• Leena Gandhi, Delvys Rodríguez-Abreu, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J Hochmair, Steven F Powell, Susanna Y-S Cheng, Helge G Bischoff, Nir Peled, Francesco Grossi, Ross R Jennens, Martin Reck, Rina Hui, Edward B Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E Gray, John Vida, Ziwen Wei, Jing Yang, Harry Raftopoulos, M Catherine Pietanza, Marina C Garassino, and KEYNOTE-189 Investigators.
• From NYU Perlmutter Cancer Center, New York (L.G.); Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria (D.R.-A.), Hospital Universitario Central de Asturias, Oviedo (E.E.), Vall d'Hebron University, Vall d'Hebron Institute of Oncology, Barcelona (E.F.), and Fundación Jiménez Díaz (M.D.) and Hospital Universitario Quirón Madrid (B.R.-V.), Madrid - all in Spain; Karmanos Cancer Institute, Detroit (S.G.); Integrated Health and Social Services Centres, Montérégie Centre, Greenfield Park, QC (F.D.A.), and Sunnybrook Health Sciences Centre, Toronto (S.Y.-S.C.) - both in Canada; Southern Medical Day Care Centre, Wollongong, NSW (P.C.), Epworth Healthcare, Richmond, VIC (R.R.J.), Westmead Hospital and University of Sydney, Sydney (R.H.), and Chris O'Brien Lifehouse, Camperdown, NSW (M.B.) - all in Australia; Otto Wagner Hospital, Vienna (M.J.H.); Sanford Health, Sioux Falls, SD (S.F.P.); Thoraxklinik, Heidelberg (H.G.B.), and LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf (M.R.) - both in Germany; Davidoff Cancer Center, Tel Aviv University, Petah Tikva, Israel (N.P.); Ospedale Policlinico San Martino, Genoa (F.G.), University of Turin, Azienda Ospedaliero-Universitaria San Luigi, Orbassano (S.N.), and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (M.C.G.) - all in Italy; David Geffen School of Medicine at UCLA, Los Angeles (E.B.G.); Kansai Medical University Hospital, Osaka, Japan (T.K.); Moffitt Cancer Center, Tampa, FL (J.E.G.); and Merck, Kenilworth, NJ (J.V., Z.W., J.Y., H.R., M.C.P.).
• N. Engl. J. Med. 2018 May 31; 378 (22): 2078-2092.

BackgroundFirst-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.MethodsIn this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.ResultsAfter a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.ConclusionsIn patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).

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