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The Evolving Mutational Landscape 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: Monday, Jan 16, 2017


Transcript:

Bruce E. Johnson, MD:
The treatment paradigms for non–small cell lung cancer are evolving. So, starting in 2004 when EGFR-mutants were discovered, a number of people tested for them, and some people gave the inhibitors of the epidermal growth factor receptor, preferentially, to those patients with mutants. We discovered, in 2009, that the use of gefitinib, one of the epidermal growth factor receptor tyrosine kinase inhibitors, worked about twice as well as chemotherapy in the EGFR-mutant population. It became a standard and approved in the United States, Europe, and around the world to target the mutation for the epidermal growth factor receptor, and to give those patients EGFR inhibitors.

Starting in 2010, when we found out that patients with ALK-rearranged tumors could more effectively be treated with crizotinib than with chemotherapy, that became a standard to test. Crizotinib then became the first favorite therapy in second line, and then later, in 2013, it was approved for first-line therapy of patients with ALK-rearranged non–small cell lung cancer. In 2015, it was discovered that crizotinib was effective in ROS1-rearranged patients, and that led to an approval. Each several years, we’ve added additional testing and we’ve added additional drugs. So, for instance, now there are 3 different drugs approved for the initial therapy of EGFR-mutant lung cancer: gefitinib, erlotinib, and afatinib. There are 3 drugs approved for ALK-rearranged tumors: crizotinib is the first one, the second one is ceritinib, and the third one is alectinib. There’s only a single drug now approved for ROS1-rearrangements, and that’s crizotinib.

When we treat patients with BRAF-mutant non–small cell lung cancer, we think that we will now be evolving toward giving dabrafenib/trametinib. It will be the fourth genomic change that we see in non–small cell lung cancer where there’ll be a specific targeted therapy available for another subset of our patients. Dabrafenib/trametinib is currently available and is approved for the use in V600E-mutant melanoma. The combination is currently being submitted to the Food and Drug Administration. We anticipate that it will be available sometime in early 2017, if the FDA rules favorably on the application for approval.

Mark A. Socinski, MD: The message for the community oncologists is that testing for a BRAF mutation should be standard. It should be done at the time of diagnosis. You have the opportunity, when diagnosing the BRAF V600E mutation, of having a regimen that has approximately a 60% response rate. These responses can often be quite durable. The price of those responses, in terms of severe toxicity, is minimal. There is some management of grade 1 or 2 toxicities that needs to occur. But, this approach can dramatically change the experience of a BRAF V600E-mutant patient compared to standard chemotherapy. And the only way to identify these patients is to test. If you test and you find the mutation, you must act with a targeted approach as shown in the phase II trial that documented the level of activity.

The approval for this combination will likely be, and should be, in patients diagnosed with the BRAF V600E mutation, specifically for that subgroup of patients. This is an activating mutation. The trials were conducted in this population, and so that should be the indication. Given the level of efficacy that we’ve seen coupled with a very attractive safety profile, I think this becomes the standard of care for all of these patients. And, I think, it then becomes standard to test for BRAF V600E because we have a therapy that can only be used if you diagnose this condition.

The appropriate dosing for this combination is dabrafenib at 150 mg twice daily and trametinib at 2 mg daily. There are appropriate dose reductions for toxicities if they occur, but that should be the starting dose, and will be the FDA-approved dose for this regimen.

Transcript Edited for Clarity
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Transcript:

Bruce E. Johnson, MD:
The treatment paradigms for non–small cell lung cancer are evolving. So, starting in 2004 when EGFR-mutants were discovered, a number of people tested for them, and some people gave the inhibitors of the epidermal growth factor receptor, preferentially, to those patients with mutants. We discovered, in 2009, that the use of gefitinib, one of the epidermal growth factor receptor tyrosine kinase inhibitors, worked about twice as well as chemotherapy in the EGFR-mutant population. It became a standard and approved in the United States, Europe, and around the world to target the mutation for the epidermal growth factor receptor, and to give those patients EGFR inhibitors.

Starting in 2010, when we found out that patients with ALK-rearranged tumors could more effectively be treated with crizotinib than with chemotherapy, that became a standard to test. Crizotinib then became the first favorite therapy in second line, and then later, in 2013, it was approved for first-line therapy of patients with ALK-rearranged non–small cell lung cancer. In 2015, it was discovered that crizotinib was effective in ROS1-rearranged patients, and that led to an approval. Each several years, we’ve added additional testing and we’ve added additional drugs. So, for instance, now there are 3 different drugs approved for the initial therapy of EGFR-mutant lung cancer: gefitinib, erlotinib, and afatinib. There are 3 drugs approved for ALK-rearranged tumors: crizotinib is the first one, the second one is ceritinib, and the third one is alectinib. There’s only a single drug now approved for ROS1-rearrangements, and that’s crizotinib.

When we treat patients with BRAF-mutant non–small cell lung cancer, we think that we will now be evolving toward giving dabrafenib/trametinib. It will be the fourth genomic change that we see in non–small cell lung cancer where there’ll be a specific targeted therapy available for another subset of our patients. Dabrafenib/trametinib is currently available and is approved for the use in V600E-mutant melanoma. The combination is currently being submitted to the Food and Drug Administration. We anticipate that it will be available sometime in early 2017, if the FDA rules favorably on the application for approval.

Mark A. Socinski, MD: The message for the community oncologists is that testing for a BRAF mutation should be standard. It should be done at the time of diagnosis. You have the opportunity, when diagnosing the BRAF V600E mutation, of having a regimen that has approximately a 60% response rate. These responses can often be quite durable. The price of those responses, in terms of severe toxicity, is minimal. There is some management of grade 1 or 2 toxicities that needs to occur. But, this approach can dramatically change the experience of a BRAF V600E-mutant patient compared to standard chemotherapy. And the only way to identify these patients is to test. If you test and you find the mutation, you must act with a targeted approach as shown in the phase II trial that documented the level of activity.

The approval for this combination will likely be, and should be, in patients diagnosed with the BRAF V600E mutation, specifically for that subgroup of patients. This is an activating mutation. The trials were conducted in this population, and so that should be the indication. Given the level of efficacy that we’ve seen coupled with a very attractive safety profile, I think this becomes the standard of care for all of these patients. And, I think, it then becomes standard to test for BRAF V600E because we have a therapy that can only be used if you diagnose this condition.

The appropriate dosing for this combination is dabrafenib at 150 mg twice daily and trametinib at 2 mg daily. There are appropriate dose reductions for toxicities if they occur, but that should be the starting dose, and will be the FDA-approved dose for this regimen.

Transcript Edited for Clarity
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