Lung Cancer Update, Issue 3, 2016 (Video Program) - Video 12J-ALEX trial: Alectinib versus crizotinib in ALK inhibitor-naïve NSCLC
8:04 minutes.
TRANSCRIPTION:
DR MOK: This is a Japanese study — alectinib at 300 mg twice daily with the standard of crizotinib. And that is for ALK-positive patients. And so the study is actually aimed at a progression-free survival difference. And then they had approximately 100, approximately, per arm. So the study was outrageously positive, with a hazard ratio of 0.34. The control arm is actually about 10.9 months, which is what you expect from crizotinib, while the median progression-free survival of the alectinib arm is actually not reached yet. So it has to be over 20 months. And so that is quite outstanding. And that is actually in line with the Japanese finding of the so-called single-arm study of alectinib, which is actually a progression-free survival of about 26 months. And that is actually what had been happening with the Japanese data. Now, whether that is going to be translated into the same outcome in the outside Japanese country, that remains to be seen. So there’s another study called the ALEX study, which is actually a bigger sample size, over 300 patients. And that study, we had already completed accrual. And now we’re just waiting for the data to become mature. DR LOVE: So yes, when I saw that hazard rate, I was just shocked. And then those numbers, exact numbers, those are the numbers in the abstract. DR MOK: There is shock, and yes and no. In a way, it’s that we know that alectinib is a more potent so-called ALK inhibitor. And second is that the CNS penetration is better. That had been reported in Ignatius Ou paper in JCO with their intracranial response rate close to 50%. And so I think a lot of the so-called progression events may actually happen in the brain, because in ALK, there’s a high incidence of CNS progression, coming anywhere close to 40% to 50%. So if you get better CNS control, you may actually win by just having a better CNS control and prevention of actually progression in the brain. DR LOVE: Wow! That makes complete sense, because either way, you see a very high rate of response, crizotinib over alectinib, right? DR MOK: Right. DR LOVE: But what you’re saying is, maybe more people break through with brain mets. DR MOK: That is one thing, and plus the response rate is actually higher, actually 85% versus 70%. DR LOVE: Yes, really interesting. And, of course, as you say, I guess survival is just really not on the table yet, too early. DR MOK: Not quite. It’s too early. Yes. DR LOVE: But it would seem also better tolerated? DR MOK: Much better tolerated in terms of GI toxicity, because the nausea/vomiting and diarrhea would be less. DR LOVE: So are you thinking that this is now going to become first-line therapy, alectinib? DR MOK: I think alectinib may become first line eventually, but I think we have to look in a little bit more detail before we change our minds, because the J-ALEX study is not purely a first-line study. It’s a combination of first- and second-line patients, because they will have some patients with prior chemotherapy before they got randomized. So in other words, it’s not a first-line study. It is just crizotinib now alectinib study. DR LOVE: Right. Got it. DR MOK: And then as compared to ALEX, is a purely so-called a first-line study. DR LOVE: But, I mean, just last night we had a satellite with 5 researchers. And all 5 of them were like, “We’re ready to give alectinib first line,” but they did bring up the one thing that you mentioned, the question that this study was done in Japan and waiting on the study in the US. And you had a really great paper in the JCO this year, Cancer Genomics: Diversity and Disparity Across Ethnicity and Geography. DR MOK: Yes. DR LOVE: You could probably spend an hour talking about it. But particularly with reference to this data and this issue, how would you contrast what you might expect in Japan and, for example, North America? DR MOK: First of all, I think we have to talk about 2 things. One is the basic ALK phenomenon. So there is actually a slightly higher incidence in Asian population with the ALK. So the incidence can be slightly different. But one thing, actually, we did not know too much about are the variants. So right now we know that there are about 15 different variants. But whether there is actually any ethnic immunological difference between the variants of one population to the other, that is not too clear cut. So would the Japanese actually have some more sensitive variant? Like, the Variant 1 is supposed to be more sensitive to the TKI. So those we probably have to learn a little bit more. The other is about the pharmacogenomics. At this moment, I mean, we are not aware of significant pharmacogenomics. The difference in the dosage, actually, is not pharmacogenomics. It’s rather to do with the drug, with the solvent, the maximum concentration of solvent you’re allowed to use in Japan. So it becomes a little bit interesting. Why we see such a phenomenal result with the Japanese population is still unknown. But that is probably likely translated, is going to be in American population. Whether the degree of difference is the same or not remain to be seen. DR LOVE: So you mentioned the issue with the brain mets. And I’ve heard about a couple of cases of people with leptomeningeal disease responding to alectinib. I’m not sure if I’ve seen it in the literature, but what do we know about that? DR MOK: Yes, there are some reported on the leptomeningeal response. But there’s a couple of issues. Number one is the documentation of response, not so easy. You may have some radiological response, but very few people will have a CSF documentation of a response. So that is slightly tricky. But then a case report of such had been actually discussed and presented before. DR LOVE: And what’s your vision in terms of why alectinib is more effective in the brain? Is it just blood-brain penetration, or something else? DR MOK: Yes. I think it’s actually the molecule and, also, the so-called crossing the blood-brain barrier ability is higher with alectinib. And also, the dosing is slightly different as well. I mean, crizotinib, due to some of the GI toxicity, you can’t really dose too high. DR LOVE: It’s interesting that it was described as being less toxic, as you say. And for oncologists in practice, I have 300 of them in a room and I say, “How many of you have had a patient, ALK disease?” Like, nobody raises their hand. It’s like this phantom disease, really. But in any event, you mentioned the variants of it. And I’ve heard some, to me, kind of scary cases of people who were FISH-negative for ALK and, quote, positive for ALK on a next-gen sequencing and then responded to crizotinib. Is that true? DR MOK: That is actually certainly true. Right now we have IHC, FISH and, also, PCR by sequencing. And then there are actually some discrepancies between what we call the IHC-positive and FISH-negative and vice versa. So the best responders are actually what we call double-positive, IHC- and FISH-positive. And that group seems to have the best response so far. And so next-gen sequencing may potentially pick up some of the cases that can be missed by FISH. DR LOVE: One more thing about crizotinib: I kind of always had this vision — again, oncologists, they’ve hardly even used the drug. But I’ve had this vision of it being very, very well tolerated, the visual things, et cetera. But how much of a problem is GI toxicity? DR MOK: It’s not too bad. I mean, in a way it’s that most patients may have some degree of nausea but never too severe. Vomiting is not too common, is manageable, in a way. But just alectinib is actually even less. That is just by comparison. This data will actually come out in the J-ALEX study as well, the comparison of the toxicity side by side. DR LOVE: Interesting. |