Advances in Treatment for ALK-Positive NSCLC - Episode 2
David Spigel, MD: The first-line treatment of ALK-positive lung cancer has really changed over the past several years. For a long time, we had 1 drug, crizotinib, a very good drug that proved itself better than chemotherapy, the standard at that time. But things have changed dramatically in the past few years now that we have 2 other agents available for first-line use, namely ceritinib and alectinib. But more recently we now have data that show alectinib is superior to crizotinib, and so that has made it a clear choice over crizotinib. And for reasons I’ll get into in a little bit, it’s probably just an easier drug to take than ceritinib. For a lot of reasons—efficacy and tolerability—alectinib for me has become the new standard of care in the first-line setting.
Alectinib found its way into the first-line setting because of the results from a randomized phase III trial where patients, about 300 patients, were randomized to either alectinib or to crizotinib. These were all patients, a global study, who had ALK-rearranged lung cancer. The randomization was simple, and the study was designed to show both progression-free survival [PFS] advantages and then in other typical outcomes like overall survival, but also outcomes that we’re very interested in, like control of central nervous system [CNS] disease.
The primary objective of the study was met. The study was better in terms of progression-free survival for alectinib compared with crizotinib by about a 50% reduction of risk of death, or progression with alectinib. A more recent update of progression-free survival suggests that the median approach is 3 years compared with just under a year with crizotinib. That’s quite substantial. We don’t have survival data, but at ASCO 2019 [the American Society of Clinical Oncology Annual Meeting] we are expecting to see updated follow-up from the ALEX trial, where we’re going to get hopefully some more information on long-term follow-up with these patients.
The other important finding from ALEX was the control of CNS metastases. If you were on alectinib, your reduction in the risk of CNS progression was about 85%. That’s quite substantial. You know patients with ALK-rearranged lung cancer, unfortunately, have a high rate of a CNS burden. And it’s a frequent clinical problem for patients, families, and clinicians to see a drug like that have such remarkable control; it is really quite outstanding. And for me, when the ALEX results first were presented, that was the most striking thing: CNS control. Because crizotinib was a fantastic drug, but the CNS control here is really outstanding.
You have a PFS advantage, and you have a CNS advantage. We’re all expecting an overall survival advantage, but honestly even if it doesn’t hit overall survival, those 2 things alone make it an obvious first-line choice for me.
The toxicity profile for alectinib on the ALEX study, and really the trial that proceeded it, mainly the J-ALEX study, fit with what we expect from ALK inhibitors. Myalgias are something you experience and can be seen—at least more serious myalgias—in about 15% of our patients. What I personally have noticed is that myalgias tend to creep up on you the longer the patients are on it. I can think of patients who have had no symptoms and then all of a sudden, after we get to about a year, they start telling me how bad things are. I always wonder if patients downplay some of their symptoms because they want to stay on the top, you know the full, the full dose of therapy.
As it turns out right now, I am dose-reducing 2 patients because of because of edema and myalgias. I think what you have to do is take a break from therapy like we used to do with crizotinib or with ceritinib. Take a break, allow patients to recover, and then start at a lower dose. And that tends to be effective for my patients. These drugs are quite potent. We don’t know how low you can go before you’re at a dose that’s just not going to be effective. But at least we know dose reductions occurred on the randomized trials, and we know a patient can do well, and we know in practice that’s a safe way to manage patients. I guess it is important to mention that alectinib is not without toxicity, but it’s manageable.
Transcript Edited for Clarity