Eric Jonasch, MD: This patient was started on lenvatinib and everolimus. They developed a grade 1 diarrhea. They did quite well on this from an overall tolerability perspective. Twelve months later, disease progression is documented, and the patient would like to continue active therapy because they’re feeling fairly well, and they’re interested in continuing treatment.

Robert Motzer, MD: With this program, there’s a fairly high percentage of patients who required dose reductions. With the lenvatinib-everolimus program, how do you decide in terms of do you reduce both drugs? How do you make a decision in terms of toxicity management? Tom, do you want to comment on that?

Tom Hutson, DO, PharmD: Generally, everolimus isn’t the agent that we’re dealing with a lot. Most people at the 5-mg dose don’t have significant adverse effects. It’s rare. The adverse effects you’d think about with that would be mucositis and things like that. But I’m not seeing that or the hematologic effects at the 5-mg dose. Thus, the focus is on lenvatinib. It seems the adjustment of that is where you get the most mileage with improvement. Build it in to specific clinical trial experience. As I said at the beginning of our program, you need to have the education of the patient and let them know that it’s common to have a dose reduction. It’s not their fault that they’re having it. The evidence suggests that if they need the dose reduction, it’s not going to compromise the efficacy of the therapy; it’s about quality of life.

The biggest thing is to make sure that you withhold therapy until the adverse effect gets down to a level 1 or gone before going on the lower dose. You do a disservice to immediately go down to the lower dose without recovery of an adverse effect.

Robert Motzer, MD: Those are some great management tips. Now, dose modifications have been built into lenvatinib both in combination with everolimus and in combination with lenvatinib pembrolizumab. Eric, could you briefly review the data that we have with these dose modifications?

Eric Jonasch, MD: The bottom line is that dose reduction doesn’t seem to result in a decrease in efficacy for patients. That would be the take-home message: if you need to dose reduce, you should. This in itself isn’t going to result in increased efficacy. There was an interesting study, not with lenvatinib but with axitinib. I published this with Brian Rini a number of years ago, and then there was an abstract at ESMO [European Society for Medical Oncology Congress] this year on cabozantinib. Those individuals who develop adverse effects on TKIs [tyrosine kinase inhibitors] are the ones most likely to have prolonged benefit. It demonstrates that those people are in a pharmacodynamic sweet spot. What you need to do is make sure they don’t get into trouble. But you can manage your way out of it. That’s the way we should think about this.

Robert Motzer, MD: The strategy with the lenvatinib everolimus has been a starting dose of 18 mg, and the dose is reduced to 14, 10, and then 8 mg as needed for modification for the dosing of lenvatinib. Let’s talk a little more about what happened with this patient.

Eric Jonasch, MD: Here we have the dose modifications that Bob just mentioned, at 18 mg, 13 mg, then 10 mg. What I love about the 10- plus 4- plus 4-mg dosing of lenvatinib is the practicality of being able to adjust this, at least when you’re giving it together with everolimus. This patient progressed. The patient wanted to continue on active therapy. Here are the questions that Bob is going to have us answer.

Robert Motzer, MD: As mentioned, this patient progressed and wanted to receive continued active therapy. In heavily pretreated patients, the question becomes: what are the goals in third line? Is it improving survival? Is it a durable response? Is it quality of life? Where do you see this discussion in your practice, Bradley, in terms of the patient in the refractory setting?

Bradley McGregor, MD: It’s all of the above. Everything comes down to the patient. We have those patients who may have 2 lines of therapy. At that point they’re at a performance status of 3 with severe toxicities from the prior line of therapy. They may not have recovered, with very symptomatic disease. That may not be a situation where they can get that next line of therapy.

But you have a lot of patients who may have gotten nivolumab-ipilimumab in the front line, had good response, progressed, and got cabozantinib. There’s still minimal VEGF exposure with good performance status and minimal comorbidities. There’s certainly an option for continued therapy. As with anything, it comes down to that discussion with the patient. We know that there are therapies that can have a benefit in the later lines. After discussion with the patient of the different risk benefits and different options that may be for them, it’s certainly worth discussing what option makes sense for them.

Transcript edited for clarity.