Advances in Treatment for ALK-Positive NSCLC - Episode 5

ALTA-1L: Brigatinib Versus Crizotinib for ALK+ NSCLC


Robert C. Doebele, MD, PhD: The phase III randomized trial of brigatinib versus crizotinib, otherwise known as the ALTA-1L trial, randomized ALK-positive patients who were ALK-TKI [tyrosine kinase inhibitor]—naïve. They never received a prior ALK inhibitor; they may have received prior chemotherapy. In that randomized study, brigatinib had a significantly improved progression-free survival compared with crizotinib.

The median progression-free survival of brigatinib was not estimated because the follow-up was too short in this first analysis of the trial. However, the progression-free survival of crizotinib was appearing similar at about 10 to 11 months for what we’ve seen in other randomized phase III trials and other prior trials of crizotinib.

However, what we can say is that the hazard ratio was very significantly improved for progression-free survival in the brigatinib group. We know that brigatinib is significantly more effective than crizotinib. Like other CNS central nervous system—penetrant drugs, we think that a lot of this may be related to its significant brain efficacy, and so in this trial approximately one-third of the patients who were enrolled had brain metastases. Similarly, to prior trials, about half of those had received prior radiation. And what’s also clear from the early evaluation is that the time to CNS progression is significantly better for the patients receiving brigatinib versus those receiving crizotinib, reinforcing the idea that crizotinib really does not have good CNS, or brain penetration, and that 1 of the major improvements that we’ve made, in treating our frontline ALK-positive patients with these TKIs, is improving brain penetration, both for those patients who have brain metastases at baseline but also those who are at risk, which is really all patients. We know that many of our patients—probably upward of 50%, 60%, perhaps even 70%—may develop brain metastases over the course of their disease when they’re not treated with ALK TKIs that are penetrated into the brain. Using these ALK TKIs up front that have good CNS penetration will treat existing brain metastases but also delay or prevent brain metastases from occurring in patients who have not yet had that observed in their brain.

David Spigel, MD: Brigatinib was compared with crizotinib in the first-line randomized phase III trial that’s actually been published. It was very much like the ALEX study. Take these patients, about 300 patients, and randomize them to either brigatinib, in this case, or to crizotinib. The trial was positive. The hazard reduction for progression-free survival approached 50%, so quite dramatic. We don’t have overall survival results. There appears to be good CNS control. And I think what everyone is wondering is, are those data in isolation better than the ALEX data? And can we extrapolate and say, “Well, therefore, head-to-head brigatinib would be superior to alectinib”? And the answer is no. You can’t do that. And you have to look at the trials in isolation and say: alectinib clearly beat crizotinib; brigatinib clearly beats crizotinib; and it looks like we have another first-line option here soon once it receives regulatory approval.

One of the challenges is, OK, now you have both drugs in front of you, what are you going to choose. And I think it’s going to come down to experience. I think there are doctors here who are getting more familiar with brigatinib in the second-line setting, and maybe they like that, and that’s the first-line drug. The lead doctors that just like alectinib or don’t. I think it’ll just come down to comfort. That’s the key with these medications: you’re managing folks over extended periods, not just a few weeks or getting to the third cycle. This could be for 3 years or more, and being comfortable in managing, reducing, dealing with adverse effects is really what it’s about to be a doctor is understanding how to help your patient have a good quality of life and live as long as possible.

Robert C. Doebele, MD, PhD: Brigatinib has a unique toxicity, or what we believe is a unique toxicity, with dyspnea or shortness of breath that is related to opacities that can be observed on imaging in the lung. These tend to be very transient, but patients can feel short of breath early on in dosing of brigatinib. That’s what’s led to the dosing schedule of the 90 mg for 1 week followed by 180 mg after that if there are no pulmonary events observed.

I think what was encouraging in this trial is that we saw fewer of these events than previously observed in some of the phase I and phase II trials. It was only about 3% of patients who have these. And there’s ongoing work to understand what causes this and whether patients can be dosed through this pulmonary toxicity. Like a lot of our TKIs, there was some GI [gastrointestinal] toxicity, although generally less than with crizotinib. So, there were fewer events of nausea, vomiting, and diarrhea. But overall it’s a very well-tolerated drug.

Thomas E. Stinchcombe, MD: The adverse effects we’ve seen with brigatinib on that trial were some increased CPK [creatine phosphokinase], increased lipase. Those were not associated with symptomatic toxicities. And then there was a rate of early onset of pulmonary events, which occurred about 3%, and these were patients who could have pulmonary events in the first week.

I think this is critical to how we use brigatinib, because you use the 90 mg daily for 1 week and then escalate to 180 mg. Personally I see the patients back on day 8 just to make sure that their symptoms are well controlled as well.

Brigatinib, I think if it is approved, will be compared with alectinib. It’s going to be very dependent on patient preference, physician preference, and differences in the toxicity profile. The challenge is there are 2 phase III trials of alectinib and 1 with brigatinib, and so the phase III trials of alectinib have a little bit longer follow-up. This is going to be a decision that is not going to be answered in the next year. It’s something that we’re going to have to watch for: what is the long-term progression-free survival. Because we’re all hoping that there’s a subset of patients who really have durable responses in progression-free survival, and we’ll probably look at the follow-up at 2, 3, 4 years at this point.

Transcript Edited for Clarity