On August 10, 2021, the U.S. Food and Drug Administration (FDA) approved the combination of lenvatinib (Lenvima®) and pembrolizumab (Keytruda®) for first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

FDA Approves Lenvatinib and Pembrolizumab for Advanced Renal Cell Carcinoma

The efficacy of the combination was investigated in a multicenter, open-label, randomized phase 3 trial (CLEAR, Study 307/KEYNOTE-581; NCT02811861) in patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. The efficacy population supporting the approval included patients randomized to lenvatinib plus pembrolizumab (n = 355) compared with those randomized to single agent sunitinib (n = 357).

Progression-free survival (PFS), assessed by independent radiologic review according to response evaluation criteria in solid tumors 1.1, and overall survival (OS) were the major efficacy endpoints. Patients receiving pembrolizumab with lenvatinib had a median PFS of 23.9 months (95% CI = 20.8, 27.7) compared with 9.2 months (95% CI = 6.0, 11.0) for those receiving sunitinib (HR = 0.39; 95% CI = 0.32, 0.49; p < 0.0001). Median OS was not reached in either arm (HR = 0.66; 95% CI = 0.49, 0.88; p = 0.0049). The objective response rates were 71% (95% CI = 66, 76) and 36% (95% CI = 31, 41; p < 0.0001) and complete response rates were 16% and 4% in the combination and sunitinib arms, respectively.

The most common adverse reactions reported (≥ 20%) in patients who received lenvatinib and pembrolizumab in clinical trials were fatigue, diarrhea, musculoskeletal pain, hypothyroidism, hypertension, stomatitis, decreased appetite, rash, nausea, decreased weight, dysphonia, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, hemorrhagic events, vomiting, constipation, hepatotoxicity, headache, and acute kidney injury. Arterial thrombotic events occurred in 5% of patients in the trial, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).

The recommended dosages for patients with advanced RCC are lenvatinib 20 mg orally once daily with pembrolizumab 200 mg administered via IV infusion over 30 minutes every three weeks, or 400 mg administered via IV infusion over 30 minutes every six weeks up to two years, until disease progression or until unacceptable toxicity.

View the full prescribing information for lenvatinib.

View the full prescribing information for pembrolizumab.

The review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. FDA approved the application approximately one month ahead of FDA’s goal date.

FDA granted the application priority review and breakthrough therapy designation for the indication. A description of FDA expedited programs is in the Guidance for IndustryꟷExpedited Programs for Serious ConditionsꟷDrugs and Biologics.

Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.