Treatment Options for BRAF V600E+ mNSCLC

Hossein Borghaei, DO:The literature regarding use of various drugs in this patient population is somewhat limited because of the small number of patients that we have. And what I mean by that is that prior to establishing the role of targeted therapies that we briefly discussed, obviously if a patient walked into the clinic with aBRAFmutation, many patients were treated with standard chemotherapy. Since most of these patients are diagnosed with an adenocarcinoma, the standard treatment in this case was a combination of platinum plus pemetrexed, which we typically use in most of our patients with adenocarcinoma.

There are both single institution and multi-institution publications looking into the outcome of patients who have been treated with the combination of platinum plus pemetrexed. And also, obviously in the era of immunotherapy, there have been single institution retrospective looks at responses that these patients have had once treated with immunotherapy. I would like to emphasize again that we don’t necessarily have controlled randomized studies to look and decide whether patients withBRAFmutations have a specific response to immunotherapy, chemotherapy.

In terms of prognosis, having a small data set of patients worldwide it makes it difficult to have a complete set of data. But multiple studies now from different institutions and also some bigger groups in Europe collecting the data, it does appear that patients withBRAFmutation have a slightly better prognosis than patients without these mutations in terms of overall survival. Now, whether some of that is related to the fact that we have effective targeted therapies for these patients remains to be seen.

For instance, in a paper that collected data from a couple of institutions in the United States, patients withBRAFmutations who had received platinum plus pemetrexed had a PFS [progression-free survival] of about 6 months, which is fairly close to the group of patients that we see without any of the mutations, suggesting that using chemotherapy is highly effective. But in the same data set, looking at patients who had, for instanceBRAFV600E, who received targeted therapies, clearly the outcome of these patients was better compared to patients who, for whatever reason, never got the targeted therapies.

There are also important clinical features that I think we have to keep in mind. For instance, the majority of patients with theBRAFV600E type of mutations, the class 1s that we briefly discussed, tend to be never-smokers. So they might be healthier in general, or they might be younger than the average patient population who has a smoking history with adenocarcinoma or are former smokers.

Other interesting clinical features suggest that patients with V600 type of mutations tend to have more intrathoracic disease as opposed to the other subpopulations withBRAFthat tend to have extra-thoracic metastatic disease. Again, metastatic burden can play a role in response to therapy, duration of therapy in how that patient does. And if you, based on published results, eliminate patients who have intrathoracic disease only or those who got targeted therapies, the prognosis and survival in response to chemotherapy for the rest of the patient population sort of becomes the same. I think paying attention to these clinical features and knowing what the smoking history is, or whether the patient has intrathoracic disease only, could have something to do with the prognosis that we are seeing.

At least in my view in the absence of controlled randomized studies looking at the patient population, it’s really difficult to be completely comfortable about the numbers in the data that we have out there. But again, the majority of the data forBRAFV600 suggest that a) targeted therapies are highly effective, and b) that these patients tend to have a better prognosis in general, perhaps due to the clinical features or perhaps to response to targeted therapies.

Then the issue that we’re facing now is that even when we do start with targeted therapy, at the time of progression, if we do not find that actionable mutation based on repeat molecular testing, what do you do with these patients? There’s been a lot of interest in looking at immunotherapy, for instance because, again, as many of you are aware, there are issues for other patients on other targeted therapies when we go from one treatment to another. And there are a lot of good data now that clearly indicate that, for instance, patients withEGFRmutations do not respond to immunotherapy as a single agent. Perhaps combinations would be better for that patient population.

The question then becomes areBRAFpatients in the same category, meaning that is it like patients withEGFRmutations, where a single agent immunotherapy might be ineffective? Again, we don’t have randomized trials necessarily, but our colleagues in France have collected the data in a retrospective manner looking at patients withBRAFmutations who had received immunotherapy. And it appears, at least from these retrospective looks, that single-agent immunotherapy could give you the same response rate, roughly around 20%, that we get in patients without mutations.

Again, we don’t necessarily have trials to clearly show us this at this point, all of these are coming. But the notion now is that immunotherapy could have some activity. There are contradictory reports. There are reports that suggest that perhaps that immunotherapy is not as effective. So, these are the areas that we’re still struggling with and we’re trying to find answers to. I would probably say in my practice, in the absence of a clinical trial, once a patient like this progresses through targeted therapy, I will have a serious discussion about not just chemotherapy but even consider adding immunotherapy, in the absence of any absolute contraindications. But obviously, our preference would be to offer these patients clinical trials, so that we can learn from the experience and figure out what the right approach is for the treatment of these patients.

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