On August 10, the U.S. Food and Drug Administration (FDA) approved the combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
The efficacy of this combination was investigated in CLEAR (Study 307/KEYNOTE-581; ClinicalTrials.gov identifier: NCT02811861), a multicenter, open-label, randomized phase III trial in patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. The efficacy population supporting this approval included patients randomly assigned to lenvatinib plus pembrolizumab (n = 355) compared with those randomly assigned to single-agent sunitinib (n = 357).
Progression-free survival (assessed by independent radiologic review according to Response Evaluation Criteria in Solid Tumors version 1.1) and overall survival were the major efficacy endpoints. Patients receiving pembrolizumab with lenvatinib had a median progression-free survival of 23.9 months (95% confidence interval [CI] = 20.8–27.7) compared with 9.2 months (95% CI = 6.0–11.0) for those receiving sunitinib (hazard ratio [HR] = 0.39, 95% CI = 0.32–0.49, P < .0001). Median overall survival was not reached in either arm (HR = 0.66, 95% CI = 0.49–0.88, P = .0049). The objective response rates were 71% (95% CI = 66%–76%) and 36% (95% CI = 31%–41%, P < .0001); complete response rates were 16% and 4% in the combination and sunitinib arms, respectively.
The most common adverse reactions reported in ≥ 20% of patients who received lenvatinib and pembrolizumab in clinical trials are 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 CLEAR study, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).
The recommended dosages for patients with advanced RCC are lenvatinib at 20 mg orally once daily with pembrolizumab at 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks or 400 mg administered as an intravenous infusion over 30 minutes every 6 weeks up to 2 years, until disease progression or unacceptable toxicity.