Expanding Targets in NSCLC - Episode 16

Advances in BRAF+ NSCLC: Targeted Therapy


Joshua M. Bauml, MD: In recent years, there have been remarkable advances for the treatment of metastatic non—small cell lung cancer. We’ve seen advances in immunotherapy, and we’ve seen advances in improving cytotoxic chemotherapies. One of the areas I’m most interested in is improving outcomes for targeted therapies. We know that particularly for patients with adenocarcinoma of the lung, tumors can harbor specific molecularly targetable genetic alterations. These can be mutations or translocations, and they often allow us to use pills to very good effect, in terms of controlling cancers. This means that for patients who have this target, we may be able to identify a more personalized approach for the treatment of their cancer.

One of the molecular alterations that has been seen in adenocarcinoma of the lung is the BRAF mutation, specifically BRAF V600E. We know that this particular mutation has been seen in melanoma, where we’ve seen efficacy for BRAF and MEK inhibitors in combination to improve outcomes for these patients. This is 1 of the great opportunities where we can take the work done in other cancers and apply it to our patients with lung cancer.

There have been multiple trials that have evaluated the efficacy of BRAF inhibitors in non—small cell lung cancer harboring a BRAF V600E mutation. What we’ve seen is that when dabrafenib and trametinib—trametinib is a MEK inhibitor, dabrafenib is a BRAF inhibitor—are given together, we can see a much higher response rate than what is seen when you give dabrafenib or other BRAF inhibitors alone.

When you give dabrafenib alone, the response rate is about 30%. When you give dabrafenib and trametinib together, the response rate is about 60%. This puts it in standing with other targeted therapies and, in my mind, cements its status as a first-line approach for patients with such targets.

There has been a study that evaluated both the first-line and the later-line uses of dabrafenib-trametinib for non—small cell lung cancer harboring a BRAF V600E mutation. It should be noted that the response rate was about the same. But in general, when I’m treating non—small cell lung cancer, I like to go with my most effective and tolerable treatment first. In my mind, targeted therapy, with a meaningful target such as BRAF V600E, is the best approach for patients harboring such alterations.

My general approach, if I have a patient who harbors any molecular target, is to use the targeted therapy first. At the time of the initial diagnosis, their tumor is the most homogenous it will be. We also know that driver mutation is driving the growth of that cancer. It’s important to know that if you identify a non-V600E mutation in BRAF, that is not something I would generally target with dabrafenib and trametinib. Such mutations rarely respond, and most of the trials have been closed early in these cohorts for lack of efficacy.

But if I have a patient who has a BRAF V600E mutation, my preference is to use targeted therapy first. In general, I’ll wait for the molecular results in a patient with newly diagnosed metastatic lung cancer to make sure that I know all my information. It’s important to remember that our treatments for lung cancer have substantial adverse effects. We want to make sure that when we give the treatment, we’re giving the best treatment for that individual person.

When we give dabrafenib and trametinib, there’s a unique set of adverse effects that can be seen. Fatigue and general malaise have been reported with this combination. The other very key adverse effect that we tend to see with this combination is fever. Fevers can be treated with Tylenol. They are not representative of an infection, but they can be quite distressing for the patient as they’re starting a new targeted therapy.

Transcript Edited for Clarity