Targeting BRAF in NSCLC

Transcript:

D. Ross Camidge, MD: Advanced non—small cell lung cancer is still a very serious disease, but for certain subgroups of patients, we are seeing long-term control of the disease. We’re moving from this binary choice—you’re alive and cured, or you’re dead—and there is a middle ground, where you are living in harmony with your cancer and it is controlled in the same way like other chronic diseases like diabetes or asthma. For example, with ALK-positive lung cancer, we now have people living, at least based on the recent series from our center, for nearly 7 years as a median. That means many people are living longer than that.

In terms of therapy for non—small cell lung cancer, we really can split it into 2 broad categories. We have the standard therapies that are going to apply to pretty much everybody—some kinds of chemotherapy, some kinds of immunotherapy—and we have individual pathways for defining molecular subtypes of lung cancer. There are now 5 FDA-approved molecular-specific subtypes with approved targeted therapies: EGFR, ALK, ROS, BRAF V600E, and NTRK gene rearrangements. There’s also a range of other molecular abnormalities, for which there are drugs in trials looking very active and, no doubt, looking for FDA licenses, or you can send patients for clinical trials. That would include MET exon 14 skipping mutations, high-level MET amplification, HER2 mutations, and and EGFR exon 20 insertions, to name a few.

BRAF mutations are well described in melanoma, but they also occur in lung cancer, particularly BRAF V600E, which is about 50% of the BRAF mutations in lung cancer. Only about 2% of lung cancer patients have BRAF mutations. The other ones are a range of different mutations, most of which we don’t know what to do with. They’re traditionally called non-V600E mutations. We saw some data at ASCO [the American Society of Clinical Oncology Annual Meeting] in 2019, maybe some provocative cell-line data that they might respond to MEK inhibition. But I think they’re very much a work in progress. What we do know is what to do when you have 1 of these BRAF V600E mutations. As I said, that’s about 2% of lung cancer.

The BRAF V600E mutation is a classic abnormality. It locks a kinase in an active confirmation and signaling through BRAF. It goes RAS, RAF, MEK, ERK. It’s part of the proliferation pathway. The goal is to inhibit it, and the initial drugs were BRAF inhibitors. They certainly can work, but they have about a 30% response rate. It turned out there was a feedback pathway, which limited their activity, and you could block that if you also give a MEK inhibitor in combination. What you now find is the licensed treatment in lung cancer, as of 2017, is a combination of dabrafenib, which is a BRAF inhibitor, and trametinib, which is a MEK inhibitor.

Transcript Edited for Clarity