Emerging Therapies and Unmet Needs in BRAF+ NSCLC

Transcript: Joshua M. Bauml, MD: One of the unique aspects of BRAF-mutant non—small cell lung cancer, which differentiates it from other molecularly driven tumors such as EGFR, ALK, and ROS1, is that patients with BRAF V600E-mutant non—small cell lung cancer tend to be patients with a smoking history. Therefore, it’s not very surprising that if you look at the immuno-target cohort that evaluated the efficacy of immunotherapy in patients with molecularly driven tumors, patients with BRAF-mutant lung cancer tended to be some of the groups that responded. But we have very limited data about the specific efficacy of immunotherapy and chemoimmunotherapy for such patients. Based on that I tend to favor targeted therapy for these patients.

Nevertheless, I think that this presents us with a unique opportunity for future trials. We know from the melanoma cohorts that we can safely combine BRAF inhibition with immunotherapy. That’s an approach that has not been safe in other targeted-therapy spaces in non—small cell lung cancer. This is a real opportunity to utilize 2 highly active treatments and combine them, and I hope that we’ll see some exciting results when that’s done.

I think 1 of the most critical elements in any targeted therapy space is to understand why resistance develops and how we can prevent as well as treat that resistance. If we look in the EGFR-mutant non—small cell lung cancer space, we can clearly see the benefit of serial molecular profiling if you look at something like the T790M story and the development of osimertinib.

In BRAF, after failure of dabrafenib-trametinib, there’s really not a second-line targeted-therapy approach that we can use, and we know very little about mechanisms of resistance. I think doing deep dives on such patients to understand mechanisms of resistance and how we can overcome those mechanisms are really critical. Globally, in the targeted-therapy space, I think we need to better understand how to prevent that resistance. The mechanisms of resistance, when they develop, tend to be heterogenous and individualized. You’re already starting with a very small subset of patients, and then it’s a small subset of a small subset. It becomes difficult to develop a unified approach that can help multiple patients with this deadly disease.

Transcript Edited for Clarity