Phase III ALTA-1L Trial of Brigatinib for ALK-Rearranged NSCLC - Episode 5

Managing ALK-Positive NSCLC Disease Progression

Transcript: Ross Camidge, MD, PhD: Progression on crizotinib tends to occur in 2 main areas. Progression in the brain, which is mostly due to poor penetration of the drug, and then progression in the body, which is due to biological evolution of the cancer.

Maybe 50% of cases are due to on-target mutations, so a range of different mutations occurring in ALK. But at least 50% could be your second driver. Some other pathway coming in, some of which we’re still working out.

We’ve already said that the patterns of progression on crizotinib are at least 50% in the brain, 50% are in the body. When you get them onto these next-generation drugs, particular alectinib, particularly brigatinib, then the brain becomes much less of a liability. If you look at the ALTA-1L data, the median progression-free survival, if you did or didn’t have brain metastases, was exactly the same. Whereas it was dramatically different in the crizotinib arm. It’s as if brigatinib is somehow neutralizing the liability of the brain.

And I think what we’re starting to see now is progression in the body. Still every 1 of these drugs has got a little Achilles’ heel. There will be some on-target mutations that one can’t cover but maybe another ALK inhibitor can cover in the future. But what we’re going to start to see is understanding of second drivers and rational combinations. Particularly for the non-crizotinib drugs. MET, which is actually 1 of the targets of crizotinib, is emerging as one of the actionable second drivers.

MET amplification has been described as an actionable resistance mechanism on alectinib. A MET activation was actually determined through a cell line on brigatinib. And what people have done is sometimes added in a drug such as crizotinib and regain control, and more of that research will come out.

Lyudmila A. Bazhenova, MD: The majority of my patients who require switching therapy from crizotinib, usually my reason to switch would be progression rather than toxicity. Although there’s certainly some proportion of patients who are not able to tolerate crizotinib or ceritinib, and in that situation I switch to another drug because the adverse effect profile is slightly different across those 2, across ALK inhibitors. But in my experience, I feel that the majority of my switches are due to systemic progression rather than poor tolerability of the compound.

We are starting to discover what type of resistance we see in the patients who become resistant to brigatinib. So far, the most comprehensive dataset is on the resistant mutations that develop when brigatinib is used in a second line, based on the ALTA-1L trial. Just a reminder, the ALTA-1L trial took patients who developed resistance to crizotinib, and then they were randomized to 2 different doses of brigatinib. Once we looked at the resistance patterns, when the patient developed resistance to brigatinib, there is no single mutation that appears to be a unifying mechanism of resistance. The majority of the resistance to a second-line brigatinib is a compound resistance. We see more than 1 mutation or we see an amplification in a mutation. The story is a little bit more complicated than, let’s say, the story of resistance to crizotinib or the story of resistance to EGFR tyrosine kinase inhibitors. It appears to be more of a compound resistance than a single mechanism of resistance.

Ross Camidge, MD, PhD: When people progress, if they’re progressing on brigatinib, because you know nearly half the patients are going to have an on-target resistance mechanism, most of these next-generation drugs are getting 50% to 70% response rates, there was no real role for rebiopsying other than for research purposes. I think now we’ve got people starting on alectinib or brigatinib in the first-line setting. There’s much more of a role.

Now 1 of the things, if we want to see the first-line data in isolation, you can do the thought experiment, where do you go next? You could go on to lorlatinib which is licensed, post and next-generation ALK inhibitor. You could, if you start on alectinib, go on to brigatinib and then on to lorlatinib. But I think what we’re going to see in the future is that we’re not just going to play the numbers game, we’re going to be rebiopsying people when they progress on these next-generation inhibitors, because some of them have got second drivers. And just throwing another ALK inhibitor at them may not be the right thing. So we are at a tipping point in the treatment of ALK where it’s not just going to be A followed by B, followed by C in everybody. I think we’re going to choose the best drug first and then we’re going to personalize.

Transcript Edited for Clarity