Clinical Perspectives on New Data in Advanced NSCLC - Episode 13

Considering Targeted Agents in BRAF-Mutant NSCLC

Transcript: Benjamin P. Levy, MD: We’re going to move on for the sake of time to our last session. We think of precision medicine in NSCLC [non—small cell lung cancer], and of course that story was first told in the EGFR and ALK chapters. But we now have other druggable mutations that we routinely identify in comprehensive genomic profiling that have made a meaningful impact on our patients. We’re going to start with BRAF, specifically BRAFv600E. David, do you want to talk about the importance of identifying BRAF and the targeted therapies that are used for this molecular cohort?

David Planchard, MD, PhD: Sure. BRAF is quite a rare alteration. It’s found in around 2% of non—small cell lung cancer cases. The most important alteration is BRAFv600E. It’s in around, I would say, 70% or 80% of BRAF alterations. What is particularly important in the BRAF population, in comparison to the ALK population or the EGFR population, is that you cannot select this population to be screened according to smoking statuses. This population is only one-third never-smokers, but two-thirds former or current smokers. That means you need to screen all patients, whatever their smoking status, which is quite different from the EGFR and ALK populations. It’s mainly adenocarcinoma. That means you need to screen all adenocarcinoma to capture this population with a BRAF mutation.

In this population, as it was done in melanoma, we used to treat with a BRAF inhibitor, which was dabrafenib or vemurafenib. It works, but the response rate is between 30% to 40% and the median PFS [progression-free survival] is around 5 months. I would say that’s not in the benefit range we might expect, whereas for the EGFR or ALK populations, you might expect a 60% response rate with median PFS around 10 months. The second part is that we know most of the tumor cells might escape with MEK activation when you block BRAF. As in melanoma, again, we performed a trial with a subcohort combining a BRAF inhibitor and a MEK inhibitor, which were dabrafenib and trametinib. There were 2 different cohorts.

One cohort of patients had received at least a platinum-based chemotherapy prior in the first line. The second cohort was treated up front, in the first line, with dabrafenib and trametinib. When you block BRAF and MEK in this case, you double the response rate. It is a 63% response rate. You also double the median PFS: It’s around 11 months. Clearly, this is a standard in all the guidelines. It’s mainly approved in all countries. This is something we need to screen for. If you don’t screen, you will never find this population. If you find this population, you might treat either first line or second line—you will have and observe the same magnitude of benefit—with dabrafenib and trametinib.

And at the latest meeting, we have seen again a cohort of patients, a French cohort, that has access to vemurafenib as monotherapy. We treat only with vemurafenib as monotherapy. And again, it’s confirmed that if you block only with monotherapy, you don’t optimize the magnitude of benefit. The response rates are around 40% and median PFS is around 5 months. It’s not enough. We really need to have this combination to have the best benefit in this population.

The last thing, because it’s also an important question when we target patients with BRAFv600E mutations, is what to do with the patient who has a non-BRAFv600E mutation. It was looked at in the French trial with vemurafenib. If you block this population with vemurafenib, the response rate is close 0% and the magnitude of PFS is between 1 or 2 months. As we already know, you should block only BRAFv600E-mutated patients; for the non-BRAFv600E—mutated population, we don’t know what to do. Perhaps we might use an immune treatment if they are a smoker.

Benjamin P. Levy, MD: Not all BRAF mutations are the same.

David Planchard, MD, PhD: Exactly. It’s the same for the EGFR population. You have a specific mutation of sensitivity. You have the intermediate mutation. You have the resistance mutation. We have exactly the same situation. We have to look if it’s exon 15 BRAFv600E mutation. If it’s BRAFv600E, these patients should probably be treated with a different combination of chemotherapy treatment or other targeted therapy.

Benjamin P. Levy, MD: Just briefly, what is the global perspective on routinely interrogating BRAF in all of your patients and using it frontline if discovered? Or is it mostly after chemotherapy?

Solange Peters, MD, PhD: Routinely assessing for these drivers in patients with advanced disease, of course, frontline: as soon as we can with an NGS [next-generation sequencing] dedicated panel. Of importance, the smoking stages help enrich our search for the probability that we think about. But I test every nonsquamous patient. When I’m not confidently facing squamous cell carcinoma advanced disease and I have no reason to think I’m making a mistake, I will just test all the nonsquamous patients for all these alterations.

Sanjay Popat, PhD, FRCP: In the United Kingdom, dabrafenib/trametinib is not commissioned by the NHS [National Health Service]. As genotyping follows the drug approval at the moment, the United Kingdom patients don’t have access to this. There have been genotypes in research programs and BRAF inhibitors in the context of the research setting.

Benjamin P. Levy, MD: Just quickly, David, what are the toxicity signals with these drugs? Pyrexia? Are there any others to be mindful of when giving dual BRAF and MEK inhibition?

David Planchard, MD, PhD: You have this type of toxicity with this type of combination that we don’t have with an EGFR TKI [tyrosine kinase inhibitor] or ALK TKI, regarding pyrexia. It’s mainly related to dabrafenib, but it’s quite easy to manage. If you need, you can decrease the dose level. It’s quite easy and generally, it’s not an issue to continue treatment. In my experience, I have never had to completely stop the treatment due to the pyrexia. You can give an anti-inflammatory corticosteroid and decrease the dose level if you need, and generally it’s completely resolved. It’s not an issue.

With trametinib, there are some patients who might develop some pulmonary toxicity. But it’s between 1% to 2%, so it’s quite a rare toxicity. In this case, you can continue the dabrafenib and stop the trametinib. And lastly, you may observe some digestive toxicity, but it mainly has 1 toxicity. So, that’s quite comfortable.

Benjamin P. Levy, MD: It’s well managed.

David Planchard, MD, PhD: Yes, and lastly, there’s the cutaneous toxicity. You potentially have a lesser proportion of cutaneous toxicity with the combination in comparison to the monotherapy. That’s why the tolerability is quite fine.

Transcript Edited for Clarity