ASCEND-4: Upfront Ceritinib in ALK-Rearranged NSCLC

Transcript:Tony Mok, MD: In the World Lung Cancer Congress in Vienna this year, there was an important study by the name of ASCEND-4 that was presented. And the ASCEND-4 is the first randomized study of a second-generation TKI, namely ceritinib, in comparison with standard chemotherapy. The study tried to establish the role of ceritinib as a first-line agent. The median progression-free survival of ceritinib was actually 16.6 months versus about 8.1 months of chemotherapy. So, it’s almost double the median, and also the hazard ratio is highly significant.

The question is whether this should be a standard or not. Now, in my opinion, it can be one of the standards because it has been shown to be superior to chemotherapy, and therefore it can be one of the options. However, it’s not a direct comparison with crizotinib, so therefore we cannot say whether one is better than the other. Although with crizotinib, it was 10 months on the median compared to 16 months on ceritinib. But we cannot really compare through different trials. So, we can only know the information that it is better than chemotherapy, and both drugs have potentially been used as a first-line scenario.

Now with the ceritinib being recognized by ASCEND-4 to be a first-line treatment, how would this impact on the clinic in a way of how doctors should select? That reminds us that ceritinib may have actual benefit of the CNS penetration that is slightly less so with the crizotinib. So, maybe in a first-line situation, if a patient has brain metastases, it is more tempting to consider the second-generation drug rather than the first-generation drug as a frontline therapy.

David Spigel, MD: Crizotinib has been a fantastic therapy for newly diagnosed patients with ALK rearrangements. And there has been the approval of next-generation drugs, ceritinib and alectinib, for patients who progress on crizotinib. The next logical question in development of therapies in this space is, can you move these potentially more active and better therapies into earlier treatment settings? Ceritinib has tried to get into this area by being compared to chemotherapy. And those data were presented recently in a trial called the ASCEND-4 study. All the ceritinib studies are named ASCEND. The ASCEND-4 study was a simple study. Patients with newly diagnosed ALK rearrangements were randomized to chemotherapy or to ceritinib. Now, this was done at a time before crizotinib was widely available. Obviously, in places where crizotinib was available, that was the standard of care. But there was a time when, still in regions of the world, you only had chemotherapy as an option. And what we found out is what was expected: that ceritinib clearly beat chemotherapy in all outcomes. That really is a monumental study because what it proves is that ceritinib belongs in the first-line setting.

Now, the next logical question is, how do you know it’s better than crizotinib? And I think, to be fair, we don’t know that answer. All we know is that we have a second drug, a next-generation drug, that appears to be more active in clinical models and preclinical models than crizotinib, appears to be getting into the brain, and now we know that it deserves to be in the frontline space. Although not yet approved to be in that, but with ASCEND-4, we think that would be good enough for that to register as a first-line therapy. But the next big question, of course, is, should it be used instead of crizotinib? And that’s something where we’ll have to wait for those trials to get done.

Alice Shaw, MD, PhD: Ceritinib has been studied in both the crizotinib-resistant setting and now actually in the crizotinib-naïve setting. Actually, the phase I trial of ceritinib originally looked at patients who were crizotinib-naïve, ALK-positive patients. And in a phase I setting, we even observed very prolonged responses when ceritinib was used as the first ALK TKI. Now we actually have randomized data from ASCEND-4 demonstrating that ceritinib as the first ALK inhibitor treatment is very, very active, and in ASCEND-4 it was compared with chemotherapy, not with crizotinib. Nevertheless, we know that ASCEND-4 was associated with a median progression-free survival of 16.6 months. Again, this is a cross-trial comparison, but generally speaking, with crizotinib, all the studies have shown that first-line crizotinib is associated with a median progression-free survival of 10 to 11 months. And so, in this kind of cross-trial comparison, it suggests that we are likely getting much longer benefits with a second-generation inhibitor used in the first-line setting.

I think ASCEND-4 is a very positive study. Ceritinib is clearly superior to platinum-based and pemetrexed-based chemotherapy. However, from ASCEND-4, we don’t know how much more superior ceritinib is than crizotinib, at least in a head-to-head comparison. We are extrapolating from cross-trial comparisons. But I think the more important thing about ASCEND-4 is that while we see this enormous benefit from first-line ceritinib, it does have to be weighed against the side effect profile of ceritinib, which is significant. In the ASCEND-4 trial, we saw similar side effects of ceritinib that we have reported previously in the phase I and II trials, and this included GI side effects, nausea, vomiting, diarrhea, weight loss, fatigue, abdominal pain. And when you compare the AE listings for ceritinib versus platinum/pemetrexed chemotherapy, it’s quite notable that ceritinib seems to be associated with even more toxicity than cytotoxic chemotherapy, at least the way it was dosed in that study, which is the current FDA-approved dosing of 750 mg a day. So, while I found ASCEND-4 very exciting because we saw such a prolonged frontline PFS with using a second-generation inhibitor, my main concern is the side effects that patients will experience during that time they’re on first-line ceritinib.

Transcript Edited for Clarity