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Are There Clinically Significant Differences Among the Second Generation ALK Inhibitors?
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Drs. Ben Solomon, Leora Horn, & Jack West evaluate the evidence and consider whether there are clinically significant differences among the second generation ALK inhibitors that would lead to a reason to prefer one over another for a particular patient.



Dr. West:  Let’s talk about ALK rearrangements; they’re present in about 4 or 5% of the population, at least outside of Asia, and we’ve gone from, just a few years ago, having one agent, crizotinib (Xalkori), as the first line treatment, to now having a plethora of second generation ALK inhibitors. Are they clinically significantly different, and is there a reason to select one over another for an individual patient? Ben, what do you think?

Dr. Solomon:  So, we know that they’re different in terms of how they work in the lab. Some of the second generation compounds are more potent inhibitors of ALK itself, and can work against some of the mutations that make tumors resistant to crizotinib, and the other difference that’s emerging in the clinic is, some of the second generation inhibitors seem to have better activity in the brain than crizotinib does. So, I think there are some significant differences, and we know from trials that some of these drugs, so, ceritinib, alectinib, and brigatinib, can work in patients whose tumors have progressed on crizotinib, and do have pretty impressive activity in the brain.

Dr. West:  Leora, what do you think? Is there one second generation ALK inhibitor you’d favor, based on its therapeutic index, or unusually good activity in the brain, or is it what’s on hand?

Dr. Horn:  So, right now, the only thing on hand is ceritinib, but as more drugs become available, I think toxicity may, again, be an issue with ceritinib being a little more toxic in terms of GI side effects than what we’ve seen with alectinib. I’m obviously biased to X396 because we’ve been leading that development for a while, and, you know, we’ve seen that it’s well tolerated, and has CNS (central nervous system) penetrants.

Dr. Solomon:  Sorry Leora, I should have added that onto the list, too.

Dr. West:  I mean, the challenge is that it gets harder and harder to penetrate into a crowded market. Can a new drug, like X396 or brigatinib, after alectinib — can these drugs differentiate themselves when there are already various alternatives out there?

Dr. Horn:  Yeah, so I think what’s interesting and different about ALK, than we see with EGFR — with EGFR we do have multiple third generation inhibitors, but they’re all targeting T790m. When patients develop resistance to crizotinib, it’s a much messier story, and there are multiple reports coming out of patients getting a second generation inhibitor, and then progressing and subsequently responding to a different second generation inhibitor. I think that an inhibitor that has good CNS penetrants is going to be interesting, even upfront, because we know that 50% of patients on crizotinib will have CNS disease as their first site of progression, but I think time will tell if there’s one second generation inhibitor that’s really going to win out.

Dr. West:  So, are you optimistic that, in the relatively near-term future, we’ll be able to characterize the mutation in acquired resistance, and select one form of second generation inhibitor for one patient and a different one for another?

Dr. Solomon:  Yeah, so I think there are certain instances where you can define a mutation and then say that mutation is covered by, for example, ceritinib, but not alectinib, or vice versa, and make a choice based on that. But, for many patients who progress on crizotinib, we don’t find mutations, and these drugs are still active, so that won’t be the entire story. So, how to choose between the inhibitors, if they’re all available, will come down to toxicity, but we might have some clues based on mutation profile, as well. But I’m not sure that will be the sole way that we’ll be able to make a rational choice.

Dr. Horn:  And I think it will come down to cost, as well.

Dr. West:  But they’ll probably be priced comparably enough that there won’t be one that’s way more appealing for cost considerations.

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