Treatment of BRAF-Mutant NSCLC

Justin Gainor, MD:BRAFmutations are found in about 4% of patients with non—small cell lung cancer. One important point to draw contrast with melanoma, whereBRAFmutations are found in about 50% of patients, is that not allBRAFmutations in lung cancer are V600E. In fact, only about 50% of lung cancers withBRAFmutations will actually have the canonical V600E mutation. So, that really brings down the frequency to about 2% of patients who will haveBRAFV600E. In general, these patients tend to have clinical characteristics in contrast withEGFR,ALK, andROS1. We do observeBRAFmutations in patients with a history of smoking. But we also know thatBRAFmutations do confer sensitivity to treatment with targeted therapies—specifically, BRAF inhibitors, as well as MEK inhibitors.

We’ve seen in non—small cell lung cancer, as well as in melanoma, that the combination of BRAF plus MEK actually results in better activity, as well as better tolerability. And this results from blocking downstream of the mutantBRAFwith a MEK inhibitor. So, in the United States, the combination of dabrafenib and trametinib is currently approved for patients withBRAFV600E non—small cell lung cancer. I should note that this is different from the experience in colon cancer. I thinkBRAFis a helpful lesson for targeted therapies more broadly because we know that the same genetic alteration can behave very differently depending upon the tumor in which it occurs in. So,BRAFV600E in melanoma and in non—small cell lung cancer is very sensitive to treatment with BRAF plus MEK. By contrast, the same mutation in colorectal cancer is far less sensitive to targeted therapies. And so, I do think that it’s an important reminder that we need to actually do clinical trials of genetic alterations across different diseases, because they may behave quite differently.

Alexander Drilon, MD:BRAF-mutant lung cancers include a proportion of patients that haveBRAFV600E mutations in their tumors, and this has been well known to be a target in the melanoma world. We found that these mutations can occur in non—small cell lung cancers, up to a frequency of about 2%, depending on the series that you look at. We know that these are highly actionable, and if you give a single-agent BRAF inhibitor like vemurafenib or dabrafenib, you might achieve response rates of approximately 30%. However, following the lead again of what we’ve seen in the melanoma world, when you give a combination of a BRAF and a MEK inhibitor—specifically, dabrafenib and trametinib—we know that the response rate more than doubles to 63% with that combination in the phase II setting. And so, that’s currently approved by the FDA for the treatment ofBRAFV600E—mutant lung cancer patients and would be my first choice for someone that’s stage IV and treatment naïve, knowing that the outcomes we’re seeing with the combination paralleled the outcomes that we’ve seen with tyrosine kinase inhibitor therapy for theEGFR, andALK, andROS1genes.

Justin Gainor, MD:For non-V600Emutations, currently, the standard of care would be the default: chemotherapy, immunotherapy, or a combination of the 2. There are actually many different types of non-V600E mutations. They generally fall into 3 different classes, and the approaches to each of those classes are different. But right now, there’s no currently FDA-approved therapy for non-V600E mutations. And so, if I were to encounter one of those patients, I would actually direct them to a clinical trial, but the standard of care to start would be as if I were approaching that type of patient.

Transcript edited for clarity.