Lenvatinib/Everolimus in Refractory mRCC

Thomas Hutson, DO, PharmD:The pivotal trial that resulted in regulatory approval of lenvatinib/everolimus as an option for refractory RCC was a phase III trial of lenvatinib/everolimus compared to single-agent lenvatinib, compared to sunitinib. It was a 3-arm trial. The data that we’re going to discuss, and what is actually involved in the FDA approval, was the lenvatinib/everolimus versus sunitinib.

In that trial, which was randomized, approximately 50 patients per arm, there was a benefit with lenvatinib/everolimus in patients with clear cell RCC in response rate, progression-free survival, and overall survival. The response rate data exceeded what we had previously seen in any agent greater than 40% response rate. The progression-free survival of lenvatinib/everolimus combination was 14.6 months and exceeded the PFS that we had seen to date among any agent. Certainly, there was much excitement in the field with this data.

Looking at the side effect profile of the combination therapy was not different than what one would expect when one uses an agent such as lenvatinib, a VEGF inhibitor, and everolimus. There were no unusual side effects or excess side effects. Most patients were able to be controlled with dose reduction or dose interruption. The standard dosing of lenvatinib/everolimus is 18 mg lenvatinib and 5 mg of everolimus. The dose level minus 1, is 14 mg lenvatinib and 5 mg everolimus. In my practice, I very rarely have to go below dose level minus 1. Most of my patients tolerate this therapy well, and I see reproducible response rates similar to what we saw in the phase II trial. Based upon the phase II trial, the combination received regulatory approval as an agent for the refractory-line setting in the United States.

To further study the combination in the frontline setting, a large phase III trial is enrolling patients, called the CLEAR study, where patients are randomized to lenvatinib/everolimus, to lenvatinib/pembrolizumab, or to sunitinib. This trial was getting close to reaching its accrual number, and we anxiously await the results.

Transcript edited for clarity.

A 70-Year-Old African-American Woman with Metastatic RCC

December 2017

• A 70-year-old African-American woman presented to her PCP with loss of appetite, fatigue, abdominal pains, and blood in her stool
• CT of the chest, abdomen, & pelvis: distal esophageal thickening and appearance of a solid mass on the inferior pole of the right kidney (3.4 × 2.6 cm); well-defined hypodense nodules in the right lobe of the thyroid (2.1 × 2.8 cm) and bilateral adrenal glands
• Biopsy of renal mass revealed neoplastic cells with clear cytoplasm arranged in nests and mitotic figures suggesting clear cell carcinoma
• FNA from the thyroid nodule revealed neoplastic clear cells on cytology
• IHC; PAX8+, CAIX+, TTF-1(-)
• Diagnosis; right-sided renal cell carcinoma with clear cell histology; thyroid and bilateral adrenal metastasis (T4N0M1)
• She underwent right radical nephrectomy, right adrenalectomy, and radiofrequency ablation of left adrenal metastasis
• She was subsequently started on sunitinib and achieved a partial response within 3 months

June 2018

• Seven months later, the patient reports having increased fatigue
• MRI shows progression in both adrenal lesions
• Therapy was changed to lenvatinib plus everolimus