At ASCO 2020 we had an update on the ALTA-1L study. Now, as you already know, there are two really good next generation ALK inhibitors – alectinib and brigatinib. One was assessed versus crizotinib in the ALEX study, that was alectinib, one was assessed versus crizotinib in the ALTA-1L, that was brigatinib. They both show remarkably similar efficacy, they’re both superior to crizotinib. But one of the things we started to say is, well, where does this field go next? It’s clear when you look at the experimental arms in both of these studies that there is a group of people who are in a long plateau of non-progressors. These people don’t have a real, pressing unmet need, they eventually progress, but the people we are most interested in are who are the people progressing before they get to that plateau? Who are the high risk ALKs?
In ALEX we had previously done a study in which if you looked at the variant of EML4 that you had there was a non-statistically significant trend that variant 3 was going to do worse, but in ALTA-1L that is now statistically significant. So variant 3 seems to be one of those higher risk features.
There is also something very interesting in this, so this is looking at cfDNA, which is only a subpopulation, but if you look at those who have EML4-ALK detectible in their blood and then you look if they also have a TP53 mutation, that’s an independent trend towards a worse prognosis, even within that group. So the idea of defining a high risk group is to say, ‘That’s the unmet need. That’s who we need to study more in the future. What is going to be their mechanisms of acquired resistance and what might we want to study in them to add in or to do other things?’ Because they’re going to read out in a clinical study much quicker, not just having to wait years for these outcomes.
Could you outline your other presentation on brigatinib?
Another presentation on brigatinib at this year’s ASCO looks at one of the recognised side effects of brigatinib. So it’s unique to brigatinib, something like 3% of patients starting brigatinib will get short of breath within the first couple of days. It’s not your classical pneumonitis because there were many anecdotal reports of patients staying on the drug and then getting better despite continued exposure. This is a relatively small study looking at detailed pulmonary function tests in the first ten patients starting brigatinib. Nine of those ten patients, even though they had no symptoms, dropped their DLCO, that’s their ability to transfer oxygen across their lungs. It dropped on average by about 13%, the range was between 5% and just over 30%. None of the patients had symptoms, they all dose escalated from 90mg to 180mg without a problem. Of all of those people who actually had follow-up up to day 15 all of them had complete reversal. Now, why does this matter? Well, instead of these early onset pulmonary events being like Russian roulette – who is going to get them, is it going to be serious and being slightly worrying – if you start to understand that everybody is going to drop their DLCO for a short period of time and then recover you can start to look at the patient in front of you and say, ‘Hey, will you be able to tolerate that or not? Have you just had a pulmonary embolism? Have you just started on oxygen?’ For those patients maybe brigatinib is not going to be their drug or you have to have an even shallower step-up regime, currently it’s 90mg and then 180mg, but you can do 30mg for three days, 60mg for three days, 90mg for three days and you still get to 180mg by day 10. There are case reports of people even on the intensive care unit being able to tolerate brigatinib with that shallower step-up regime.
So suddenly we go from a scary, rare, serious side effect to an entirely predictable one and you can look at the patient in front of you and say brigatinib yes or no. If I’m going to use brigatinib this is maybe the regime that I want to use if you’re at higher risk, if you’re not going to tolerate that temporary drop in your DLCO.
What are the benefits of having these treatment options for lung cancer patients?
The more you understand the ability to give these drugs, their side effects, their efficacy, their pill burden, you can tailor it to the patient in front of you. What we’re trying to achieve, what is the achievable goal for ALK positive lung cancer is, in theory, perfect control of disease, normal quality of life for years. The more options we have the greater a chance that we can achieve that in an individual person.
