Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain.
In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point.
A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy.
Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).
The New England journal of medicine. 2024 Apr 18 [Epub]
Toni K Choueiri, Piotr Tomczak, Se Hoon Park, Balaji Venugopal, Tom Ferguson, Stefan N Symeonides, Jaroslav Hajek, Yen-Hwa Chang, Jae-Lyun Lee, Naveed Sarwar, Naomi B Haas, Howard Gurney, Piotr Sawrycki, Mauricio Mahave, Marine Gross-Goupil, Tian Zhang, John M Burke, Gurjyot Doshi, Bohuslav Melichar, Evgeniy Kopyltsov, Ajjai Alva, Stephane Oudard, Delphine Topart, Hans Hammers, Hiroshi Kitamura, David F McDermott, Adriano Silva, Eric Winquist, Jerry Cornell, Aymen Elfiky, Joseph E Burgents, Rodolfo F Perini, Thomas Powles, KEYNOTE-564 Investigators
From Dana-Farber Cancer Institute and Harvard Medical School (T.K.C.) and Beth Israel Deaconess Medical Center (D.F.M.) - all in Boston; Poznan University of Medical Sciences, Poznan (P.T.), and Provincial Hospital in Torun, Torun (P.S.) - both in Poland; Samsung Medical Center, Sungkyunkwan University School of Medicine (S.H.P.), and Asan Medical Center, University of Ulsan College of Medicine (J.-L.L.) - both in Seoul, South Korea; Beatson West of Scotland Cancer Centre and the University of Glasgow, Glasgow (B.V.), Edinburgh Cancer Centre and the University of Edinburgh, Edinburgh (S.N.S.), and Imperial College Healthcare NHS Trust (N.S.), Barts Health NHS Trust and the Royal Free NHS Foundation Trust, Barts Cancer Institute (T.P.), and Queen Mary University of London (T.P.), London - all in the United Kingdom; Fiona Stanley Hospital, Perth, WA (T.F.), and Maquarie University, Sydney (H.G.) - both in Australia; Fakultní Nemocnice Ostrava, Ostrava (J.H.), and Palacký University and University Hospital Olomouc, Olomouc (B.M.) - all in the Czech Republic; Taipei Veterans General Hospital, Taipei, Taiwan (Y.-H.C.); Abramson Cancer Center, Penn Medicine, Philadelphia (N.B.H.); Fundación Arturo López Pérez, Santiago, Chile (M.M.); University Hospital Bordeaux-Hôpital Saint-André, Bordeaux (M.G.-G.), Hôpital Européen Georges Pompidou, Université Paris Cité, Paris (S.O.), and Centre Hospitalier Universitaire de Montpellier, Montpellier (D.T.) - all in France; the University of Texas Southwestern Medical Center, Dallas (T.Z., H.H.), and Texas Oncology-Houston, Houston (G.D.); Rocky Mountain Cancer Centers, Aurora, CO (J.M.B.); Omsk Clinical Oncology Dispensary, Omsk, Russia (E.K.); the University of Michigan, Ann Arbor (A.A.); the University of Toyama, Toyama, Japan (H.K.); Instituto de Cancer e Transplante de Curitiba, Curitiba, Brazil (A.S.); the London Regional Cancer Program, London Health Sciences Centre, Western University, London, ON, Canada (E.W.); and Merck, Rahway, NJ (J.C., A.E., J.E.B., R.F.P.).