Experience with Ceritinib for ALK+ NSCLC
Transcript:Alice Shaw, MD, PhD: Ceritinib is actually the first of the second-generation class of ALK inhibitors, and it was tested initially in a global phase I trial a number of years ago now. I believe it has been over 5 years, and this more potent ALK inhibitor also inhibits the most common crizotinib resistance mutations as well. Not only is it more potent, but it can overcome the known on-target resistance mechanisms to crizotinib. We tested ceritinib first. In this phase I study, it was a dose escalation followed by dose expansion at the maximum tolerated dose. And this was quite a remarkable trial because in addition to defining the safety and the dosing of ceritinib, we also observed very impressive anti-tumor activity of ceritinib in ALK-positive patients—those who had failed prior crizotinib, so they were crizotinib-resistant—and also those who had never been on crizotinib. And subsequent to the phase I trial, which actually led to accelerated approval of ceritinib for crizotinib-resistant patients, we then confirmed the data in phase II as well as now a phase III trial. It’s across all of the studies of ceritinib. What we do see is that ceritinib is highly active in patients who have failed crizotinib. The response rate is between 40% and 50% in all of the ceritinib studies, and the median progression-free survival is in the range of 5 to 7 months. So, most patients who fail on crizotinib will go on to respond to ceritinib.
In the phase I study, we also looked specifically at the resistance mechanisms that were driving relapses on crizotinib. And what we saw was that patients with resistance mutations, like the gatekeeper mutation with an ALK, and also patients without ALK-resistant mutations did also seem to respond to ceritinib, a more potent ALK inhibitor. So, we believe that ceritinib and other more potent second-generation and third-generation ALK inhibitors really are a new standard of care for patients when they fail crizotinib.
Tony Mok, MD: Some of the patients may become intolerant to crizotinib due to toxicity, either liver toxicity or pulmonary toxicity. The common thing to do is to switch to another TKI, or tyrosine kinase inhibitor, namely either ceritinib or alectinib. In general, there’s no cross sensitivity between the first-and second-generation drug, so patients who develop a toxicity to crizotinib may not necessarily develop a toxicity to ceritinib or alectinib. So, therefore, these 2 drugs potentially can be considered.
David Spigel, MD: Ceritinib has been a fantastic therapy. We know in patients who are crizotinib-naïve, and in patients who’d received prior crizotinib, that ceritinib is very active. Ceritinib is, of course, approved to be used in that setting beyond the first-line setting following crizotinib. It has been proven to be a more effective strategy than moving on to chemotherapy, and by itself, it’s quite active, has high response rates, and has a high effect in terms of control of CNS metastases. It’s a safe medication as well. It has some issues that are more GI-related, so patients can have more nausea, vomiting, and even diarrhea with this medication. Sometimes, there’s even just a general malaise or fatigue that comes with ceritinib.
But what is common, for practitioners who use ceritinib, are dose reductions. And so, starting at the full dose of ceritinib, 750 mg, is achievable for some patients, but for a lot of patients, we just simply make dose reductions down to 600 mg, for example. We also do things like give it at night time, have patients take it with an antiemetic, or take it with food. And there are data at this World Conference on Lung Cancer meeting in Vienna to show that that’s a more useful strategy for tolerability. So, there are ways to adjust around some of these toxicities and allow patients to achieve all the benefits of ceritinib. Many of us have stories of patients who’ve been on drugs like ceritinib following long periods of good control on crizotinib, patients who have been ceritinib for years doing quite well.
We, at our center in Nashville, had the privilege of being involved in some of the earliest ceritinib studies when we were trying to understand the role of ceritinib. And so, patients got access to this active drug far before it was approved. I am happy to report that we still have patients on those agents doing quite well. In fact, I just saw one of these patients from another state just a couple of weeks ago. We’ve had to make some adjustments in her care. That’s a good example of the things that you do in real life. So, we’ve had to lower her dose of medication. Actually, believe it or not, now going on to 4 years here, we’ve had to lower her medication a second time, even after doing so well on the first dose reduction for an extended period. But she’s doing well and continues, fortunately, to have good disease control.
It’s worth mentioning her because we’ve had to deal with issues like brain metastases during her care. So, a good example of a patient who actually had a brain lesion at diagnosis was asymptomatic. We were allowed to put her on the trial with ceritinib. We got good control of that lesion for years until we found growth in that and a new lesion. We’ve treated those with stereotactic radiosurgery, controlled that, and she has systemically maintained control of disease with ceritinib even at the dose reductions. So, it’s keeping somebody on a therapy, but incorporating radiation at periods in her therapy to deal with issues like brain metastases. A little bit different than how we normally treat lung cancer with just chemotherapy and moving on to another drug when someone progresses.
Transcript Edited for Clarity
