Non–Small Cell Lung Cancer Clinical Care - Episode 12

ALK Inhibitors and BRAF/MEK Inhibitors for NSCLC

Anne Tsao, MD: There’s an enormous paradigm shift that’s occurred in the ALK and ROS1 populations, mostly because we’ve had additional therapies that have become FDA approved. Previously we had only crizotinib, which did not cross the blood-brain barrier, and it was a very good TKI [tyrosine kinase inhibitor]. But a lot of these patients develop metastatic disease in the brain. And so luckily, ceritinib came on to the landscape, and this was used for salvage ALK inhibitor, ALK-translocated non—small cell lung cancer patients. And it crossed the blood barrier. But very shortly after ceritinib became approved, alectinib was approved for the front-line setting. And this is a very well-tolerated agent. Many patients are on this for a significant duration with excellent response both in the CNS [central nervous system] and in the body.

The good news is we now have 2 additional ALK inhibitor agents: brigatinib as well lorlatinib. And so lorlatinib has FDA-accelerated breakthrough designation, but you can get it now for your patients. Generally, the current treatment paradigm is many patients are getting alectinib front line, and then after that going to either brigatinib or lorlatinib, first for the ALK-translocated patients.

For ROS1, it’s important to note that not all these ALK inhibitor agents have ROS1 coverage. For instance, alectinib does not cover ROS1.

In the ROS1 population it’s important to remember that not all of these ALK agents will actually cover ROS1. So the usual treatment paradigm we have is you can use crizotinib and then you could also go to ceritinib. And recently there have been clinical trial data suggesting that lorlatinib might have benefit in ROS1 patients. It is not FDA approved yet for ROS1, but it’s something that we’re keeping our eye on. And there, again, are many agents in the pipeline that hopefully will provide additional options for these patients with oncogenic-driver mutation.

My personal preference in the frontline setting is to actually go to alectinib, mostly because of patient tolerance. But we do know now that there are certain resistance mechanisms that occur with each of these ALK inhibitor agents. And so there is an ALK master protocol, which is specifically looking at patients who have these ALK driver mutations and biopsying them after they develop resistance to a particular ALK agent, and then depending on their mutation, they may be allocated then to a specific ALK inhibitor. We need to learn more about the resistance mechanisms in order to optimize the sequence of these ALK inhibitor agents for these patients.

Roy Herbst, MD, PhD: The whole idea of BRAF V600E and dabrafenib has been a wonderful story. And of course, you use a MEK inhibitor, trametinib, because when you block BRAF, you upregulate MEK, so you have to block MEK as well to sort of keep things going. In lung cancer, it’s a good regimen. This is not a targeted therapy like you’re thinking about with an osimertinib or an ALK inhibitor, alectinib or something like that. Because response rates are only in the 20%, 30% range. Toxicity is a little bit later. The duration is reasonable. I think it was 3 to 5 months on the median, something like that. So it’s a good result, but it’s not quite as good as some of the other drivers we have. But clearly, if you have a patient who has this, they should be getting this, probably not in the first-line setting yet, although first-line trials are ongoing right now. I haven’t seen those results. I think they should be maturing pretty soon. But I think clearly it’s an active regimen and 1 to think about. The BRAF and MEK combination needs for be tested for in lung cancer because if we can use it, it ca