New Biological Insights and Recent Therapeutic Advances in the Management of Lung Cancer: A Clinical Investigator Think Tank
Potent activity of the ALK inhibitor ceritinib accompanied by significant gastrointestinal toxicity
4:13 minutes.
TRANSCRIPTION:
DR OXNARD: The rationale for ceritinib is, this is a potent ALK inhibitor. Crizotinib is a multikinase inhibitor of ALK, ROS, MET, and it doesn’t actually get to really potent ALK doses. I actually have a number of patients on crizotinib who respond on the first scan and progress on the next scan, making me think they’re getting some inhibition, but not that potent inhibition, which is why there are all these drugs trying to beat crizotinib. And I think it’s going to be easier to beat crizotinib than it is to beat erlotinib, which is a potent inhibitor of mutant EGFR. And so the ASCEND study, this is a report on 246 patients in the expansion cohort, international trial, to get this kind of an N from such a rare population. Some of them are naïve to a TKI. Some of them had previously received TKI. And the bottom line is, dramatic waterfall plot, dramatic responses. The response rate in the TKI-naïve is 55%. The TKI-treated — now, I want to make sure I’m finding the right plot, actually. Overall response rate, 66% in TKI naïve; 54% in prior crizotinib patients, and so clearly dramatic activity. And I think what’s more is the duration of response we’re seeing in the median PFS. In the ALK TKI-naïve patients, the PFS is nonestimated — it exceeds 12 months. So really, when you give a potent ALK inhibitor, you can definitely beat crizotinib, is the kind of signal we’re getting from this. And after a prior ALK inhibitor, you can recontrol a cancer. They show brain activity in this report. I will point out, these are previously treated, relatively stable brain metastases, and they’re reporting some responses. The question is, is this a drug that can work for those patients with progressive brain metastases? I have young patients who don’t want whole brain radiation, are progressing just in the brain on crizotinib. And that’s where I’m actually starting to use ceritinib, trying to regain control of the brain to avoid whole brain radiation. The key challenge with this drug is toxicity. The majority of patients require a dose reduction from 750 mg, 5 pills a day, down to 3 or 3 pills a day, 600 or 450 mg. In my practice — and again, thinking that there are patients who haven’t treated ALK at all, we have so many tricks we’ve started to use on how to use this drug safely. My patients take it at night. They premedicate with a nausea pill. They wake up in the morning and take a nausea pill. And that’s how they manage to control the very real GI side effects that most patients feel with this drug. I do have patients where I start it at less than full dose, at 600 mg or even 450, if they’re delicate. But if you’re trying to get into the brain, you need that full dose to get the CNS control. DR LOVE: And they actually presented some CAT scans of a patient who responded in the brain. Can you talk a little bit more about the tolerability issues, anything beyond GI? I think there was some pneumonitis. DR OXNARD: Yes. I think any TKI is going to have some cases of pneumonitis. It was not a high incidence, so I’m not alarmed at that. I think it’s within the expected spectrum. There is a significant proportion with Grade 3 LFT abnormalities. You do need to monitor LFTs in these patients, like we’re doing with crizotinib. So every couple of weeks, you want to be checking the liver function until you’re sure that a patient’s going to tolerate it. Anorexia, I’ve seen people just waste away, losing weight, trying to keep that dose up. And I’m like, “No. Bring the dose down. We’ve got to tolerate this. It’s a long road.” DR LANGER: I don’t want to trivialize the GI toxicity. It can be quite severe. And at least in my experience in a couple of patients, we’ve required 5, 6, 7 different drugs in combination to put the lid on it, not really eliminate it but make it semitolerable. So, at least compared to the other second-generation compounds that target ALK, just from a toxicity standpoint this is the most toxic of the agents. DR KRIS: Yes. My toxicity is real. The dose of this is too high. It’s just too high. And I would routinely start at 450, and I go up when I can. And I occasionally have to come down. But I think dose reduction is the first thing. I’m sorry. I used to have a prior life as an expert in nausea and emesis control. You cannot put people on these drugs for life. It’s not possible. So you need to come up with a better strategy — dose reductions probably the best way. |