Lenvatinib Combination Data in mRCC

Robert Alter, MD: Recently, there have been data from the CLEAR clinical trial, which is a multicenter open-label phase 3 trial comparing the safety and efficacy of lenvatinib in combination with everolimus or pembrolizumab in patients with advanced renal cell carcinoma. This was compared with the comparative arm, or the standard-of-care arm, sunitinib.

A primary end point was progression-free survival by independent review, with secondary end points being objective response rate, overall survival, treatment-emergent adverse events, discontinuation based on toxicity, and of course safety and health-related quality of life. There was just a press release last week talking about how the company end points were all met in regard to the primary and secondary end points and in regard to progression-free survival, overall survival, and response rate.

Patients who received the combination of lenvatinib and pembrolizumab were compared with patients receiving sunitinib. There was even a benefit regarding all 3 of those parameters when patients received lenvatinib and everolimus compared with sunitinib. We are seeing, through the CLEAR trial and the KEYNOTE-426 and CheckMate 214 trials, that the standard-of-care arm of sunitinib is going to be phased out.

This brings another combination I/O [immuno-oncology]–TKI [tyrosine kinase inhibitor] therapy to light. Again, as another arm, the TKI/MTOR combination, or lenvatinib and everolimus being the combination, is subject to approval. These are for patients on first-line therapy, not second-line therapy.

Recently, Dr Tom Hutson presented data utilizing the combination of lenvatinib and everolimus in patients with non–clear cell renal cell carcinoma. This was a single-arm, phase 2 clinical trial he presented at the International Kidney Cancer Symposium. The primary end point was overall response rate, utilizing the dose of lenvatinib at 18 mg daily and everolimus at 5 mg daily. The response rate was noted to be 25.8% in patients through all different non–clear cell histologies, which is important.

It was also very important that there was a stable disease rate of 58%. Here, you do have a disease control rate of 83.9%, which means, in essence, that 5 of every 6 patients have the stabilization for regression of the disease. We have always had issues with non–clear cell renal carcinoma. We have never quite known how to take care of these patients utilizing single agent TKIs. It has always been a about immunotherapy. The KEYNOTE-426 trial talked about that.

These appeared to be very strong numbers in regard to efficacy. Tolerability was as expected; there were no new signals like fatigue, diarrhea, hypertension, or anorexia, which I see in approximately half my patients. The GI [gastrointestinal] toxicity of nausea and vomiting were also noted as well. Bile thrombocytopenia was noted, but this was overall a combination that was well tolerated, and again it is an eye-opener when it comes to the significant amount of efficacy.

There is also a presentation by Dr Hilary Glen talking about the dosing of lenvatinib in a phase 2 clinical trial, utilizing everolimus dosed at 5 mg once a day but lenvatinib dosed at 18 or 40 mg. This was a double-blind phase 2 clinical trial. The conservative course was not just tolerability but efficacy, which was quite important. Dose interruptions seem to be equal through both arms. The tolerability was good. 

The primary end point was overall response rate at 24 weeks, with secondary end points being progression-free survival and overall objective response rate throughout the study. The typical response rate was slightly better for patients receiving 18-mg doses, at close to 21%. In patients who received lenvatinib at 14 mg, the response rate was 35%. The median duration of the response was similar in both cases. Progression-free survival was slightly better for patients who received 18 mg, with a rate of 14.7 months. Patients who received the 14-mg dose had a progression-free survival rate of 11.1 months. The median duration of patients on therapy was slightly more, with patients receiving 18-mg doses.

Toxicities were relatively the same when it came to hypertension, diarrhea, proteinuria, and anorexia. Based on the progression-free survival and the trend in overall survival, the results seem to be favoring an 18-mg dose rather than a 40-mg dose. They found no difference in the toxicity profile. The recommendations were for the patients to maintain lenvatinib at 18-mg doses in combination with everolimus at 5-mg doses.

Toxicities noted in the study by Dr Glen did not show any new signals. We are always concerned about the toxicity of not only TKIs but also MTORs. In this study, there was bone marrow suppression with MTORs and few cholesterol concerns. For the most part, however, it was well tolerated. Hypertension diarrhea, proteinuria, anorexia, and GI toxicities all must be considered when it comes to TKI therapies. Rashes also seem to be concerning.

The aggressive attention we offer patients when it comes to these toxicities is how we allow our patients to tolerate this therapy so well. We have been using TKIs for close to 14 or 15 years. We are all a little wet by the ears now. We have challenges with our patients as well, but aggressive actions take care of any concerns with blood pressure. I like to work with my primary care physician or cardiology colleagues and have our patients managed. It is 1 less thing that I, as an oncologist, can take care of, because they are significantly more qualified.

The diarrhea or rash should be aggressively monitored and managed. The communication between the patient and physician or health care providers is what drives our patients’ quality of life to improve, allowing patients to avoid grades 2, 3, and 4 toxicity. Part of our conversation with our patients, initially, is about the importance of communication. 

Based on the toxicity of these oral therapies and intravenous therapies and what they can possibly do to patients, our awareness and interventions early in the process has led our patients to have better tolerability and to have better efficacy.

The recent press release does talk about the patients in the CLEAR clinical trial having a statistically significant benefit over other patients with overall response rate, overall survival, and progression-free.

Transcript edited for clarity.