Expanding Targets in NSCLC - Episode 2
Transcript: Bruce E. Johnson, MD: We’ve been able to join forces with members of the pharmaceutical industry to bring joint inhibition to patients with BRAF V600E-mutated non—small cell lung cancer. We did a series of trials that started in 2011, where you administered the BRAF inhibitor, dabrafenib, as a single agent to patients. It had rather predictable activity, with a response rate of about 33% and a progression-free survival of 5.5 months. So although it worked, somewhat, most of the patients did not respond. And in those who did respond, it was relatively short, working for only about 5 or 6 months.
Once they had determined the antitumor activity of dabrafenib as a single agent in BRAF V600E-mutated non—small cell lung cancer, we did the same thing they did in melanoma and added the MEK inhibitor, trametinib, to the combination. With that, the response rates went from 33% to 63%—a near doubling. The duration that it worked went from about 5 to 6 months to around 10 months. Therefore, it was rather dramatically effective.
The other part that was very helpful about it was that it also prevented the development of skin cancers. The skin cancers were related to the activation of the MAP kinase pathway. So by inhibiting MEK, you ended up inhibiting the development of the skin cancers, making it easier to manage.
The single FDA and EMA [European Medicines Agency] approved regimen for BRAF-mutated non—small cell lung cancer is dabrafenib and trametinib. That’s the only 1 that’s been through trials. The other available combinations are vemurafenib/cobimetinib and encorafenib/binimetinib. There will be a trial opening for encorafenib and binimetinib soon. There are also some basket trials, meaning that they take different tumors with BRAF V600E mutations and treat patients with the combination of vemurafenib and cobimetinib.
So there are 3 different regimens available. All 3 of those are approved in melanoma, but the last 2 have not yet been tested and reported on in cohorts of non—small cell lung cancer.
One of the common features of the oncogenic drivers for which we have targeted treatments, mutations of the epidermal growth factor receptor, rearrangements of ALK and ROS, and also MET exon 14 mutations and NTRK rearrangements: These commonly arise in nonsmokers. The checkpoint inhibitors don’t work very well in patients who haven’t smoked very much. And at least in the EGFR-mutated and ALK-rearranged tumors, the checkpoint inhibitors aren’t very active.
The thing that’s different about the BRAF-mutated patients is that most of them have smoked, so it’s quite different. You typically see between 70% and 80% of those other oncogenic drivers in never-smokers. Whereas in those with BRAF mutations, it’s only about 30% to 40%. The reason why they bring that up is because the patients who smoke are the ones who carry the most mutations, and are the ones who are most likely going to respond to checkpoint inhibitors. Therefore, the bigger question with the BRAF-mutated patients is, how effective would the checkpoint inhibitors be in this patient population compared to the BRAF V600E mutated?
We’re collecting some real-world data on this to try to understand it, but we don’t have a firm answer yet about how active the checkpoint inhibitors are in this patient group. And as I said before, I think it’s important because this is a group—the smokers—who are likely to respond to the checkpoint inhibitors.
We would not use BRAF inhibitors or MEK inhibitors as single agents. For instance, we would not use them sequentially. It’s important to use the combination because the MEK inhibitors are not very active as single agents against BRAF-mutated non—small cell lung cancer. When we did the sequential trials using dabrafenib and trametinib, we had to show that there was a component of each drug that was contributing to the therapeutic efficacy. That’s the reason why we did dabrafenib as a single agent, even though that had a lower response rate versus the combination in melanomas with the V600E mutations. But we showed the response rate was about 33%. And then, when you added the second drug, the MEK inhibitor, you ended up seeing a response rate of about 63%—nearly a doubling. Therefore, you knew that each drug was contributing in part to the response.
BRAF-mutated non—small cell lung cancer has about 50% of V600E, with the others scattered throughout the BRAF gene. It turns out that, thus far, there’s no effective targeted agents against those other BRAF mutations. So there’s an ongoing effort to catalogue the different BRAF mutations. There are hundreds of them. Part of the problems of sequencing is that if you end up finding a sequence that’s different than what you think of as normal—some are just normal variation, and some are activating the different downstream MAP kinase pathway—they begin to categorize these BRAF mutations into class 1, 2, and 3, depending on how much they activate the MAP kinase pathway or whether these are just variants of unknown significance. So there are lots of different mutations. Thus far, it’s not terribly important to identify them because they don’t have an effective targeted agent developed against them. Just the BRAF V600E mutations, which is half of the BRAF mutations in non—small cell lung cancer.
The patients with BRAF mutations other than V600E should be treated the way we treat other adenocarcinomas. The BRAF mutations are detected almost exclusively in the adenocarcinomas, so they should be treated the way we treat other adenocarcinomas. They should also undergo the characterization that’s similar to other adenocarcinomas. The things we use for predictive markers for whether you should get immunotherapy, immunotherapy plus chemotherapy, or chemotherapy alone has to do with PD-L1 [programmed death-ligand 1] testing and determining tumor mutation burden. This helps determine whether to give the immunotherapy by itself, the immunotherapy plus chemotherapy, or chemotherapy.
Transcript Edited for Clarity