Outcomes With Chemotherapy in BRAF-Mutant NSCLC

Transcript:Roy S. Herbst, MD, PhD: Until recently, V600E BRAF mutations were treated like any other in lung cancer—everything was lumped together. So, those patients would have lacked a driver mutation—ALK, EGFR, ROS1—and they would have been treated with chemotherapy, usually a platinum-based chemotherapy.

Most of those patients would have nonsquamous tumors, so they’d probably get carboplatin and pemetrexed in the United States. Some would use bevacizumab as well. They certainly could get carboplatin/paclitaxel or several other regimens, but they would have just gotten standard chemotherapy. Everyone was lumped together. In fact, many of them still get frontline therapy with that, and people save specific therapy for V600E for the second-line setting at this point. But, now, with the molecular testing, you can be more specific. You can give some of the drug that’s going to work against a specific molecular driver, V600E, and have increased efficacy and spare them some of the toxicities associated with combination chemotherapy or even single-agent chemotherapy.

Mark A. Socinski, MD: In the BRAF V600E mutation, we have data for targeted therapy. But the question is, how did these patients behave on standard chemotherapy agents (which I think are the standard of care and have been the standard of care for quite some time)? We don’t have a wealth of data. The data that appear to be there suggest that these patients do behave, typically, as we’ve seen with chemotherapy in the past. So, for instance, recent data looking at the V600E population in the second-line setting suggested that they had a response rate to docetaxel of around 9% and a progression-free survival time of around 2 1/2 to 3 months, which is typical for the population. I don’t think there’s anything prognostic about BRAF with regard to standard chemotherapy, and I assume that these patients get similar benefits from chemotherapy. So, I generally recommend it as an option. But we clearly need more data in this setting to understand this a little better.

Bruce E. Johnson, MD: The current management of advanced non—small cell lung cancer is to characterize those for the oncogenic drivers for which we have targeted therapies. At the current time, that’s EGFR mutations, where you can give one of the EGFR tyrosine kinase inhibitors, the ALK rearrangements for which there’s 3 different ALK inhibitors that are approved. And for the ROS1 rearrangement, crizotinib is approved. For those patients who’ve had BRAF mutations, where we have not had targeted therapy before (these are nearly all adenocarcinomas and the standard therapy for all adenocarcinomas, which would include the BRAF mutants), we have pemetrexed and cisplatin. The outcomes of patients with BRAF mutations who have been treated with chemotherapy have compared to those with other oncogenic drivers, and those that don’t have an oncogenic driver. They’ve been looked at in relatively large cohorts, at our own institution, other places in the United States, and in Europe. It turns out the progression-free survival of the patients treated with chemotherapy who have a BRAF mutation is similar to those patients who don’t have another oncogenic driver.

So, for instance in the first line setting, the progression-free survival of those patients is about 7 months. Now, in contrast, the progression-free survival of the patients who had an EGFR mutation, an ALK rearrangement, is about 15 months. It’s about twice as long. In addition, the median survival, where it’s been looked at in the previously untreated patients, is typical to what we see in unselected patients. That is, in patients who have not had an EGFR mutation or an ALK or ROS1 rearrangement.

In the previously treated patients, that is, typically those who have had cisplatin-based chemotherapy, the progression-free survival is similar, or perhaps a bit shorter, than getting standard chemotherapy. The progression-free survival of the BRAF mutants is typically somewhere around 1 month or 1 1/2 to 3 months; whereas it’s about 3 months for nearly all the other chemotherapy-treated patients. So, therefore, the outcome of the BRAF mutants in the absence of targeted therapies appears to be similar to the patients who are ones who have not been selected for a driver mutation—those patients who don’t have an EGFR mutation or an ALK or ROS1 rearrangement.

Transcript Edited for Clarity