Managing Adverse Effects During a Lenvatinib plus Pembrolizumab Combination Therapy Regimen


Dr Scott Tykodi muses on how he would alter treatment for a patient with advanced clear cell RCC after side effects develop.

Nizar Tannir, MD: After a few cycles of treatment with lenvatinib, the patient developed diarrhea. We have some questions. This is a quick [question] for both of you. What do you do when a patient has diarrhea? This could be from the TKI [tyrosine kinase inhibitor] or from the anti–PD-1. We know which one is causing the diarrhea simply by holding the TKI and seeing whether the diarrhea improves. Scott, when we start the patient on the full dose of lenvatinib, 20 mg a day, and the patient develops diarrhea, what do you do? How do you take them to a lower dose? Obviously, you interrupt. What do you do next?

Scott Tykodi, MD, PhD: Nizar, I agree. If the patient isn’t unstable, we typically would hold the TKI and support them and see what happens as our guide to try to judge which drug is the culprit. Sometimes you feel like you know. If the tempo of diarrhea slowly builds over time, that’s more of a TKI exposure profile. A crescendo effect over a few days is sometimes an explosive presentation of autoimmune colitis. But if we’re convinced the TKI is the culprit and the patient feels much better after a few days off therapy, and we’re going to restart a dose reduction, I typically go from 20 mg to 14 mg. You could do 18 mg—obviously, lenvatinib comes as 10-mg and 4-mg [capsules]—but that isn’t enough of a change to impact how the patient feels. For most patients, 14 mg would be the starting point.

For strictly pragmatic issues, you have to submit a new prescription and get 4-mg [capsules] for patients who have only 10-mg [capsules]. Sometimes we might have the patient try 10 mg and make sure they tolerate it and then delay escalating to 14 mg before we go through the bother of represcribing. That’s one of the dilemmas of drugs that don’t come in even [capsule] size increments. It creates a practical phenomenon in the clinic of a lot of busy work for you, your nurse, and your pharmacist to keep changing doses and keep cycling through insurance approval for these patients.

Nizar Tannir, MD: There’s an exchange program where the patient can send up to 15 of their doses and get a new 15-day supply of the next dose. Moshe, what do you do for your patients? Do you follow basically the same algorithm as Scott?

Moshe Ornstein, MD, MA: I do it a little differently. As Scott mentioned, there are times when you have a good sense of whether it’s an autoimmune colitis, and the time to give steroids is when you think about it. But for the dosing of lenvatinib, it depends. I start all patients at 20 mg. After I stop, I ask myself a couple of questions. I first ask, did the patient just not have sufficient supportive measures? I’d ideally like to keep patients at 20 mg if it isn’t interfering too much with their life. If we didn’t educate the patient well enough or they weren’t able to obtain loperamide or other antidiarrheals, then I’d try to restart at the same dose if I think the patient can tolerate it.

When it comes to dose reductions, there’s what the label says, and there’s what we do in clinical practice. It’s very patient specific. There are certainly patients for whom I’m worried about giving 20 mg or 18 mg. I drop them down to the 14-mg dose. Whether it’s the dose exchange or the time it takes to submit a new prescription, usually that time off therapy is really helpful for them. But if a patient is borderline, I’d probably still rechallenge them at an 18-mg dose, and give them a 10-mg and 2 of the 4-mg [capsules].

So much of this is about expectations and prepping the patient ahead of time. I tell patients that most of them are going to require a dose reduction. But because the trial started at 20 mg and dosing is important, we start at 20 mg. I caution them that it’s OK if we have to dose reduce. Most patients in the trial had dose reductions, and the patients in the trial did well overall compared with the prior standard of care. But I try to drop them down by only a 10% decrease, first to 18 mg, and then if I’m still running into trouble, down to 14 mg.

Nizar Tannir, MD: You both provided excellent advice and recommendations for the practitioner who’s beginning to use lenvatinib plus pembrolizumab for their patients. This is good advice.

Transcript edited for clarity.

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