Advances in Treatment for ALK-Positive NSCLC - Episode 6

Progression in ALK+ NSCLC After Frontline Therapy


David Spigel, MD: When you have somebody on a very effective therapy for any cancer setting, but we’re talking about ALK-positive lung cancer, you want to be sure it’s not working before you stop it, before you go to something else. You have to define progression the way we classically do. Are there new lesions? Are they symptomatic? Is there symptomatic deterioration due to cancer that you could point to on a scan?

I think it’ll take visible and clinical evidence for me to abandon a strategy like alectinib in this example. To then say, OK, we’re ready for second-line therapy. In my experience it’s not been a subtle thing like it can be with immunotherapy, or even in the EGFR setting. In my experience with ALK, progression tends to be obvious, and you know when you need to abandon that strategy.

If you had only 1 drug, if you had only alectinib, you would stay on that as long as you could, even with new liver or brain lesions, and you’d find strategies to deal with that.

Some of my colleagues keep alectinib going and add chemotherapy to it. and I don’t think that’s wrong necessarily, we just don’t have data to tell us that makes sense to do. For me, it’s changing to another therapy. We have a trial that I mentioned earlier where you get brigatinib. But even if we didn’t have a study, I think that would be what I would try next.

I would profile the patient and try to see if I could identify a resistant mutation. But I have to tell you, I’ve done that, and I haven’t yet had it change the way I practice. I think chemotherapy is the ultimate next thing to go to, but I probably would ride out the TKI [tyrosine kinase inhibitor] train as long as I could before I had to spill to chemotherapy. And then, of course, the bigger questions are, where does immunotherapy fit in? Should you give a checkpoint inhibitor after you try chemotherapy? Should you give it with chemotherapy? We don’t have data to help us there yet.

At least for now I haven’t identified a specific clinical pattern when it comes to efficacy or resistance for each of the drugs—brigatinib progression always looks like this, or crizotinib progression looks this, or alectinib progression looks like this. I think we would say, “Well, crizotinib is not as good as controlling cancer in the brain as alectinib, so I’m going to expect more failure in the brain with patients on that.” None of us are using crizotinib any more so it’s kind of a moot point.

I define response the way we always have. Are patients feeling better? Did symptoms go away once you started therapy? And often they do very quickly—you know in the first week, in the first 72 hours before, they will tell you they feel better. I’ve had patients tell me in the first hour they felt better. Imaging obviously is the gold standard to show that cancer is responding, and I find that to be a very reliable tool still to use for patients to assess benefit. I do have colleagues that say, “You know, David, if my patient is doing well, looking great, and they weren’t before, I’m not sure how much imaging is going to change my mind. I can’t imagine doing a scan and finding anything that would have me take them off therapy. And I get that. But I do think it’s worth looking, particularly in the brain. That’s an area where I think patients can go down fast.

That’s the other thing about ALK progression. And I think what has been written about but certainly discussed with colleagues is that transition point when you’re coming off 1 agent on to another, it can be precipitous, and so it’s a little bit different from progressing on, say, a platinum therapy: pemetrexed. It tends to be folks can get sick quickly, and so I find you need to be decisive. You need to know what you’re going to do, and do it. And often we don’t stop the TKI that they’re progressing on until we’re ready to go with our next therapy. Stopping and saying, “come back in a month and we’ll figure it out,” is not going to work. I mean, it shouldn’t work for anybody in any setting anyway.

But this is 1 where I tell patients, stay on alectinib until the brigatinib has arrived at the house, or it’s in your hands, or we’ve decided to do some other clinical trial, or chemotherapy. This is 1 where there’s been a well-described phenomenon of kind of rapid progression for folks who are where the drops stop working.

I try not to switch therapies just because we have them. You never know how the next thing is going to work until you try it. When I have something that’s worked well for a long time, I’m reluctant to switch until I’m 100% sure that we’ve got a problem. I was just with an older woman yesterday, 2 days ago, who’s been on alectinib for a year. But she’s now got pretty bad anasarca, and we’ve held therapy and given her diuretics, and it gets better. We started her on a lower dose; she’s doing fine. She wanted to go back up on her dose, and we did that, and everything came back.

I’ve talked to her about this is kind of a marathon we’re running here. We’re trying to keep disease in control, and it’s still in control, and give her a good quality of life. She’s pretty miserable with the anasarca, with pain from swelling. She’s not mobile. And so that’s frustrating. It’s tempting to say, well, we’re going to stop that drug and put you on another drug like brigatinib. But who’s to say brigatinib is going to work as well or that she won’t have similar toxicity? I’m going to try to wring out as much duration on alectinib as I can, even at a lower dose, to give her a good quality of life to continue disease control. We’re not going to change how we assess her cancer. We’re still watching her closely. But all that’s hard for her and her family. They don’t want to lower the dose. They don’t want her to take breaks. They don’t want to get off something that’s worked well for her for over a year, and I completely understand that. I try to be disciplined about staying with a therapy that’s worked for us, and managing toxicity. And when we reach a wall, either because of progression or we just simply can’t stay on that dose, then I think it’s time to abandon it for another strategy.

Transcript Edited for Clarity