Targeted Therapies for BRAF V600E-Mutated mNSCLC

Hossein Borghaei, DO:We’ve had a lot of experience in the world of lung cancer with targeted therapies. We’re learning more and more about these potential targets for which we have very effective drugs. Case in point, for instance, anNTRKmutation, now we have very effective therapies.

For aBRAFmutation, again, we learn a lot from our colleagues in the melanoma world also. Starting with a single-agent BRAF inhibitor was shown to be effective. But because of the bypass mechanisms that we briefly referred to, meaning that blockade of a specific pathway can lead to cancer cells choosing a slightly different parallel pathway for uncontrolled growth, that led to the discussion that perhaps dual therapy forBRAFmutation would be of importance.

If you think of this as a cascading signaling pathway, the way we simplistically but routinely think about these pathways, in the top of the pathway is probablyRASfollowed by V600EBRAFmutation. A little bit lower down you haveMEKand then at the bottom, downstream from all of that is ERK. If you follow this signaling cascade, you will see that inhibition of the particular growth pathway at 2 separate points,BRAFandMEK, it can be a bit more effective. In fact, that is what trials have shown us.

Just as an example of the responses and all of that with the combination of dabrafenib and trametinib in patients who are previously untreated, the response rates can be as high as 64% with a disease control rate of roughly 75%, and a median PFS [progression-free survival] of just around 11 months. These are really good numbers to have, for again, fairly well targeted therapy as opposed to, for instance, a single-agent drug where the response rates are probably closer to about 30% to 40%, with PFS that’s roughly around 5-and-a-half to 6 months. This is highlighting that the combination of the targeted therapies, at least in this case, does seem to be a lot more effective than single agent. And also, it takes care of common potential resistance mechanisms for this particular patient population. So that’s why the dual targeted therapies have become the standard of care.

Obviously, for patients with metastatic disease, quality of life is really important and it’s something that we have to emphasize and pay attention to. Under that category, every time we talk about treatments that we think are effective, it becomes a conversation of pros and cons. We have good responses, good progression-free survival. Overall survival seems to be better, but at what cost? What are the toxicities of these regimens? As clinicians, we’ve become accustomed to saying these are well tolerated. But from the patient perspective, sometimes these are different. And the process of having a patient go through a specific treatment involves informing the patient of all the adverse effects like we do.

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