Dabrafenib and Trametinib in BRAF-Mutated NSCLC

Mark A. Socinski, MD: This patient has stage 4 adenocarcinoma. Because of her history of hemoptysis, she is not a candidate for bevacizumab. It’s not safe to give bevacizumab in patients who have active hemoptysis, so I would not consider that as an option for this patient. I do think that her treatment should be a platinum-based doublet. Her performance status is good, and she has no prohibitive comorbid illnesses. My choice would be pairing pemetrexed with one of the taxanes. Pemetrexed, I think, has some toxicity advantages relative to the taxane. So, in this setting, my typical doublet would be carboplatin/pemetrexed, which is how this patient was treated and which I think is perfectly reasonable.

Unfortunately, after 3 cycles of treatment, this patient had worsening symptoms—: weight loss, some dyspnea—that is always very concerning. These things should be getting better, not worse. If they’re getting worse, you have to be very suspicious of disease progression. She was reevaluated by CT scan and, in fact, showed that her disease was progressing. She was not really getting any benefit from the platinum-based doublet she was receiving, so we need to move on in this case.

Knowing that she has aBRAF V600Emutation, we have data in this setting with the combination—well, actually, we have data in both dabrafenib as a single agent as well as the combination of dabrafenib/trametinib in this setting. And we know that as a single agent, dabrafenib was associated with a response rate of about 35% to 40%. The addition of trametinib, so that you have dual inhibition of the pathway, was associated with a response rate of about 65% or so, or so there seemed to be—at least based on response. This was not randomized data, this was successive cohorts—a higher response rate with the dual blockade of theBRAF/MEKpathway, inhibiting both theBRAFas well asMEKpathway with the 2 agents.

In this setting, knowing that she has aV600Emutation, I would strongly recommend the use of targeted agents. In patients without oncogenic drivers, immunotherapy is the standard of care. She would be a perfect candidate for immunotherapy. However, the response rates associated with immunotherapy hover in the 20% range, so we do have data on a treatment with a much higher response rate. Now, I will admit we don’t have mature data on survival in theBRAFpopulation treated with the targeted regimen of dabrafenib and trametinib. But I think this patient, particularly because she’s progressing and getting clinically worse, is in dire need of a response. And so, I would use a treatment that I knew had a higher response rate in this setting. Immunotherapy is not going to go away as an option for her; you could use that as the third-line of therapy, but, in this case, I would highly recommend the targeted approach.

The combination of dabrafenib and trametinib in patients withBRAF V600E-mutated stage 4 non—small cell lung cancer has been performed and reported. The phase II trial included 59 patients. Again, it had an objective response rate assessed by the investigators of about 65%—63% to be exact. The typical toxicities were pyrexia, or fever, anemia, and some GI disturbances. Overall, I think the impression of the investigators was that it was a very tolerable and manageable side effect profile—no surprises. We know that this has been a regimen approved for the melanoma population for quite some time, with no significant safety issues. We don’t have any data yet, or at least no mature data, on survival outcomes in this population. But, certainly, with such a high response rate in this population, I think this opens up the possibility of this combination being a new standard, because of this very robust response rate seen in these molecularly characterized patients.

One of the things that’s important to consider, as an oncologist, is the concept of getting the right patient the right drug at the right time. And I think this population of patients withBRAFV600E-mutant non—small cell lung cancer is a nice example. We understand that this is a driver pathway. We understand how it works. We understand that dual inhibition with both dabrafenib and trametinib is associated with very high response rates. I think that this has the potential to change the course of the disease for these patients, given the high response rates.

Again, we’re waiting for trials to mature and tell us how this may influence survival outcomes. But I would almost put this in the game-changer category, because it follows that mantra of right treatment to the right patient at the right time. The right patient is a patient we’ve tested with an extensive panel. We find theBRAF V600Emutation, we have a drug for this patient, and we know that the response rates are in the range of other oncogenic drivers, likeEGFRmutations andALKtranslocations. And they’re much higher than we expect from standard chemotherapy or immunotherapy in this population. So, I do think, for these patients, that this really creates an option that is potentially highly effective.

Transcript edited for clarity.

• 67-year-old female, former smoker (30 pack-years, quit 10 years ago) presented to her pulmonologist with increased cough, dyspnea and hemoptysis.
• Past medical history of mild COPD.
• Patient swims three times a week and is continuing normal activities.
• ECOG PS was assessed as 1.
• CT scan of chest and abdomen show a lower right lobe lung nodule with several small liver lesions.
• PET/CT scan indicated lung cancer with liver metastases.
• Core needle biopsy was performed in the liver. Pathology report showed adenocarcinoma consistent with non-small cell lung cancer (NSCLC).
• Mutation testing showed aBRAF V600Emutation.
• PD-L1 status was negative.
• Patient was started on pemetrexed and carboplatin.
• After 3 of 6 planned cycles patient showed worsening signs of dyspnea with a weight loss of 10%.
• Repeat CT scan showed progression of primary lesion.
• Patient was started on dabrafenib + trametinib.