Novel Therapy for NSCLC With ALK Rearrangements


Focusing on ALK-rearranged non–small cell lung cancer, expert panelists review data behind alectinib, brigatinib, and lorlatinib.


Benjamin Levy, MD: Let’s move on to ALK. [Give us] a brief overview of the drugs in ALK and where we are therapeutically.

Heather Wakelee, MD: We have a wealth of options in the ALK setting, which is fantastic. Obviously, we started with crizotinib, and that’s still used in the rest of the world quite a bit. The problem, of course, is that it doesn’t get into the brain as well. It’s not quite as potent. Then there’s ceritinib, which was better than crizotinib worked after it, but a little more toxic. There’s some brain activity, but when we got to the alectinib data, that’s where most of us are still using first-line data with the ALEX trial. I know you were very happy with that name.

Alexander Spira, MD: I came up with the name all by myself.

Heather Wakelee, MD: There’s phenomenal disease-free survival, and now we’ve got OS [overall survival] data. Those look great, with wonderful brain activity and pretty good tolerability for most patients. Since that time we’ve had data looking at brigatinib vs crizotinib, ensartinib vs crizotinib, and lorlatinib in the CROWN trial. Each of those studies has been positive, showing that the newer-generation ALKdrugs are definitely better than crizotinib.

We’re left with which to choose. Alectinib was the first that got there, so that’s still what most of us are using. When I think about brigatinib, yes, it’s a reasonable trial. It has slightly different toxicity profiles, and we’ve done a lot of work with ensartinib. We still use that on trial for some patients because the toxicity profile is very different. I realize that most people don’t have access to that, but it’s probably going to be developed outside the United States. The lorlatinib CROWN data were just updated at AACR [American Association for Cancer Research Annual Meeting], and that 3-year disease-free survival is pretty impressive.

Benjamin Levy, MD: That’s CNS [central nervous system] activity.

Heather Wakelee, MD: CNS activity of lorlatinib is a little better than brigatinib and alectinib, though they’re both really good. Am I going to switch to lorlatinib first line? I don’t know because it’s so toxic, and it’s toxic in ways that are hard. People aren’t quite themselves. They’re a little depressed. It’s hard to manage those lipids. I can’t get the triglycerides down in some patients.

Benjamin Levy, MD: Put your internal medicine hat on, Heather.

Heather Wakelee, MD: You can do it, but you wonder how many people are going to start having cardiac issues if their lipids are staying high for 3, 4, or 5 after when they’ve already been through a few years of other drugs. It works great after those other ALK drugs. It’s harder to think about it there, but it’s hard to argue with disease-free survival at 3 years that was over 50%. It was pretty darn good.

Benjamin Levy, MD: Really good.

Heather Wakelee, MD: I think it’s still evolving and it’s just fantastic. I mean when I have a patient diagnosed with ALK I can look them in the eye and say you’re probably going to be here in 5 years. I mean how awesome is that with metastatic disease?

Benjamin Levy, MD: The frontline decision, just like EGFR, is really quick. Jonathan, what do you do post alectinib at the time of disease progression if there’s a need for a therapeutic switch? Are you a lorlatinib guy, or are you biopsying? How do you approach these patients?

Jonathan Wesley Riess, MD: That’s a great question. I always send plasma to see if I can identify if the out fusion is present in circulating tumor DNA, if there’s an on-target mutation, or if there’s a bypass track. If I could detect it, and there’s an on-target mutation, I often will do lorlatinib. There are some published data that response rates are higher in those situations. I go to that heat map, where you may be able to match to lorlatinib or another drug depending on that on-target resistance mutation. Sometimes if there’s a bypass tract, I’ll go to carboplatin-pemetrexed. Pemetrexed-based chemotherapy can be quite effective in patients with ALK-positive lung cancer, so I don’t always reach for lorlatinib. That’s a situation where I may do carboplatin-pemetrexed. We’ve published some data. For example, if I’ve had a patient with a mechanism of resistance and high MET amplification, I’ve gone back to crizotinib and gotten responses when there’s both an ALK mutation and METamplification as the mechanisms of resistance.

Benjamin Levy, MD: We have a lot to learn with mechanisms of resistance and how they inform treatment decisions both for EGFR and ALK. We didn’t get a chance to talk about the KRASG12C mechanism of resistance. We’ll have some data from ASCO [American Society of Clinical Oncology Annual Meeting] looking at the largest circulating tumor DNA postdiscussion within the resistance setting. But it’s a lot to learn over the next few years about how to leverage it use it.

Transcript edited for clarity.

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