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Ceritinib Alternative Dosing for ALK+ NSCLC

Insights From: Tony Mok, MD, Chinese University of Hong Kong; David Spigel, MD, Sarah Cannon Research Institute; Alice Shaw, MD, PhD, Harvard Medical School
Published: Tuesday, Mar 28, 2017


Transcript:

Alice Shaw, MD, PhD:
Among the different ALK inhibitors, we have first-generation crizotinib and we have several different second-generation inhibitors like ceritinib and alectinib. And now we even have third-generation inhibitors. Among all of those, I would say that ceritinib is a rather challenging drug in terms of side effects and, in particular, gastrointestinal side effects. What we saw across all the trials of ceritinib is that the majority of patients who are treated with the standard dose of ceritinib—which is 750 mg once a day, fasting—will have nausea, vomiting, or diarrhea. It was about 80% of patients who experienced these GI side effects. And most of the time, these GI side effects were mild. They were graded as 1 or 2, but there are a minority of patients who do have more severe GI side effects, particularly vomiting and diarrhea. So, I think ceritinib, among all of the ALK inhibitors, is probably the most challenging in terms of dealing with the GI side effects.

Other common side effects with ceritinib include liver function abnormalities, particularly elevated transaminases. Again, I would say the risk of having elevated transaminases is even higher with ceritinib than with other ALK inhibitors, and that’s using the standard dose of ceritinib. There are some other side effects that are worth noting with ceritinib including fatigue, abdominal pain, and weight loss. Again, I think many of these side effects all tie back to the GI issues, which are often nausea, vomiting, and diarrhea. So, I think we often very aggressively and proactively manage patients when they are treated with ceritinib—meaning prophylaxis with antinausea medicines, very aggressive treatment of diarrhea.

I would also note that there have been studies now exploring alternative dosing regimens of ceritinib because of this toxicity. As I said earlier, the standard dose of ceritinib is currently 750 mg once daily and fasting, but there has now been a report at the World Conference on Lung Cancer this past year looking at different doses of ceritinib taken with food. And what this study, which is called ASCEND-8, showed is that a lower dose, 450 mg, of ceritinib once a day taken with food seems to give comparable exposures of ceritinib in the plasma as the standard 750 mg once a day while fasting dose. And the reason that’s important is because we’re achieving similar exposure, and yet what we also see, with the lower dose with food, is significantly fewer GI side effects. So, I think going forward, we’re very hopeful, as we get more data from ASCEND-8, that 450 mg of ceritinib taken with food will be shown to be comparable in terms of exposure as well as efficacy, and that will become a new dosing regimen for ceritinib. That will make it much more tolerable for patients.

At present, when I prescribe ceritinib, I actually am prescribing it at the alternative dosing, which is 450 mg once a day dose instead of 750 mg once a day. I do encourage patients to take the dose with food, and I find that the lower dose combined with food really helps to mitigate side effects. However, patients can still develop the GI side effects, and so I do have patients monitored very closely in terms of their nausea and particularly in terms of diarrhea. For nausea, we often will use ondansetron or prochlorperazine, and sometimes prophylactically even—meaning that we don’t wait for the nausea to develop. But knowing that the patient has developed nausea in the past, prior to dosing with ceritinib, they will take a prophylactic dose of one of the antinausea medications. And for diarrhea, again, just very close monitoring of diarrhea and counseling of patients, so that they know that they can take antidiarrheal medications as soon as they have the first episode of diarrhea.

Tony Mok, MD: Ceritinib has been used in the clinic in the past few years. The most important and significant toxicity is the GI toxicity, namely the nausea, vomiting, and diarrhea. How do I manage it? Although the label says that you are not supposed to take it with food, generally taking a small, small snack may actually temper some of the nausea sensation. So, I usually suggest to the patient that if they have the nausea, they should take a small amount of food, either a biscuit or a small sandwich, before they take the medications because some of this GI upset is related to local irritation. Some other patients who get continuous significant nausea and vomiting may require the continuous use of antiemetics, such as ondansetron, that may actually help the control. And if it still doesn’t work, then we may have to reduce the dose. As a matter of fact, for Asian patients, I don’t usually start them off at the standard dose of 750 mg. I may start them off at 450 mg or 600 mg. If they were able to tolerate the medication, only then do I slowly increase the dose for them.

Transcript Edited for Clarity
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Transcript:

Alice Shaw, MD, PhD:
Among the different ALK inhibitors, we have first-generation crizotinib and we have several different second-generation inhibitors like ceritinib and alectinib. And now we even have third-generation inhibitors. Among all of those, I would say that ceritinib is a rather challenging drug in terms of side effects and, in particular, gastrointestinal side effects. What we saw across all the trials of ceritinib is that the majority of patients who are treated with the standard dose of ceritinib—which is 750 mg once a day, fasting—will have nausea, vomiting, or diarrhea. It was about 80% of patients who experienced these GI side effects. And most of the time, these GI side effects were mild. They were graded as 1 or 2, but there are a minority of patients who do have more severe GI side effects, particularly vomiting and diarrhea. So, I think ceritinib, among all of the ALK inhibitors, is probably the most challenging in terms of dealing with the GI side effects.

Other common side effects with ceritinib include liver function abnormalities, particularly elevated transaminases. Again, I would say the risk of having elevated transaminases is even higher with ceritinib than with other ALK inhibitors, and that’s using the standard dose of ceritinib. There are some other side effects that are worth noting with ceritinib including fatigue, abdominal pain, and weight loss. Again, I think many of these side effects all tie back to the GI issues, which are often nausea, vomiting, and diarrhea. So, I think we often very aggressively and proactively manage patients when they are treated with ceritinib—meaning prophylaxis with antinausea medicines, very aggressive treatment of diarrhea.

I would also note that there have been studies now exploring alternative dosing regimens of ceritinib because of this toxicity. As I said earlier, the standard dose of ceritinib is currently 750 mg once daily and fasting, but there has now been a report at the World Conference on Lung Cancer this past year looking at different doses of ceritinib taken with food. And what this study, which is called ASCEND-8, showed is that a lower dose, 450 mg, of ceritinib once a day taken with food seems to give comparable exposures of ceritinib in the plasma as the standard 750 mg once a day while fasting dose. And the reason that’s important is because we’re achieving similar exposure, and yet what we also see, with the lower dose with food, is significantly fewer GI side effects. So, I think going forward, we’re very hopeful, as we get more data from ASCEND-8, that 450 mg of ceritinib taken with food will be shown to be comparable in terms of exposure as well as efficacy, and that will become a new dosing regimen for ceritinib. That will make it much more tolerable for patients.

At present, when I prescribe ceritinib, I actually am prescribing it at the alternative dosing, which is 450 mg once a day dose instead of 750 mg once a day. I do encourage patients to take the dose with food, and I find that the lower dose combined with food really helps to mitigate side effects. However, patients can still develop the GI side effects, and so I do have patients monitored very closely in terms of their nausea and particularly in terms of diarrhea. For nausea, we often will use ondansetron or prochlorperazine, and sometimes prophylactically even—meaning that we don’t wait for the nausea to develop. But knowing that the patient has developed nausea in the past, prior to dosing with ceritinib, they will take a prophylactic dose of one of the antinausea medications. And for diarrhea, again, just very close monitoring of diarrhea and counseling of patients, so that they know that they can take antidiarrheal medications as soon as they have the first episode of diarrhea.

Tony Mok, MD: Ceritinib has been used in the clinic in the past few years. The most important and significant toxicity is the GI toxicity, namely the nausea, vomiting, and diarrhea. How do I manage it? Although the label says that you are not supposed to take it with food, generally taking a small, small snack may actually temper some of the nausea sensation. So, I usually suggest to the patient that if they have the nausea, they should take a small amount of food, either a biscuit or a small sandwich, before they take the medications because some of this GI upset is related to local irritation. Some other patients who get continuous significant nausea and vomiting may require the continuous use of antiemetics, such as ondansetron, that may actually help the control. And if it still doesn’t work, then we may have to reduce the dose. As a matter of fact, for Asian patients, I don’t usually start them off at the standard dose of 750 mg. I may start them off at 450 mg or 600 mg. If they were able to tolerate the medication, only then do I slowly increase the dose for them.

Transcript Edited for Clarity
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