Advances in Treatment for ALK-Positive NSCLC - Episode 9

ALTA II: Brigatinib in Crizotinib-Resistant ALK+ NSCLC


David Spigel, MD: Brigatinib found its way into the second-line setting when a phase II study was performed looking at 2 dose levels of brigatinib in patients who had progressed on crizotinib. At the time, crizotinib was the standard of care, and brigatinib was just trying to show its role following that. Obviously, there are other things you could do now, including chemotherapy. That study basically found that brigatinib is a very active agent in terms of response rates and progression-free survival. The higher dose of brigatinib had a higher response rate associated with it, and so that was the dose carried forward. Those data from the phase II study essentially got it into more of a standard use.

There are other studies ongoing now. I mentioned 1 previously in which the role of brigatinib in another phase II study, following first-line alectinib, and there’s only 1 dose level. The role of brigatinib following alectinib is being studied now. That trial is open and enrolling. It would be good data to accumulate because we don’t know much about what to do after alectinib, but we know in common practice doctors do a lot of different things.

Accumulating some data about efficacy for brigatinib following alectinib would fill in the blanks for what doctors are doing or think they should be doing now. That study would have been nice if it was done a couple of years ago, but you had to get brigatinib on the market first, and then find its way into a first-line setting. Dealing with a post-alectinib population was maybe not something that was anticipated, but it’s a real clinical question right now.

Pneumonitis is a risk of brigatinib. Brigatinib is an interesting compound. It actually, in addition to inhibiting ALK, has an EGFR inhibition part to it. It’s not clear if the pneumonitis is directly related to with the EGFR inhibition or ALK inhibition. I think it may have more to do with the latter. Pneumonitis is a risk in a small proportion of patients who start brigatinib. It can happen at any time on any ALK inhibitor therapy, but for that reason, you start brigatinib at a lower dose and work your way up. There’s a loading period, and then you go to a standard dose with brigatinib. I have not personally seen pneumonitis with brigatinib. I’ve seen pneumonitis, however, with other ALK inhibitors sporadically. I’ve not seen it with alectinib. I’ve seen it with ceritinib and with crizotinib. Pneumonitis can be tricky. Patients have lung cancer. They tend to have comorbid lung conditions like COPD [chronic obstructive pulmonary disorder]. Some of them have received thoracic radiotherapy in the past, and so it can be tricky to figure out what’s pneumonitis. But when you start a drug and then somebody struggles and has changes on their scan, it becomes apparent.

Pneumonitis has been a more frequent clinical problem with the introduction of checkpoint inhibitors, and we’ve been used to managing rare pneumonitis even with things like EGFR TKIs but more commonly with ALK TKIs [tyrosine kinase inhibitors]. You can see them with any TKI, rarely with chemotherapy radiation, more common in of course immunotherapy. We manage all those clinical settings pretty much the same way. You stop the therapy that you think is the offending agent, in this case an ALK inhibitor, and then allow patients to recover and sometimes use steroids.

You can be fooled sometimes where you have to cover for a potential infection and antibiotics are used. But for a lot of patients, we’ll stop, hold—should say, “let patients recover”—and then resume but often at a lower dose. There are some patients—it’s rare, I’ve had it happen to me maybe twice in the last 5 years, I should say—where we had to just stop and couldn’t go back on it, because it wasn’t something you could dose reduce low enough or manage your way out of it. I’d say that is really rare but certainly has been experienced and reported.

Transcript Edited for Clarity