colon cancer. So, we wanted to assess what the activity was as a single agent in the previously treated patients. We were hoping it would be somewhere between the 10% to 50% that was seen within both colon cancer as well as melanoma.

We also included Cohort B because we knew from BRAF-mutant melanoma that the activity of the 2 drugs was greater than each individually, and we wanted to assess the impact of adding the trametinib to dabrafenib so we could have some kind of an idea about how much that drug was adding to the dabrafenib activity. Because it’s not been proven in lung cancer and that there were other diseases (ie, colon cancer), where those 2 drugs were not very active , we thought it was important to go in the previously treated patients where an expected response rate was about 10%. So, we thought that we would not be harming and potentially helping the patients in this clinical setting.

The last step, if we saw a certain level of activity, we would move it into first-line therapy if we thought that it was doing as well or better than chemotherapy based on the results of the testing in Cohort B; that is, the previously treated patients with BRAF-mutant lung cancer treated with the 2-drug combination, dabrafenib and trametinib.

We recruited 59 patients to the dabrafenib/trametinib combination study of patients with non–small cell lung cancer with V600-/BRAF-mutant lung cancer. And we saw in the cohort of 57 patients, who were previously treated, that 36 of those 57 responded; this is a response rate of 63%. This was the amount that we had hoped for and was relatively similar to the response rates seen with V600E BRAF-mutant melanoma.

The other efficacy endpoint that we assessed was progression-free survival. And for those 57 patients, the progression-free survival was about 10 months. This is something that you’ve seen in other oncogenic driver-treated non–small cell lung cancers, similar to what we initially saw with gefitinib and erlotinib in EGFR-mutant lung cancer, as well as crizotinib for the patients with ALK-rearranged non–small cell lung cancer.

Mark A. Socinski, MD: The data with the combination, or the dual inhibitory approach of dabrafenib and trametinib, is actually quite compelling when you compare and contrast it to monotherapy with dabrafenib. The response rates are doubled. The PFS, in comparing the 2 cohorts, is much better with dual inhibition. There’s really a minimal difference in overall toxicity. I think it’s a win-win for the dual inhibition versus monotherapy. So, I don’t know that monotherapy has a clear role at this point. And I think we should be thinking of both drugs in combination, given the clinical data we have to date.

The primary endpoint of Cohort B was investigator-assessed overall response rate. Secondary endpoints were investigator-assessed PFS, overall survival, safety, and some pharmacokinetic endpoints. It’s important to realize that Cohort A, or dabrafenib monotherapy, was not a randomized experience. So, this was a cohort that was accrued to and treated only with dabrafenib. In Cohort B, it was a similar population, previously treated patients, but they received the combination of dabrafenib plus trametinib.

When you compare and contrast these 2 things, clearly you get the message that dual inhibition of this pathway is more efficacious based on response rates, based on progression-free survival times. Overall survival data are a bit immature to know that, with the caveat that this was not a randomized experience. I think. moving forward, the most effective regimen appears to be the dual inhibitory approach. And I personally would not be enthusiastic about exploring a trial that tested dabrafenib alone versus dabrafenib plus trametinib, because I think these data are compelling. Dual inhibition is the optimal approach in this patient population.

The dosing for dabrafenib is 150 mg twice daily, and for trametinib, 2 mg daily. In the trial design, like we’ve seen in a number of trial designs that did allow for treatment beyond progression, RECIST-defined progression can occur. It often occurs in a situation where, from the clinician’s point of view, there may be a little bit of uncertainty as to whether it really represents true progression, and the patient may be doing quite well clinically. And so, many clinicians will make the judgment that there’s continued benefit despite meeting what we would call “RECIST criteria” for progression. But we think it’s clinically indicated to treat beyond that progression.

Transcript Edited for Clarity
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Transcript:

Roy S. Herbst, MD, PhD:
It’s very exciting now that we can actually find mutations and also then match them to specific drug or drug combinations. In lung cancer, V600E, a BRAF mutation, is present in 3% to 5% of patients, probably closer to 3%. But lung cancer is the most common cause of cancer death, and there are 200,000 or more cases alone in the United States. So, there are still a good number of cases. Data initially were based on using trametinib alone in this setting. Now, trametinib plus dabrafenib in a single-arm trial has been quite impressive. I believe the response rates were upward of 30% to 40%. That’s certainly a combination that’s being looked at. It was presented at one of the recent meetings, and people are excited about that combination now for patients with a V600E mutation.

Bruce E. Johnson, MD: The design of the trials that have studied dabrafenib and trametinib for BRAF-mutant lung cancer were written to assess the activity of the drugs individually and together, and both in previously treated patients as well as previously untreated patients. When we designed the trial, we decided to write the trial to assess the activity of dabrafenib by itself as a monotherapy. And at the time, we knew the response of dabrafenib in BRAF-mutant melanoma was approximately 50% while the responses were less than 10% in BRAF-mutant colon cancer. So, we wanted to assess what the activity was as a single agent in the previously treated patients. We were hoping it would be somewhere between the 10% to 50% that was seen within both colon cancer as well as melanoma.

We also included Cohort B because we knew from BRAF-mutant melanoma that the activity of the 2 drugs was greater than each individually, and we wanted to assess the impact of adding the trametinib to dabrafenib so we could have some kind of an idea about how much that drug was adding to the dabrafenib activity. Because it’s not been proven in lung cancer and that there were other diseases (ie, colon cancer), where those 2 drugs were not very active , we thought it was important to go in the previously treated patients where an expected response rate was about 10%. So, we thought that we would not be harming and potentially helping the patients in this clinical setting.

The last step, if we saw a certain level of activity, we would move it into first-line therapy if we thought that it was doing as well or better than chemotherapy based on the results of the testing in Cohort B; that is, the previously treated patients with BRAF-mutant lung cancer treated with the 2-drug combination, dabrafenib and trametinib.

We recruited 59 patients to the dabrafenib/trametinib combination study of patients with non–small cell lung cancer with V600-/BRAF-mutant lung cancer. And we saw in the cohort of 57 patients, who were previously treated, that 36 of those 57 responded; this is a response rate of 63%. This was the amount that we had hoped for and was relatively similar to the response rates seen with V600E BRAF-mutant melanoma.

The other efficacy endpoint that we assessed was progression-free survival. And for those 57 patients, the progression-free survival was about 10 months. This is something that you’ve seen in other oncogenic driver-treated non–small cell lung cancers, similar to what we initially saw with gefitinib and erlotinib in EGFR-mutant lung cancer, as well as crizotinib for the patients with ALK-rearranged non–small cell lung cancer.

Mark A. Socinski, MD: The data with the combination, or the dual inhibitory approach of dabrafenib and trametinib, is actually quite compelling when you compare and contrast it to monotherapy with dabrafenib. The response rates are doubled. The PFS, in comparing the 2 cohorts, is much better with dual inhibition. There’s really a minimal difference in overall toxicity. I think it’s a win-win for the dual inhibition versus monotherapy. So, I don’t know that monotherapy has a clear role at this point. And I think we should be thinking of both drugs in combination, given the clinical data we have to date.

The primary endpoint of Cohort B was investigator-assessed overall response rate. Secondary endpoints were investigator-assessed PFS, overall survival, safety, and some pharmacokinetic endpoints. It’s important to realize that Cohort A, or dabrafenib monotherapy, was not a randomized experience. So, this was a cohort that was accrued to and treated only with dabrafenib. In Cohort B, it was a similar population, previously treated patients, but they received the combination of dabrafenib plus trametinib.

When you compare and contrast these 2 things, clearly you get the message that dual inhibition of this pathway is more efficacious based on response rates, based on progression-free survival times. Overall survival data are a bit immature to know that, with the caveat that this was not a randomized experience. I think. moving forward, the most effective regimen appears to be the dual inhibitory approach. And I personally would not be enthusiastic about exploring a trial that tested dabrafenib alone versus dabrafenib plus trametinib, because I think these data are compelling. Dual inhibition is the optimal approach in this patient population.

The dosing for dabrafenib is 150 mg twice daily, and for trametinib, 2 mg daily. In the trial design, like we’ve seen in a number of trial designs that did allow for treatment beyond progression, RECIST-defined progression can occur. It often occurs in a situation where, from the clinician’s point of view, there may be a little bit of uncertainty as to whether it really represents true progression, and the patient may be doing quite well clinically. And so, many clinicians will make the judgment that there’s continued benefit despite meeting what we would call “RECIST criteria” for progression. But we think it’s clinically indicated to treat beyond that progression.

Transcript Edited for Clarity
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Medical Crossfire®: 3rd Annual Miami Lung Cancer Conference®May 31, 20171.5
A Look at the Near Future of Lung Cancer TreatmentMay 31, 20171.0
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