Subtypes in NSCLC: BRAF and RET

Transcript:Mark A. Socinski, MD: One of the other oncogenic drivers that has been described principally in adenocarcinoma of the lung is an alteration in BRAF. The most common one is the V600E, which is very similar to the alteration we see in metastatic melanoma. Obviously, knowing that this is present in 1% to 2% of BRAF patients, the use of BRAF inhibitors—both dabrafenib as well as vemurafenib—have been studied. And there is a clear level of activity. The initial data with dabrafenib in BRAF-mutant patients with V600E showed an objective response rate of about 35% to 40%. These data have matured a little bit and that response rate has held in the 30%-to-35% range.

Like in melanoma, the dual inhibition of both BRAF and MEK, with the addition of trametinib, has been a successful strategy in melanoma. That has been studied in non—small cell lung cancer in successive cohorts. This was not a randomized trial. But if you look at the initial dabrafenib data with a response rate of about 30% to 35%, the combination study using dabrafenib and trametinib actually had a response rate of about 65%, so about double with the use of dabrafenib alone, mirroring some of the data in melanoma where the combination appears to be superior to the single agent alone.

Most of this has been studied in refractory disease. We have just finished accrual to a first-line, previously untreated cohort of BRAF-mutant patients using that combination. I think that with further study, this is a very attractive approach. Again, it follows the theme, like we’ve seen in EGFR mutations—ALK, ROS, down the list. BRAF is now on that list. If you’re a practicing oncologist, you need to think about BRAF and you need to test for it. Because, again, these targeted agents, targeting BRAF plus or minus MEK, that data will mature and we’ll know. It may be a very effective strategy for these patients with known BRAF mutations. It adds to the list of things you have to think about as an oncologist in managing adenocarcinoma of the lung.

Gregory J. Riely, MD: BRAF mutations are very common in patients with melanoma. We’ve heard a lot about targeting BRAF-mutant melanoma. What’s less known is BRAF-mutant non—small cell lung cancer. BRAF mutations happen in about 1% or 2% of patients with non–small cell lung cancer. Importantly, only about half of those are the key BRAF V600E mutation. The other half are inactivated mutations that are a little bit less well understood.

Approximately 1% of patients with lung cancer have the BRAF V600E mutation. As with melanoma, the first way to evaluate patients with BRAF V600E is to look at single-agent BRAF inhibitors. Both dabrafenib and vemurafenib have been explored as single-agent BRAF inhibitors in patients with BRAF-mutant non—small cell lung cancer. Response rates for these drugs are in the 30%-to-40% range, which is certainly good, but it is only rivaling first-line chemotherapy. We always want to do better for our patients with oncogene-addicted cancers. We want to do better than conventional chemotherapy.

At ASCO this year, we saw some very exciting data showing that the combination of a BRAF inhibitor, dabrafenib, along with a MEK inhibitor, trametinib, led to significantly higher response rates: a response rate above 60% for patients with BRAF-mutant lung cancer. This really transforms BRAF from being an interesting niche to something that we really have to identify and target going forward. I think BRAF-mutant lung cancer should be identified as part of any initial screen for patients with lung cancer. BRAF should be part of the oncogene panel that you do for your patients with non—small cell lung cancer.

We learn more and more about individual subtypes of lung cancer. Some of these are rare, 1% or 2%, but it’s really important to identify these because we do have targeted therapies that can help these patients. Sometimes these therapies are even more effective than chemotherapy and even more effective than the immunotherapy we hear so much about. One relatively uncommon, but important subtype, is RET-rearranged lung cancer. RET is not something we typically think about when we think about thyroid cancer, but about 1% or 2% of patients with non—small cell lung cancer have RET gene rearrangements. These rearrangements are important in driving the cancers. I

f we look at it in laboratory models, we see that these RET rearrangements can cause cancer in these models. And when we identify this in patients, we have to think about how we can treat them. There aren’t a lot of significant RET inhibitors, but there are drugs that do have activity against RET. And cabozantinib is a great example of a drug that targets a number of kinases—but RET is one of them. One of my colleagues, Alex Drilon, at Memorial Sloan Kettering has done a prospective trial in which he enrolled only patients with RET-rearranged lung cancer and evaluated their response to cabozantinib. What he found is a response rate that’s above 30% for those patients with RET-rearranged lung cancer, suggesting that cabozantinib is a very real option for those patients.

Transcript Edited for Clarity