Upfront Therapy for ALK/ROS1-Rearranged NSCLC

Transcript: Suresh S. Ramalingam, MD: Let’s talk about ALK disease, another subset of non—small cell lung cancer. This is about 4% or 5% of patients. Once again, we’ve seen similar ratios. We’ve had the first generation ALK inhibitor, crizotinib. Now, in the second-line setting, there are a handful of more potent second-generation ALK inhibitors. Alectinib among them has shown data in the frontline setting. Ceritinib has shown data in the frontline setting. Which agent should be used first? Which agent should be used second? There are very similar kinds of issues, but it’s a fascinating time for patients and physicians to have all these options. To take us through the data, maybe we’ll start off with the ASCEND-4 trial, chemotherapy versus ceritinib, which is now a new frontline option. Benjamin, what are your thoughts on the ASCEND-4 trial? Talk a little bit about the data and how this trial affects the treatment landscape.

Benjamin Besse, MD, PhD: Crizotinib was the first ALK inhibitor to be approved 6 years ago, so it’s yesterday’s news, and now we have, as you said, a lot of drugs. Crizotinib, as you can see, is quite similar among all the trials. The PFS will be 11 months. In the first-line setting, ceritinib, a second-generation inhibitor, gives us a PFS of 16 months. Alectinib, a second-generation inhibitor, gives us a PFS in first-line that is probably between 24 and 26 months. And there are next-generation inhibitors like brigatinib— we don’t know if it’s second- or third-generation—and lorlatinib. As we said for patient with EGFR-mutated NSCLC, it’s a marathon. It’s not only 1 line, and that’s even more true for the patients with ALK-positive NSCLC.

In all the retrospective series, and also with the first crizotinib upfront study, the overall survival was at least 5 years. And given the multiplicity of the TKIs, it may be more. There is a huge French retrospective series from the expanded access program of crizotinib with more than 300 patients. In the patients who received 2 TKIs, the overall survival was more than 7 years. So, it’s true that all these new PFS rates are impressive, but we really have to put all of these PFS rates in perspective of a very long overall survival. It’s a marathon. We should probably not rush to the best drug up front. I still think that crizotinib is a reasonable option in the first-line setting. We have to learn, as for the EGFR field, what the mechanism of resistance is, and maybe add to our strategy based on that.

A last word on ceritinib, because I had to comment on the ASCEND-4 study. The usual dose for ceritinib is 750 mg per day. It’s quite toxic. Usually, you have to decrease to 600 mg, sometimes 450 mg, per day. Some very interesting emerging data show that if you take the drug during a meal at 450 mg, you have the same range of drug in your blood as if you took it before a meal at 750 mg, and the tolerance is much better. So, ceritinib can be flagged sometimes as a very toxic drug. I think it’s unfair. Maybe the dose and the way we take the drug are not right, and I really think that we should look at these data of low-dose delivery during meals. And it will be cost-effective.

Suresh S. Ramalingam, MD: So, 450 mg with food is as effective as 750 mg, with less toxicity. Now, ceritinib in the ASCEND-4 trial had a median PFS of close to 17 months in the frontline setting, which is impressive. It is, in the United States, FDA approved for the frontline treatment of ALK-positive disease.

Transcript Edited for Clarity