ALK Gene Rearrangements As A Therapeutic Target in Non-small Cell Lung Cancer - Episode 3

Mechanism of Action of ALK-targeting Therapies in NSCLC

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Jyoti Patel, MD, elucidates the mechanism of action of various ALK targeting agents in NSCLC and the optimal formulations and dosing strategies in patients with advanced NSCLC.

Karen Reckamp, MD: Based on this, we do have many drugs approved in the frontline and the second-line setting. I’ll present them in the order that they were approved: crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib, and then there are also data for ensartinib in the frontline setting, though not FDA approved at this time. Can you tell us about the mechanisms of action, how they might be different from each other, and some of the aspects of the drugs up front?

Jyoti Patel, MD: Yes. The story of drug development in ALK [mutations] is instructive on many levels, seeing the clinical observation in a trial that may not have been enriched for patients with ALK mutations, to now a drug in which there are a multitude of very specific targeted therapies. Crizotinib was the first TKI [tyrosine kinase inhibitor] that was approved for ALK, and remember crizotinib is a great MET inhibitor, and that’s where it was being developed. In a patient on an early trial, there was a very deep response to crizotinib, and then subsequent therapy ensued from that clinical observation. Crizotinib is effective, it’s more effective than chemotherapy, but it shouldn’t be used unless nothing else is available or there are toxicity issues. It’s a multitargeted TKI and is probably the least potent of the drugs.

The next drug that was approved was ceritinib. Ceritinib is also quite potent. It’s probably less preferred than alectinib and brigatinib. Initially it was difficult, it was approved after crizotinib at a dose of 750 mg per day. Importantly, there was a randomized, open-label study that demonstrated efficacy at a lower dose, at 450 mg with food versus 750 mg without food; it was much better tolerated. When we first started using ceritinib, many of us would say let’s start low and then titrate up. Many of our patients had a lot of GI [gastrointestinal] effects. There is a cost savings with a lower dose; it’s a drug that nonetheless is exciting, but probably has moved to an older drug status in the United States in particular.

Alectinib is the drug that’s used commonly in the United States, and it’s approved in the frontline setting as well as after progression on crizotinib. Alectinib is overall well tolerated, there’s efficacy in patients with CNS [central nervous system] metastasis, in patients who have impaired performance status. Generally, it’s well tolerated. It’s given in split dosing. The formulation of the pill is a little bit tougher, the starting dose is 600 mg twice a day, that’s 4 tablets twice a day. And there are unique adverse effects for it. There can be some GI upset, some edema, but generally, again, well tolerated.

More recently, brigatinib was another next-generation ALK inhibitor. It targets a very broad range of ALK mutations and has demonstrated activity after crizotinib and in the frontline setting. Initially, in the early studies, there was a little pulmonary toxicity noted. We call it a pulmonary event, patients would have some edema. But the dosing was changed in which it was stepped up, and when that’s the case it’s quite rare, it’s less than 1% of patients. It’s once-a-day dosing, which is certainly nice for some patients. It has some toxicities like higher myalgias, which most of these drugs do, but your CPK [creatine phosphokinase] can get high, you can have some hypertension. But again, it’s generally well tolerated. Brigatinib and alectinib have never been compared head-to-head, so everything we talk about is to a comparator arm, which is dated. It makes it difficult to talk about significant differences between these trials. The number of patients enrolled is certainly small, but ethnicity might be different, comorbidities might be different, and it’s important to keep in mind.

Then finally, most recently lorlatinib was approved. It’s now approved in the frontline setting, certainly after progression on other TKIs was the first indication. In the frontline setting, we know it’s an active drug. It’s highly CNS penetrant and has a real role for some of our patients. But many of us would not necessarily jump on it as a frontline drug because of some of the AEs [adverse events], like the neurocognitive and mood effects as well as hypercholesterolemia. We’re talking about patients, again as Dr Reckamp mentioned, who are on these drugs chronically, hopefully for years, so even low-grade toxicities are ones that we have to keep in mind.

Certainly, all these drugs work as tyrosine kinase inhibitors, and they’re all small molecules. Chemically, their structures are quite similar. Some of the structures are different in that they’re more CNS penetrant, but there are tweaks. For most of us, we would say that the clinical activity probably trumps the biochemical structure when we’re making a decision.

Transcript edited for clarity.