Next-Generation ALK-Targeted Agents in NSCLC

Transcript:Mark A. Socinski, MD: We only have 1 comparative trial to date, the J-ALEX trial, that compared alectinib to crizotinib. We saw that at ASCO 2016. This was a trial that was done exclusively in Japan. It randomized ALK-positive patients to either crizotinib, as the control arm, versus alectinib. Now remember, crizotinib was developed as a MET inhibitor. Alectinib is a true ALK inhibitor. This trial was strikingly positive in favor of alectinib. There was more than a doubling of the progression-free survival. The hazard ratio for the progression-free survival, which was the primary endpoint of the trial, was 0.36—a very powerful advantage to alectinib versus crizotinib.

This year at ASCO, we’ll see the results of the North American ALEX trial, and I think many of us are anticipating similar results from that trial. But this, to date, is the only data we have from a direct comparison of the second-generation agents to the first-generation drug crizotinib.

One of the advantages of the second-generation drugs is they have much better CNS penetration. Brain metastases are a problem in lung cancer in general, but are typically a problem in adenocarcinoma. Almost all of the patients with ALK-positive non—small cell have adenocarcinoma histology. And the ALK patients certainly have a predilection for brain metastases. The advantage of the second-generation drugs such as alectinib, brigatinib, and crizotinib is that they have much better CNS penetration. All of these agents have demonstrated activity in either previously treated brain metastases or previously untreated brain metastases.

We do MRI testing of brains fairly frequently. We often find disease that is asymptomatic, subclinical. On the MRI, it is small in volume and not threatening in any way. And again, I think the important message is the patient is asymptomatic. I think we have more than adequate data at this point where, historically, we might have used radiotherapy options to treat these patients. I think that we can safely say today that it is okay to treat this with an orally administered second-generation drug, such as alectinib or such as brigatinib. Those would be favorable overexposing the patient to radiation therapy because of the toxicity of these agents. And these second-generation ALK inhibitors have clearly been demonstrated to have very nice CNS activity.

Transcript Edited for Clarity