Robert Motzer, MD: Let’s move on to follow the path of this patient.
Eric Jonasch, MD: This patient was put on lenvatinib and everolimus. They developed grade 1 diarrhea. They did quite well in terms of overall tolerability. Twelve months later, the progression of the disease is documented and the patient wishes to continue the active treatment because he is feeling well enough and wants to continue the treatment.
Robert Motzer, MD: With this program there is a fairly high percentage of patients who required dose reductions. With the lenvatinib-everolimus program, how do you decide to reduce the two drugs? How to make a decision in terms of toxicity management? Tom, do you want to comment on this?
Tom Hutson, DO, PharmD: In general, everolimus is not the agent we deal with a lot. Most people at the 5 mg dose do not have significant side effects. It’s rare. The side effects you would think about would be mucositis and things like that. But I do not see this nor the hematological effects at the 5 mg dose. Thus, the focus is on lenvatinib. It seems like adjusting this one is where you get the most mileage with the upgrade. Make it part of a specific clinical trial experience. As I said at the start of our program, you need to educate the patient and let them know that it is common to have a dose reduction. It’s not their fault that they have it. Evidence suggests that if they need a dose reduction, this will not compromise the effectiveness of therapy; it is a question of quality of life.
The most important thing is to make sure that you stop the treatment until the side effect reaches a level 1 or goes away before switching to the lower dose. You do not do a service to go down to the lower dose immediately without recovering from a side effect.
Robert Motzer, MD: This is great management advice. Now, dose modifications have been incorporated into lenvatinib both in combination with everolimus and in combination with lenvatinib pembrolizumab. Eric, could you briefly go over the data we have with these dose changes?
Eric Jonasch, MD: The bottom line is that reducing the dose does not appear to result in decreased efficacy for patients. That would be the take home message: if you need to reduce the dose, you should. This in itself is not going to result in increased efficiency. There was an interesting study, not with lenvatinib but with axitinib. I posted this with Brian Rini a few years ago and then there was a summary at ESMO [European Society for Medical Oncology Congress] this year on cabozantinib. People who develop unwanted effects on TKIs [tyrosine kinase inhibitors] are most likely to have prolonged benefit. This shows that these people are in an ideal pharmacodynamic zone. What you need to do is make sure they don’t get into trouble. But you can manage your exit. This is how we should think about it.
Robert Motzer, MD: The strategy with lenvatinib everolimus has been an initial dose of 18 mg, and the dose is reduced to 14, 10, then 8 mg as needed to modify the lenvatinib dosage. Let’s talk a little more about what happened with this patient.
Eric Jonasch, MD: Here we have the dose changes that Bob just mentioned, to 18mg, 13mg, then 10mg. What I like about the 10 plus 4 mg lenvatinib strength is the ability to adjust it, at least when you give it with everolimus. This patient has progressed. The patient wanted to continue active treatment. Here are the questions that Bob will have us answer.
Robert Motzer, MD: As mentioned, this patient progressed and desired to receive continued active treatment. In heavily pre-treated patients, the question becomes: what are the third-line goals? Does it improve survival? Is this a lasting response? Is it the quality of life? Where do you see this discussion in your practice, Bradley, in terms of the refractory patient?
Bradley McGregor, MD: This is all of the above. It all depends on the patient. We have these patients who can have 2 lines of therapy. At this point they have a performance rating of 3 with severe toxicities from the previous treatment line. They may not have recovered, with very symptomatic illness. It might not be a situation where they can get that next line of therapy.
But you have a lot of patients who may have received nivolumab-ipilimumab first line, had a good response, progressed, and received cabozantinib. There is still minimal exposure to VEGF with good performance index and minimal comorbidities. There is certainly an option for continued treatment. As with everything, it comes down to this discussion with the patient. We know that there are therapies that may have an advantage in later bloodlines. After discussing with the patient the different risks-benefits and the different options that may be for him, it is certainly worth discussing which option makes sense to him.
Transcription edited for clarity.
