Nuances in Treating Advanced Lung Adenocarcinoma - Episode 11

Evolving Approaches for Treating ALK-Positive NSCLC


Mark A. Socinski, MD: Let’s switch to how EGFR was described in 2004. Let’s fast-forward to 2007 and out. Recently, in the past 2 months or so, we have the approval of brigatinib, the third second-generation ALK inhibitor.

Ross Camidge, MD, PhD: You can call them any generation you like, which becomes a little bit more marketing than science. So, if you and I want to develop a drug, we’ll call it fifth generation.

Mark G. Socinski, MD: So, walk us through that drug, the FDA approval, and your thoughts about it.

Ross Camidge, MD, PhD: On the one hand, you can say, “Well, do we need another next-generation drug, another next-generation ALK inhibitor?” We already have ceritinib licensed postcrizotinib, alectinib licensed postcrizotinib, and now we have brigatinib. And if you look at their response rates, they’re all about exactly the same. They’re about 50% to 55% postcrizotinib.

But as we’ve seen the data mature, we can see that there are differences. In terms of efficacy, 1 of the 2 big differences is the duration of that control. So, if you look at the median progression-free survival, for ceritinib it’s about 6 months, for alectinib it’s about 7 or 8 months, and for brigatinib we have 2 studies—in which patients are dosed—where the up-to-date data are running nearly 16 months. And that’s clear water from alectinib.

The other area where you get a feeling there are differences, but it’s hard to really compare, is their CNS efficacy. And the reason it’s hard is because we backed into the idea that we need to capture robust data in the CNS setting. There are a lot of retrospective elements. Again, they all have responses in the CNS, but when you start to pull apart the duration of those responses, bear in mind that not everybody got MRIs at the same frequency or caught the target lesion in the same way. But if we use brigatinib, because that has the most recent data, it has a median duration response of 18 months in the CNS, so that is pretty impressive.

Mark A. Socinski, MD: Mark, do you have thoughts about the increasing number of ALK inhibitors?

Mark G. Kris, MD: Well, I think it’s a good thing. Just as Ross said, these drugs are not exactly the same; they’re pharmacologically different. They have a different spectrum of side effects. They clearly have different efficacy. I have no doubt that alectinib is a more effective drug everywhere, in CNS and systemically, than crizotinib. There are randomized trials that have shown that. It’s good to have more drugs, though, for individual patients. And then, if you get into what’s the best drug for the different kinds of resistance mutations, having more drugs gives us more options.

Mark A. Socinski, MD: Getting to your point, last year at ASCO, we saw the J-ALEX trial. This year at ASCO, we’ll see the ALEX trial. Is that going to change our standard of care?

Ross Camidge, MD, PhD: I think it will. I really think this is the beginning of a sea change. There are analogies with FLAURA—what happens if you take a drug that has a potentially broader spectrum of coverage in 2 ways? Maybe it covers a different part of your body, the brain. Maybe it also covers some of the mechanism’s resistance, too. And so, that’s alectinib versus crizotinib. In J-ALEX, we’ve seen in the most up-to-date data that the median progression-free survival is more than double when you go on alectinib. It’s something like 11 months with crizotinib and is about 25 months in the latest data with alectinib. I think ALEX is going to look very similar to J-ALEX. So, it changes the standard of care.

Mark A. Socinski, MD: Does crizotinib have a role?

Ross Camidge, MD, PhD: Crizotinib will have a little plaque in the museum.

Mark G. Kris, MD: It’s a MET inhibitor.

Ross Camidge, MD, PhD: And a ROS1 inhibitor.

Mark G. Kris, MD: Yes, it’s going to be very hard to beat for ROS1 inhibition.

Mark A. Socinski, MD: If alectinib is going to move up to be our new standard, what do we know about the other 2 agents?

Ross Camidge, MD, PhD: That is it. You have these moving pieces of the puzzle, and we are in the somewhat data-free zone. So, we have essentially very little data other than anecdotal for ceritinib or brigatinib given post-alectinib. There is another experimental drug, which received breakthrough status designation, called lorlatinib. They have shown response rates running about 25% to 30% after multiple ALK TKIs, which is encouraging, but there’s a little bit of a devil in the details. Exactly what ALK inhibitor were you on? What dose were you on? Because as we’ve said, they’re not all identical. If it does get its breakthrough therapy label, it’s after 1 or more ALK TKIs. So, that is also going to join this crowded space postcrizotinib or, conceivably, postalectinib.

Transcript Edited for Clarity