The ALTA-1L Phase III Trial

Transcript: Ross Camidge, MD, PhD: The ALTA-1L trial was a randomized phase III study in the ALK tyrosine kinase inhibitor naïve setting. You were allowed prior chemotherapy, but it was a head-to-head between crizotinib, the first-generation drug, and brigatinib, one of the next-generation drugs that’s had one of the more promising progression-free survivals in the post-crizotinib setting.

The randomization was 1-to-1. You were allowed in if you had prior chemotherapy. You didn’t have to, however; you were allowed in with any ALK diagnostic test, whether it was FDA approved or otherwise. You were stratified by whether you’d had prior chemotherapy, and you were stratified by whether you had brain metastases, and untreated asymptomatic brain metastases were allowed in.

Lyudmila A. Bazhenova, MD: In my view, the ALTA-1L trial brings 1 more treatment option for our patient with ALK-fused newly diagnosed non—small cell lung cancer. Now we have 2 clinical trials comparing second-generation tyrosine kinase inhibitors [TKIs] to first-generation tyrosine kinase inhibitors, and both of those trials showed improvement in outcome with a second-generation TKI compared to crizotinib. So to me, it adds another option to my practice.

Ross Camidge, MD, PhD: The primary end point of the ALTA-1L study was blinded, independent radiology review-assessed progression-free survival. That was clearly a positive study. The hazard ratio by the IRC [independent review committee] was 0.49, what had been shown before. So it was confirmed with longer follow-up, clearly superior to crizotinib. In addition, we saw updated health-related quality of life showing superior duration of improvement in quality of life, longer time to deterioration in quality of life, and then specific domains clearly favoring brigatinib and not actually favoring crizotinib at all.

Lyudmila A. Bazhenova, MD: As expected, because of the results of the ALTA-1L trial, brigatinib now has a category 1A recommendation in NCCN [National Comprehensive Cancer Network] guidelines, which is usually reserved for drugs that have robust evidence behind them, and a phase III clinical trial, in my mind, is robust evidence.

Ross Camidge, MD, PhD: Brigatinib is generally a very well tolerated drug. Within the clinical trial it was interesting. The dose reduction rate is actually quite high, it’s 38%, going up from 29% with the earlier follow-up. Almost all of that is for laboratory abnormalities. Elevated creatine phosphokinase, elevated amylase, elevated lipase. The vast majority of people have no symptoms. So very interesting. Outside of a clinical trial what would the dose reduction rate be? If you take away those laboratory abnormalities, the dose reduction rate is only about 20%. One of the things that I think we learned early on is there is a very rare early adverse effect with brigatinib. It happens only in a tiny proportion of patients, 3% of patients. So unless you’re treating 30 ALK patients, you’re probably never likely to see it.

It happens within a few days of going on the drug, and you get short of breath. But if you stay on the drug, a few days later you recover. What we think might be going on is in everybody you are reducing the oxygen transfer for a few days, and then it gets there. We don’t entirely know the mechanism. I think there are some patients who are quite fine, they tolerate it. Maybe they drop their oxygen transfer by about 10%. They don’t even notice and then it recovers all by itself. I think if you have a patient who’s a little rougher around the edges who maybe couldn’t tolerate that, there are now guidelines published in the Journal of Thoracic Oncology that suggest you could actually do a slower step-up dosing regimen—30 mg for a few days, 60 mg for a few days, 90 mg, and then up to 180 mg. And that seems to work like a charm, at least in my practice.

Transcript Edited for Clarity