Next-Generation Agents for ALK-Positive NSCLC - Episode 3
Shirish Gadgeel, MD: Brigatinib is another next-generation ALK inhibitor that was recently approved for patients with -positive non—small cell lung cancer who were previously treated with crizotinib. The approval was based on a randomized phase II study that looked at brigatinib administered at a dose of 90 mg once a day versus a dose of 90 mg once a day for 7 days and then escalated to 180 mg. A brief background to this study is that in the phase I dose-escalation study, efficacy was observed in patients with -positive non—small cell lung cancer who were treated with crizotinib and then, subsequently, had disease progression.
In addition to the efficacy that was observed, they did observe toxicity. A unique toxicity among ALK inhibitors is that patients, within the first 7 days of starting to take the drug, experienced pulmonary side effects. These were characterized by shortness of breath and coughing, and, in some patients, the effects were severe enough to be labeled as grade 3 or 4. What they noticed was that this tended to occur in as many as 13% to 15% of patients at doses of 180 mg per day or higher. Interestingly, if patients were started at 90 mg and then after 1 week—if they did not experience these pulmonary events—they were escalated to 180 mg, the rate of these pulmonary events was much lower, in the range of about 2% to 3%.
So, the objective of the ALTA trial was to evaluate the benefits of taking brigatinib at a daily dose of 90 mg versus taking 90 mg for a week and, if the patients did not experience the pulmonary events, increasing the dose to 180 mg. What they found was that, though efficacy was observed in both arms, patients who received 90 mg and that were subsequently escalated to 180 mg had much better activity: both overall activity as well as activity in the central nervous system. The overall response rate was about 55%, and the median progression-free survival with the 180-mg dose was 15.6 months, as reported at the last update at the International Association for the Study of Lung Cancer’s World Conference on Lung Cancer 2016. With 90 mg, the response rate was more in the range of 45%, and the median progression-free survival was in the range of about 8 to 9 months.
Another important difference between the 2 dose levels was that at 180 mg, the response rate in the brain was about 67%, whereas the response rate in the brain was much lower—in the mid-40% range—at the lower dose. So, clearly, the escalated dose provided greater benefit, and not only greater benefit, but also a more sustained benefit than what was observed at the lower dose of 90 mg.
The concern, of course, was this issue of pulmonary events, and they did observe acute onset pulmonary events occurring within 7 days of starting the drug. It was in the range of about 3%. None of the patients who escalated to 180 mg—if they did not experience pulmonary adverse events at the 90-mg dose—experienced any of the pulmonary adverse events. In patients who did experience pulmonary adverse events, discontinuing the drug—and in some patients, managing the effects with steroids—did appear to reverse the symptoms. Those patients were continued on 90 mg, but this occurred in a very small minority of patients.
And so, based on these data, the FDA recently approved brigatinib at the dose of 90 mg for a week, followed by dose escalation to 180 mg, for patients who have been treated with crizotinib for -positive non—small cell lung cancer and had subsequent disease progression.
Transcript Edited for Clarity