Standard of Care in BRAF V600E+ mNSCLC

Hossein Borghaei, DO:BRAFV600E again is one of the manyBRAFmutations that we can detect. As many of you are aware, these mutations are also found in patients with melanoma. The biology of theBRAFmutation at this point suggests that there are 3 separate classes of these mutations, which I’m not really going to go into detail about, but theBRAFV600E is considered to be a class 1 mutation. These are activating mutations for the most part. And under the category ofBRAFmutation, the literature suggests that about half of these fall underBRAFV600E, meaning that there are other potential mutations under this category that could have a differential response to various treatments.

For theBRAFV600E mutation, as you saw in the case, based on multiple published reports, the combination of dabrafenib and trametinib has become our standard of care because of the efficacy and the clinical activity and also tolerability of this particular combination. We did start trials with single-agent BRAF inhibitors; however the literature does show that a combination of a MEK inhibitor plus a BRAF inhibitor can actually improve not just response rates but survival and PFS [progression-free survival] of patients who are being treated with this particular combination. That’s why that has become the standard of care for patients who can tolerate it as opposed to a single-agent drug.

Keep in mind that much like what we have learned from the world ofEGFRand evenALK, patients who are treated with these targeted therapies unfortunately eventually do develop resistance mechanisms. And there’s a lot of work going on to better define the nature of these resistance mechanisms. But I think it’s good to very quickly review that BRAF sits in a signaling pathway that allows these cancer cells to basically bypass a particular block and be able to move into a different direction, and that’s how cancers can basically progress.

This also highlights that many of these patients, once they have any evidence of progression, should undergo repeat biopsies to see if other potential mechanisms of resistance can be found. Because again, for some of these new resistance mechanisms, we might be able to have specific clinical trials with targeted therapies to establish the role of new potential treatments for patients who are progressing on frontline doublet therapy, as we discussed here.

Transcript edited for clarity.

Case: A 69-Year Old Man With MetastaticBRAFV600E—Mutated Metastatic NSCLC

Initial presentation

• A 69-year old man presented with a chronic dry cough and dyspnea on exertion
• PMH: history of hypercholesterolemia, medically treated; 20 pack-year smoking history, quit 6 years ago
• PE: decreased breath sounds on auscultation

Clinical workup

• Labs: WNL
• Chest X-ray showed a ~4-cm
• Chest/abdomen/pelvic CT showed a 3.7-cm solid pulmonary lesion in the right lobe, ipsilateral mediastinal and subcarinal lymph node involvement
• Bronchoscopy biopsy of the lung lesion and lymph nodes revealed lung adenocarcinoma
• Contrast-enhanced MRI of the head showed a small brain lesion
• Molecular and biomarker testing:
  • PD-L1 TPS 20%
  • EGFR-, ALK-,BRAFV600E+,ROS1-
• Stage T2aN2M1b; ECOG PS 0

Treatment and Follow-Up

• Patient started on dabrafenib 150 mg PO qDay BID + trametinib 2 mg PO qDay; achieved partial response
  • Patient developed intermittent grade 1 fatigue, which was tolerable; continued treatment
• Imaging at 3, 6 and 9 months showed sustained partial response