ASCO 2015

Next generation inhibitors help overcome problems of resistance in ALK positive lung cancer

Dr Ross Camidge - University of Colorado, Denver, USA

ALK positive lung cancer was discovered in 2007 and it really came to everyone’s notice because it responded beautifully to this drug called crizotinib. Crizotinib now has a licence in both treatment naïve and in post-chemotherapy treated patients in many countries around the world but it’s not a cure. So crizotinib will still, after initially great responses, the patient’s cancer will still progress.

And to put this in context, what proportion of patients with non-small cell lung cancer are susceptible to ALK directed agents?

It’s somewhere between 2-7%, depending on the degree of enrichment. So we know it’s slightly more common in adenocarcinomas and never smokers; there doesn’t appear to be a race or gender specific bias. But the figures which have the higher percentage have enriched for never smoking adenocarcinomas, the general feeling is it’s running about 2-4%.

So an important minority but when it comes to treatment, we’ve been here before in other cancers, you can get resistance developing to this wonderful agent.

Yes, so probably on an average between about 8 and 10 months after you start on this drug some degree of resistance will occur, either in the body or you can progress in the brain and they’re probably different mechanisms.

Enter, then, next generation ALK directed therapy.

So next generation ALK inhibitors have come on, there’s one licensed one, ceritinib, made by Novartis. They actually attack both things, so one is they attack a number of the known biological mechanisms of resistance so you can get new point mutations occurring in ALK, you can have increases in the number of copies of your rearranged ALK gene to get round the crizotinib and these drugs work best in those. Also, because crizotinib is relatively poor at penetrating into the brain, these drugs get better into the brain and now you deal with that as a mechanism of acquired resistance too.

So can you tell me about brigatinib and what you’ve been… why you were using it and what you’ve been doing with it?

So I’ve used all of the next generation ALK inhibitors, brigatinib is one made by a relatively small company called ARIAD. They tried to develop a drug that was active against a very broad range of these resistance mechanisms and it also has very good penetration into the central nervous system. So we’re seeing that maybe not all next generation inhibitors are actually the same. So, for example, the median progression free survival for many of the ALK inhibitors post-crizotinib is running about six or seven months. With brigatinib in our study it’s now running over a year, 13.8 months, and when you start to look at the brain as a separate part of your body and you capture that data robustly, you can see responses in the brain running about 50%.

Can you tell me what you did in this study to establish that?

This is a second line study, post-crizotinib, where people go on brigatinib with the dose having figured out in the phase I proportion of the study. So it’s an expanded phase I/II looking primarily in the post-crizotinib although some patients are in there too.

And how many patients did you look at and what sort of levels of response did you get? You got beyond a year, you were saying, but in how many patients?

About a hundred patients, we’re getting a response rate of about 70% and the duration of response is very good and, as I said, the median progression free survival is over a year.

Could you tell me what, then, are the clinical implications first of all of this specific therapy, brigatinib, and the perhaps of the other next generation inhibitors?

Brigatinib has received FDA breakthrough status which just means they have a hotline through to the FDA. So the FDA is watching this closely. There is a registration single, while technically it’s a two arm study because they’re exploring two doses but there’s only the one drug in there, going on at present. If that shows these same kinds of promising results the hope is this will become a licensed drug, at least by the FDA, within a year or so. The other drugs, alectinib made by Genentech Roche, also a very good drug. Similarly has got breakthrough status and they will be filing there. We’ve already seen their data, they’re running about a 50-60% response rate, median progression free survival 7 or 8 months. Then ceritinib is already licensed.

What sort of toxicity were you getting with brigatinib?

It’s very well tolerated in most people. Early on there was a slightly mysterious signal; people were getting what they called early onset pulmonary symptoms. So literally within hours, sometimes days, of going on it a very small proportion of people were getting what was essentially inflammation in their lungs. What we realised from actually studying one particular patient, because they’d been in anecdotes of people who said, ‘Well I got short of breath, I didn’t want to bother you, doctor, and then it got better.’ We actually had a patient who we knew very well who went on the brigatinib, got this and we actually kept him on the drug and monitored him, monitored his oxygen saturation, gave him steroids, and he clearly pushed through this all by himself whilst still being exposed to the drug. So if you get it and you can tolerate it, after about four or five days you get better. That led to the idea that maybe we could reduce the incidence by starting at a low dose, getting through this if you were going to have it sub-clinically, and then going up on the dose. So, remember I said the phase II study is two doses? One is starting at 90 and then escalating to 180, the other is staying at 90. So that sort of sub-clinical dosing for one week is very interesting and it seems to have really dropped down the rate of these pulmonary symptoms.

And based on the information we now have about these next generation agents, what should clinicians be thinking about doing soon?

At the moment you only have access to the licensed treatments but you need to know these other ones are coming. When they come, obviously people will present various bits of data, but you need to start to look at what are the differentiating things. So how good is their data in the central nervous system, not we’ve got an MRI and things got smaller, but what is the proportion of people shrinking, what is the duration of benefit in the brain? Then, what is the duration of benefit in the body? Are we supressing as many resistance mechanisms as we can?

So, based on the evidence you’re presenting here at the ASCO meeting, what’s the brief summary of it all?

I think the realisation as these data mature that maybe not all of these next generation inhibitors are the same, they’re going to have strengths and weaknesses. Brigatinib is looking very good but it’s up against some big players too.