Efficacy and Safety of Lenvatinib/Everolimus in mRCC

Robert J. Motzer, MD:I participated in the phase I study, and in the randomized phase II trial, and in studies afterwards with lenvatinib and everolimus. Including the pivotal phase III trial that’s ongoing, with lenvatinib/everolimus, compared to lenvatinib/pembrolizumab, compared to sunitinib in first-line treatment—a nearly 800-patient trial referred to as the Clear Cell trial, to investigate the lenvatinib/everolimus regimen, and lenvatinib/pembrolizumab in first-line therapy.

As part of standard management and in the earlier studies, my experience with lenvatinib/everolimus has been very favorable, particularly with regard to its efficacy. There’s certainly safety aspects associated with that, with a frequent dose reduction. Most patients do experience an adverse event of one type or another, but I felt that overall, the adverse events are manageable, and I have been very impressed by the efficacy for the regimen.

Lenvatinib is a typical tyrosine kinase inhibitor, and its predominant side effects include hypertension. It can cause diarrhea; it can cause skin toxicity. One of the adverse events that we see that are higher with lenvatinib compared with some of the other TKIs like sunitinib and pazopanib, is proteinuria as well. So, those are important to monitor in patients treated with lenvatinib.

Everolimus, a very well tolerated drug, adds little to the toxicity. The main side effects with everolimus are stomatitis and also, it can rarely cause pneumonitis. So, in the combination of lenvatinib/everolimus, overall it was pretty well tolerated for patients in the phase II trial, although frequent dose reductions were required. In that study, about 60% of patients required a dose reduction, which was generally of the lenvatinib.

Oftentimes, toxicity is seen with that particular regimen, but one of the philosophies of that regimen is to start out with full dose, anticipating that many patients will require a dose reduction. The dose reductions are most common for hypertension, diarrhea, or the proteinuria.

Transcript edited for clarity.

A Japanese-American Male With Recurrent RCC

November 2015

• At the age of 49, a Japanese-American man presented to the ER with abdominal pains
• CT of the abdomen and pelvis revealed diverticulitis with an incidental left renal mass (4.2 cm × 8.6 cm × 2.8 cm)
• SH: Marathon runner; nonsmoker; social drinker
• He underwent sigmoid colon resection; left radical nephrectomy
• Pathology; sigmoid colon pathology revealed diverticulitis; renal pathology revealed RCC, clear cell type
• Diagnosis: RCC stage PT2a
• KPS: 90
• Fuhrman Grade: 3/4

September 2017

• Follow-up CT showed residual soft tissue in the left nephrectomy bed, pulmonary lung metastasis, and an expansile lucent osseous lesion in the right pubic ramus
• Biopsy of one of the osseous lesions confirmed mRCC
• He began systemic therapy with sunitinib for 20 weeks and achieved stable disease and some shrinkage of the bone lesion
• KPS: 90
• MSKCC risk score: Intermediate

July 2018

• The patient now complains of left pelvic pain
• Imaging shows marked progression in retroperitoneal mass; new lung metastasis
• Laboratory values:
  • CBC: WBC - 7; Hgb - 12.6; Platelet - 190; ANC — 5.2;
  • CMP; Creatinine - 1.82 mg/dL; LFTs - WNL; Calcium - 9.2 mg/dL; LDH — WNL
• MSKCC risk score: Intermediate
• KPS: 80
• The patient was treated with palliative radiation therapy to bone metastasis
• He was then started on treatment with lenvatinib/everolimus