FDA Approval: Frontline Ceritinib for ALK+ NSCLC

Transcript:Mark A. Socinski, MD: So, historically, crizotinib has been our standard in the first-line setting, but we have a couple of examples of the second-generation drugs moving into a first-line setting. One is, as I previously mentioned, the J-ALEX trial, and then at this year’s ASCO, the ALEX trial has compared alectinib to crizotinib. I think many of us were reluctant to take the J-ALEX trial done in Japan and use it as the standard of care after last year’s ASCO. I think this year, if we see the ALEX data replicate the J-ALEX data, there will be a rapid shift from using crizotinib in the first-line to using alectinib in the first-line. So, that is one example of moving the second-generation drugs into the first-line setting. A second example is the recently reported ASCEND-4 trial in which ceritinib was compared to chemotherapy in the first-line setting. This trial had about 370 patients on it. The primary endpoint was progression-free survival. And ceritinib led, again, to a doubling of the progression-free survival, and I believe the progression-free survival hazard ratio was 0.55. So, there was very impressive prolongation of progression-free survival relative to chemotherapy in the first-line setting.

Now, how do we interpret that trial? We have data with crizotinib in one of the PROFILE trials. And tested in the first-line setting, crizotinib was better than chemotherapy. We have ceritinib as better than chemotherapy, and we have alectinib as better than crizotinib. So, those are indirect building blocks to say that we’re transitioning from crizotinib being the standard of care in the first-line setting to one of the second-generation drugs being a standard of care. And I certainly think right now, with the data we have, that to use either ceritinib or alectinib in the first-line setting is a very reasonable choice, based on phase III data that we just discussed.

In the ASCEND-4 trial, the dose of ceritinib that was used was 750 mg, which is the currently approved FDA dose for ceritinib. Many of us feel that that dose is associated with having a lot of GI toxicity and liver toxicity. Most patients have to be dose reduced to either 600 mg or 450 mg. This is an agent that does have a food effect. And there was a recent study that looked at low-fat diets in different doses of ceritinib. If you administer ceritinib either at the lower dose of either 450 mg or 600 mg with a low-fat diet, then the PK exposure that you see is very similar to the 750-mg dose given at a fasting state.

It’s a small study; I don’t think we can necessarily take too much out of it. But one of the early observations in that study was, if you can give the 450-mg dose with food, and its comparable, from a PK point of view, to the higher dose without food, the 750-mg dose, is there a reduction in the rate of toxicity? This early dose-finding study suggested that there were lower rates of GI toxicity at the lower dose of 450 mg. We would also have to have some efficacy data, which we don’t quite know from this trial yet, but we want to make sure that the lower dose isn’t associated with less efficacy. I think many of us would be completely surprised if that were the case, but it’s good to be reassured with some data.

The practical implications of the ASCEND-4 trial are that it creates an option in the first-line setting to use a second-generation ALK inhibitor—ceritinib in this case—knowing that it is substantially better than the combination chemotherapy that was used as the control arm. It does create that option in the first-line setting. Is it now an FDA-approved option? As I mentioned before, there was a near doubling, or about doubling, of the progression-free survival rate in that trial. So, I think the questions are, should you use ceritinib? Should you use alectinib based upon the ALEX trials that we’ve discussed in the past?

But the nice thing about ASCEND-4 is it’s a very nice, well-conducted study. It had a very dramatic benefit in terms of the primary endpoint of PFS over chemotherapy. And I think one of the questions that we have to think about going forward is, if we are going to have 2 FDA-approved second-generation drugs in the first-line setting—alectinib as well as ceritinib—is there an advantage of one over the other? Can you use, for instance, some of the biomarker data to help us decide in which patient is one better versus the other? I don’t think we know that yet, but it does create a couple of options for patients.

Transcript Edited for Clarity