Advanced Lung Cancer: A Year in Review - Episode 13

ALK-Rearranged & MET Exon 14 NSCLC Treatment Options


Naiyer Rizvi, MD: What about ALK fusions? There are a dizzying number of drugs for ALK out there now. Leora, when 1 stops working, how do you choose the next therapy? Do you go to the next? What’s your plan here?

Leora Horn, MD, MSc: We definitely have a wealth of options to choose from. Right now the choice is fairly easy. The ALEX data are the most compelling data comparing alectinib with crizotinib. The progression-free survival—although we shouldn’t be doing cross-trial comparisons—with ALEX does look better than the ALTA-1L data that were updated with the progression-free survival with brigatinib, and technically brigatinib is not FDA approved in the first line. So our first-line treatment is alectinib, and that’s what we’ve been using preferentially. I think it’s really important to biopsy patients at the time of progression. There is a master ALK protocol that is open across the United States, where based on mechanisms of resistance, patients can be randomized to 1 of the many ALK inhibitors that are approved. A lot of patients on the second-generation ALK inhibitors are going to have G12O2R. Lorlatinib is the drug that is most effective in those patients, when they have a G12O2R mutation present, and so right now our first-line therapy is alectinib. Interestingly, I’m not sure if you guys have seen this, but it more seems to be the ALK patients who are high PD-L1 [programmed death-ligand 1] expression than the EGFR patients. And it is definitely—yes, you are PD-L1 positive, but now you need to wait 10 days until your molecular testing comes back because, you know, you’re young, you’re a never smoker, and even if you’re a smoker, you might have something we can target with an oral agent. A long answer to an easy question, I guess alectinib is my preferred first-line option.

Naiyer Rizvi, MD: That’s very good, but Jacob, you don’t have the master protocol. Are you going to send a plasma test off to help you decide which TKI [tyrosine kinase inhibitor] to use second?

Jacob Sands, MD: That’s the perfect question for what I wanted to say, which is that there is also the SPACEWALK trial, which is a remote plasma-based testing to also look at these fusions or these mutations. There is a study actually for exactly the answer to your question and doing plasma-based testing.

Naiyer Rizvi, MD: OK, so let’s say you’re not doing the trial, and you send off tests.

Jacob Sands, MD: Right, no trials.

Naiyer Rizvi, MD: And you send off a Guardant360 assay. How are you going to interpret the results?

Jacob Sands, MD: No trials. I do think it’s reasonable to send off plasma-based testing. But if you don’t have an answer from that, then I think you’re still looking at biopsy again. If you don’t have anything else to target within there, you’re looking at chemotherapy.

Joshua Bauml, MD: Jacob, just to comment on the SPACEWALK study. I know my patients have participated in this. Your center does not need to have SPACEWALK open. The patients are being contacted directly by the SPACEWALK investigators and send their blood off. They get the results so that we can use it. But this is information. We don’t need to open a separate trial to get access to this sort of information.

Jacob Sands, MD: That’s right. This is a remote-based enrollment.

Naiyer Rizvi, MD: Great. Now we do see these MET exon 14 splice mutations. Josh, do you want to tell me what you do for those patients?

Joshua Bauml, MD: Any patient who has a MET exon 14 skipping mutation at this time, just as Leora’s question was complicated but also easy, we have only 1 drug that is FDA approved at this time. Crizotinib has activity in this space. There are multiple drugs coming out that seem exciting, that seem to have a higher response rate. Capmatinib and tepotinib are some of them, and there are more. Once those drugs get approved, this question will get more complicated because both capmatinib and tepotinib have CNS [central nervous system] penetration, whereas crizotinib does not. I think I would be more likely to use 1 of those drugs when it is FDA approved, but at this time I do not have access to it.

The critical thing to remember about MET exon 14 skipping mutations is that that mutation occurs in an intron. As a result, if your NGS [next-generation sequencing] panel is only exon based, you are going to miss this. Even our panel at the University of Pennsylvania, we usually don’t see it on our mutation panel. We see it on our fusion panel, as a MET exon 13 to 15 fusion; that’s MET exon 14 skipping. It’s something that we need to be aware of as we are doing testing.

Naiyer Rizvi, MD: There’s been a small series that was presented last year at, I think, World Lung [World Conference on Lung Cancer] showing some really remarkable responses to immunotherapy in these patients. Have other people seen exceptional responses with MET exon 14 splice mutations to I/O [immuno-oncology] even in never smokers?

Leora Horn, MD, MSc: I have not, and there was another series that showed that those patients didn’t respond to immunotherapy. So I don’t know. These patients are more likely to be the smokers. There we do see MET a lot in patients with a history of smoking, so maybe there are a lot of confounding factors. But I have yet to see 1 patient respond.

Joshua Bauml, MD: That series that you’re quoting there I believe was out of France, and the series that showed it didn’t work was in New York City. I’m wondering if there are different patient populations between Memorial Sloan Kettering Cancer Center and France.

Transcript Edited for Clarity