BRAF Molecular Testing in NSCLC

Mark A. Socinski, MD: Our current guidelines tell us that we should test forEGFRmutations,ALKandROS1translocations, and PD-L1 in newly-diagnosed patients. There are several other things that we know, potential oncogenic drivers, one of which is theBRAF V600Emutation. In my practice, at the time of diagnosis, I tend to do more testing beyondEGFR,ALK, andROS1, because I do think we have evidence now, that presumably, in theBRAFpopulation, the use of targeted therapies to theBRAFmutation is associated with much higher response rates than we typically see with chemotherapy. Now, what we don’t know yet is the impact on progression-free survival, as well as overall survival, but studies are currently ongoing to help characterize that.

In the population of patients who haveBRAF V600Emutations, there is some heterogeneity in the nature ofBRAFmutations, so I think you have to be specific and realize that we’re talking about theV600Emutation, which is actually the same mutation that patients with melanoma have—quite similar. Many of the oncogenic drivers likeEGFR,ALK, andROS1are typically seen in never-smokers or former light-smokers. TheBRAFmutations may be seen in never-smokers, but are also commonly seen in smokers. There doesn’t seem to be any sex predilection; most can be seen in men and in women.

Getting back to theV600Eversus non-V600Emutations—it’s about 50% to 70% of patients. There are a number of series that have looked at this. One of the problems with interpreting the series is that some of the series are heavily weighted with surgical patients and early-stage patients. Some of them are heavily weighted with stage 4 patients, like our patient here. We actually looked at this from the original Lung Cancer Mutation Consortium study, which was all stage 4 patients. About 70% of theBRAFmutations wereV600Eversus non-V600Ein that study. Others have suggested it’s about a 50/50 distribution. I still think we’re learning a little bit about this, but the importance is to understand that we’re really looking for theBRAF V600Emutation in this setting.

Again, these patients—you could call them typical lung cancer patients—aren’t like theEGFR-mutant patients who are typically female, never-smokers, or Asian adenocarcinoma patients. These patients are principally adenocarcinoma patients, but they can be smokers, non-smokers, men, or women. It’s a very average sort of lung cancer population.

Current guidelines really call for the testing of 3 molecular alterations:EGFR,ALK, andROS1. Over the past couple of years, there has been clear evidence thatBRAFmutations,METalterations, highly amplified patients or patients who haveexon 14skip mutations, and patients who haveRETalterations orHER2mutations, there have been clear responses associated with targeted agents directed at those molecular alterations, I think in the first-line setting. I’m actually interested in going beyond the big 3 to things likeBRAF,RET, andMETbecause right now we have targeted agents that may help these patients. And unless you multiplex or do more, you’re not going to find these alterations.

My personal belief is that there are probably only about 7 or 8 things that I’ve mentioned, in the first-line setting, that would make a real difference to me. You can multiplex and do several hundred genes, and sometimes you will find things that may be helpful to the patient, but going beyond where we have data, you could characterize it as a bit of a fishing expedition. Sometimes, you find things that aren’t meaningful or you find things for which we don’t have drugs that target the alterations, or we find things for which we don’t know if the drugs that might target them are going to work. So, it’s relatively controversial, what you do. But I think there are 7 or 8 things, that if a family member of mine were diagnosed with lung cancer, I would want my oncologist to know. And one of them isBRAF V600Emutation status, because we have targeted agents that are effective in these patients.

Transcript edited for clarity.

• 67-year-old female, former smoker (30 pack-years, quit 10 years ago) presented to her pulmonologist with increased cough, dyspnea and hemoptysis.
• Past medical history of mild COPD.
• Patient swims three times a week and is continuing normal activities.
• ECOG PS was assessed as 1.
• CT scan of chest and abdomen show a lower right lobe lung nodule with several small liver lesions.
• PET/CT scan indicated lung cancer with liver metastases.
• Core needle biopsy was performed in the liver. Pathology report showed adenocarcinoma consistent with non-small cell lung cancer (NSCLC).
• Mutation testing showed aBRAF V600Emutation.
• PD-L1 status was negative.
• Patient was started on pemetrexed and carboplatin.
• After 3 of 6 planned cycles patient showed worsening signs of dyspnea with a weight loss of 10%.
• Repeat CT scan showed progression of primary lesion.
• Patient was started on dabrafenib + trametinib.