Lenvatinib+pembrolizumab shows RCC benefit
- Updated reporting on renal cell carcinoma treatment centers on older but still relevant trial data showing lenvatinib plus pembrolizumab produced durable activity in metastatic disease and later became an approved first-line regimen. - In KEYNOTE-146, the combination reached a 55.8% week-24 response rate in patients previously treated with immune checkpoint inhibitors; in CLEAR, median progression-free survival was 23.9 months versus 9.2 with sunitinib. - The biomarker claim comes from an exploratory ASCO analysis, while U.S. approval rests on the phase 3 CLEAR trial and newer non-clear-cell data have extended the regimen’s reach. (fda.gov)
Kidney cancer drug combinations work in two ways at once: one drug chokes off a tumor’s blood supply, and the other tries to lift the immune system’s brakes. (fda.gov) (pmc.ncbi.nlm.nih.gov) The pairing in this story is lenvatinib, a targeted pill, plus pembrolizumab, an immune checkpoint inhibitor sold as Keytruda. Researchers tested it in metastatic renal cell carcinoma, the most common form of kidney cancer that has spread beyond the kidney. (pmc.ncbi.nlm.nih.gov) The biomarker headline traces to an exploratory analysis from Study 111, also called KEYNOTE-146, presented at the 2022 ASCO Genitourinary Cancers Symposium. That analysis found no statistically significant link between gene signatures and outcomes, and said clinical benefit was seen regardless of VHL, PBRM1, BAP1, or SETD2 mutation status. (asco.org) (d32wbias3z7pxg.cloudfront.net) The underlying KEYNOTE-146 renal cell cohort was a phase 1b/2 study, not the trial that won approval. It enrolled 145 patients from July 2015 through October 2019, with 143 included in efficacy analyses and a median follow-up of 19.8 months. (pmc.ncbi.nlm.nih.gov) In that study, the week-24 objective response rate was 72.7% in treatment-naive patients, 41.2% in previously treated patients who had not received an immune checkpoint inhibitor, and 55.8% in patients who had. Oral lenvatinib was given at 20 mg daily and pembrolizumab at 200 mg every three weeks. (pmc.ncbi.nlm.nih.gov) The regimen’s regulatory weight comes from a different study: the phase 3 CLEAR trial, also called KEYNOTE-581. The Food and Drug Administration approved lenvatinib plus pembrolizumab on August 10, 2021, for first-line treatment of adults with advanced renal cell carcinoma. (fda.gov) In CLEAR, patients were enrolled regardless of PD-L1 tumor expression status, and the combination beat sunitinib on the main measures. Median progression-free survival was 23.9 months versus 9.2 months, objective response rate was 71% versus 36%, and complete response rate was 16% versus 4%. (fda.gov) The safety tradeoff was substantial. The FDA lists fatigue, diarrhea, hypothyroidism, hypertension, stomatitis, rash, nausea, proteinuria, and acute kidney injury among common adverse reactions, and arterial thrombotic events occurred in 5% of patients in CLEAR. (fda.gov) The combination has also moved beyond the classic clear-cell form of the disease. Updated results from the phase 2 KEYNOTE-B61 trial, published online on July 23, 2025, reported a 51% objective response rate in previously untreated advanced non-clear-cell renal cell carcinoma after a median 22.8 months of follow-up. (urotoday.com) That update included 158 treated patients, 13 confirmed complete responses, and a median duration of response of 19.5 months among responders. Grade 3 or 4 treatment-related adverse events were reported in 58% of patients, with no treatment-related deaths. (urotoday.com) A separate combination, cabozantinib plus atezolizumab, also posted activity in non-clear-cell disease in COSMIC-021, with a 31% response rate at a median 37.2 months of follow-up in a 32-patient cohort. That leaves renal cell carcinoma with several active immune-therapy-plus-targeted-drug pairings, but the lenvatinib-pembrolizumab regimen is the one backed by phase 3 first-line approval data. (ascopubs.org) (fda.gov)
