DR REILY: So the second generation of ALK inhibitors are, I have to say, just remarkable. Crizotinib was developed first as a MET inhibitor. And ALK showed up in the profile and it was taken advantage of and has been key to its development. But these drugs, LDK378 and another drug called alectinib, are purpose built to target ALK. And these drugs are in development right now, and both of these drugs are relatively early in the development, which is to say that they’re at the end of Phase I into early Phase II trials. But as we saw with crizotinib, while that may seem early in its development, they may hit the clinic much sooner than you’d ever imagine.
So just to talk briefly about LDK378, the data that we’ve seen so far is all based on the Phase I trial. And this is like every other Phase I trial. It allows patients with multiple prior therapies and, in this case, specifically allowed patients either with or without prior crizotinib. And in developing the right dose and that sort of thing, it’s now hit the maximum tolerated dose or the recommended Phase II dose, and that’s 750 mg once a day. And that’s what’s currently being investigated. The data that’s been presented so far, though, includes doses down to 400 mg a day, because there didn’t seem to be a big difference in the response rate for 400 versus 750 mg.
But that response rate is high. So in patients who’ve had prior crizotinib, the response rate to LDK378 is about 59%. Similarly, in patients who have not had prior crizotinib — so those are ALK-positive patients, no prior crizotinib — similar 59% response rate. So dramatic response rates. They’re excellent response rates. It’s very surprising, though, that the response rate is the same, whether you had prior crizotinib or no prior crizotinib. The median progression-free survival for this drug in this setting is about 9 months. I think that’s kind of a recurring theme in our development of kinase inhibitors in lung cancer, median progression-free survival of about 9 months.
I think one other really interesting piece of data that was presented was based largely on the specimens from Mass General in patients who progressed on crizotinib. Patients were then biopsied, and they looked for mechanisms of acquired resistance to crizotinib. So we know a little bit less about this, a lot less about this than we know about EGFR tyrosine kinase inhibitors, but we know that in acquired resistance to crizotinib, there are second-site mutations in ALK. There are other bypass track activation mechanisms. But importantly, when they looked and they saw this broad variety of mechanisms of acquired resistance, there was no linkage to response to LDK378. LDK378 worked without regard to the type of acquired resistance that was observed. So it was really a remarkable thing, I think, and it makes us question what we truly understand about these mechanisms of acquired resistance. Are they real mechanisms, or are they just phenomena that we’ve observed and that are associated with acquired resistance? But either way, it shows that this stuff seems to work very well either with or without prior crizotinib.
DR LOVE: So the waterfall plot for this one, as well as alectinib, are very impressive as typically we see with TKIs with driver mutations. But they had this really interesting waterfall plot. I think it’s what you were referring to in terms of response in, quote, molecularly defined crizotinib-resistant tumors. And again, everything went down.
So what about the other compound that you were talking about, the CH5424802? Actually, there’s a paper in Lancet Oncology this year about it.
DR RIELY: Right. So this is alectinib. This is the competitor, second-generation kinase inhibitor. This drug saw its initial development solely in Japan. And this was developed between 2010 and 2012 in Japan. The Phase I was done there. And this is the report of the Phase I trial.
All these patients, during this time crizotinib had not been available widely in Japan, neither approved nor available on clinical trials. So as a consequence, all the patients in this trial were crizotinib-naïve. That said, the response rate at the recommended Phase II dose here of 300 mg twice daily, was 93.5%. Ninety-three percent response rate in these crizotinib-naïve patients. So really a remarkable response rate.
We again know relatively little about the adverse events, given that it’s a relatively small patient population, but we do know this isn’t actually a maximum tolerated dose at 300 mg twice daily. They stopped for nontoxicity reasons.
DR LOVE: Now, has this drug either in this or any other study been reported in terms of patients who have clinical crizotinib resistance, the way LDK378 has?
DR RIELY: Yes. So there’s been some early data presented showing that this has a similar efficacy to LDK378 in the population of patients who have crizotinib-acquired resistance.
DR LOVE: So what’s the thinking in terms of developing these kinds of agents and these two, in particular? I would think that people are talking or thinking about up-front treatment. What are some of the strategies?
DR RIELY: Yes. I think certainly people want to initially get this drug to patients who need it. And that’s really the patient population who’ve had prior crizotinib and are beginning to fail. So that’s a group of patients who need it, and I think that’s the most likely path to its initial approval.
Of course, people wouldn’t want to always have to take 2 drugs if they could do better with the first drug. And so I can imagine a setting in which we’ll explore first-line therapy with either of these new drugs.
I think the challenge there is what we’ve seen with LDK378, which is that the response rate and progression-free survival are similar for patients who have not had prior crizotinib as to those who’ve had prior crizotinib. So if you can get a response and progression-free survival of, say, 9 months on crizotinib, and then you can add another response and another 9-month progression-free survival with LDK378, that may be the sensible thing for a patient. And I think we’re definitely going to need to have some data to help us guide that path.