A 58-Year-Old Man With Advanced Renal Cell Carcinoma - Episode 5
Robert Alter, MD: The initial data that were presented on lenvatinib in combination with everolimus were presented by Robert Motzer, MD, approximately 4.5 years ago. The data explored the utilization of lenvatinib and everolimus after patients progressed on a first-line tyrosine kinase inhibitor [TKI]. Patients could have received 2 lines of TKI therapy, utilizing the dosage of lenvatinib at 18 mg daily along with everolimus at 5 mg daily.
It was a small phase 2 clinical trial. This was an impactful clinical trial. Patients had a progression-free survival of 14.6 months. Response rates were noted to be 37%, with patients having improvement in overall survival. It was a clinical trial looking at lenvatinib plus everolimus compared to single-agent lenvatinib, compared to single-agent everolimus. That seemed to not only reveal the benefit of lenvatinib, that being a multikinase inhibitor to VEGF, FGFR, KIT, and RET, but it also has now led to more studies looking at lenvatinib as a second-line therapy. Lenvatinib was presented at ASCO [the American Society of Clinical Oncology annual meeting] 2020 in combination with pembrolizumab, and other ongoing clinical trials are looking at utilizing lenvatinib as a first-line therapy.
Discussing the use of lenvatinib in combination with everolimus, there are things to remember. We have used everolimus for more than 10 years as a single agent for metastatic renal cell carcinoma. The dose of everolimus as a single agent is 10 mg a day. In the clinical trial comparing everolimus to lenvatinib to the combination of lenvatinib and everolimus, the single-agent dose of everolimus was 10 mg. However, in combination with lenvatinib, the dose of everolimus was 5 mg.
When you look at the toxicity profile of lenvatinib and everolimus, everolimus does cause peripheral edema, stomatitis, pneumonitis, and can cause laboratory changes in regard to lipids and glucose. We are familiar with its toxicities, which include diarrhea, taste changes, hand-foot syndromes, hypertension, poor wound healing, bleeding, risk of thrombosis. If you’re on a clinical trial, or if patients are receiving the combination of everolimus and lenvatinib and toxicities do ensue, based upon our experience you can differentiate which therapy has to be adjusted. For the most part, the toxicities are mostly going to be caused by the lenvatinib. Dose reductions would go from 18 mg down to 14 mg, still maintaining the dose of everolimus at 5 mg daily. You can then decrease the lenvatinib dose to 10 mg, and subsequently down to 8 mg if necessary.
If you have truly defined the toxicities as being purely caused by everolimus, you can actually hold the everolimus, maintain the lenvatinib at the present dose, and reincorporate the everolimus back into the combination profile.
We are utilizing 2 mechanisms, similar to how we’re utilizing TKI and I/O [immune-oncology] therapy. I think at times if one has the ability to utilize 2 mechanisms of agents to fight a disease, when one has concerns of second-line therapy and rapid disease progression, having both agents may be quite important so patients can have good, durable responses.
In patients receiving the combination of everolimus and lenvatinib, the benefit of the therapies leading to improvement in median progression-free survival as well as response rate truly indicated, based upon good tolerability of the therapies in combination, that most of the patients were able to maintain the doses of lenvatinib. Upon toxicity of lenvatinib, patients were mostly reduced to 14 mg a day from the 18-mg dosage. Patients are able to maintain the everolimus dosage of 5 mg a day. I think it’s important to recognize, despite the second-line TKI [tyrosine kinase inhibitor] therapy—and even though one believes that if you had toxicities from a first-line TKI that you would subsequently have toxicities from the second-line TKI—TKIs tend to be different despite the fact that they do have some overlapping inhibition of VEGF.
The tolerability to these therapies are still considered to be individualized. And I would say that, in my practice, when patients do switch from a first-line TKI to a second-line TKI, I still don’t utilize the therapy at its PI [prescribing information] dose, at the standard dose of initiation, with dose adjustments based upon toxicities. Recognizing a lot of the data that have been presented over the course of the last 13 years utilizing TKI therapies, it’s important to recognize that what we’re utilizing in patients at the initial starting doses is based upon the clinical trials.
Transcript edited for clarity.
Case: A 58-Year-Old Man With Advanced Renal Cell Carcinoma