David Spigel, MD: ASCEND-4 was designed to compare ceritinib versus chemotherapy in the first-line setting and really was a very rational design. It was taking patients with newly diagnosed, advanced nonsmall cell lung cancer who hadALK-rearranged cancers, and they were randomized to either chemotherapy, a platinum doublet, or to ceritinib alone. The trial met its overall endpoint. It improved progression-free survival for patients who received ceritinib compared with chemotherapy. And this trial has moved ceritinib from the second-line setting into the first-line setting as a new standard of care for patients withALK-rearranged lung cancer.
Ceritinib is a fantastic drug. It’s very effective in treatingALK-rearranged lung cancer. It’s effective at penetrating the CNS and helping treat patients with brain metastases as well. One challenge for ceritinib use has been toxicity, namely gastrointestinal toxicity. We use ceritinib at the approved dose of 750 mg/day, but we often have to reduce the drug to make it more tolerable for patients because of that GI toxicity. Often, we will have patients dose this away from food. That’s the approval, to not take it with food: Food increases its absorption. And so, lowering the dose from 750 mg/day to 600 mg/day is a common strategy, and even going to as low as 450 mg/day.
There are tricks, too. We try dosing this at nighttime, and sometimes we use antiemetics prior to dosing with the therapy. But there are recent data that suggest taking ceritinib at a lower dose with food, a low-fat meal, can obtain serum concentrations that are equivalent to the full dosing and hopefully minimize toxicity. Although this hasn’t gotten onto the label, I think this is a strategy that hopefully, one day, could get into the label or at least be how patients use this drug. Instead of giving the drug at 750 mg/day without food, if you took it with a low-fat meal at 450 mg/day, you could achieve the same serum concentrations.
In theory, that could hopefully maintain efficacy and perhaps reduce toxicity as well. The original trials were not designed to look at that dose with food, so the published registration data that we have used the 750 mg/day dose. It’s important to emphasize. This may be an alternate strategy, as we learn over time that this looks to be as good from an efficacy standpoint and maybe safer for patients, but there’s more to show. At least, potentially, it’s an alternate strategy to help patients stay on this drug longer.
The 450 mg/day dose with food looks to be equivalent from a pharmacokinetic profile to the 750 mg/day fasted dosing. Again, the 750 mg/day fasted dosing is the FDA-approved dose on label. But these new data suggest that a 450 mg/day dose with a low-fat diet, a low-fat meal, achieves the same pharmacokinetic profile that the approved dose has. And hopefully that would lead to a better safety profile for patients. More prospective data would be ideal, but dose reductions are common in routine use in the community setting. Learning more about how food could actually improve the efficacy and maintain safety is an important step forward in certinib’s use. So, I think these data are very important. It’s a small study that may one day, with confirmatory data, expand the label, and at least patients and doctors can better manage some of the toxicity they’re experiencing.
Gastrointestinal toxicity is one of the main toxicities of ceritinib, and there are different strategies we use to help mitigate that. The most common is simply lowering the dose, so starting at 750 mg/day in a fasting state and then lowering it to 600 mg/day, sometimes to 450 mg/day. It can be an effective strategy. There are other effective strategies, too, that can include nighttime dosing. So, having the patient dose this before they go to sleep is one way to make this a more tolerable therapy from a GI perspective. The other is the use of antiemetics. I tend to use antiemetics pretty frequently as a pre-dose with this. A lot of my colleagues don’t do that, but I find this to be an effective strategy.
So, taking an antiemetic such as ondansetron or granisetron can make this a more tolerable regimen for patients. But everyone is different. You have to adjust things at the patient level to see what works, but there are at least a few things you can try. Again, some earlier data suggest that taking it with a low-fat meal at a lower dose, 450 mg/day, can achieve the same serum pharmacokinetic parameters and hopefully make this a more tolerable regimen for patients.
Ceritinib is a fantastic drug. I remember when it was first presented, it was standing room only a major breakthrough for patients, a drug that helps not only patients who never received crizotinib but also patients who had been through crizotinib. The experience with ceritinib has been that it has helped a lot of patients do well for not just a short period of time. There are some patients who can do well for years. In fact, my first patient on ceritinib, as part of a clinical trial, had remained on therapy for over 3 years with excellent control, even with the development of brain metastases prior to going onto the drug. The patient remained asymptomatic and remained on therapy with good control of that lesion for years. This is a drug that has to be adjusted in most patients. It’s very unusual that you can stay at the full dose and schedule, and as with many oral therapies we use, we make adjustments, and patients can do very well. It is a very effective therapy. Fortunately, we have several effective therapies in this setting for patients withALK-rearranged lung cancer, and even more on the horizon, but this is one of those that have helped a lot of patients.
Transcript edited for clarity.