CLEAR (KEYNOTE-581)

CLEAR, also KEYNOTE-581, trial NCT02811861 sponsored by Eisai and Merck and reported in 2021, produced the combination with the longest progression-free survival ever reported in first-line kidney cancer, at nearly two years. It randomised 1,069 patients with untreated advanced clear-cell renal cell carcinoma to lenvatinib plus pembrolizumab, lenvatinib plus everolimus or sunitinib, met its primary progression-free survival endpoint with a very large effect and a high response rate including many complete responses, and showed a survival benefit whose curves separated late, leading to FDA approval in August 2021, although the 20 mg lenvatinib dose drives high toxicity with dose reductions in about seventy percent. Whether a lower lenvatinib starting dose would keep the efficacy is the open question.