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N Engl J Med. 2018 May 31;378(22):2078-2092. doi: 10.1056/NEJMoa1801005. Epub 2018 Apr 16.

Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.

Collaborators (133)

Bray V, Houghton BB, Kannourakis G, Pandey R, Burghuber O, Hartl S, Lamprecht B, Olschewski H, Philipp-Abbrederis K, Reiter M, Schumacher M, Studnicka M, Lambrechts M, Ocak S, Aucoin N, Castonguay V, Speranza G, Robinson A, Snow S, Soerensen JB, Hansen KHH, Stelmach MJ, Myllarniemi M, Tiainen S, Carmier D, Godbert B, Goldwasser F, Molnier O, Poudenx M, Tredaniel J, Brueckl W, Engel-Riedel W, Gessner C, Gruening W, Heilmann M, Kollmeier J, Lang S, Schuette W, Wehler TC, Bambury R, Coate L, Cuffe S, Hanrahan E, Morris P, Bar J, Gottfried M, Ariad S, Lazarev I, Merimsky O, Nak S, Wollner M, Zer A, Adamo V, Bearz A, Borra G, Bria E, Cognetti F, de Marinis F, Gridelli C, Livi L, Morabito A, Horinouchi H, Nogami N, Takeda M, Aerts JGJV, Smit JM, Smits-van der Graaf C, Isla D, Delda Iniesta C, Collazo A, Fuentes Pradera J, Lopez Vivanco G, Marse R, Reguart Arasany N, Vidal OJ, Arkenau HT, Blackhall F, Chao D, Boleti E, Mulatero C, Clarke K, Lee SM, Nicolson M, Talbot T, Agarwala S, Awad M, Behl D, Conkright W, Costa DB, Dragnev K, Krabak M, Duvivier H, Gainor J, Gillani AA, Graham M, Gralla R, Guarino MJ, Gubens M, Hall R, Halmos B, Hauke R, Jafri S, Kassar M, Kloecker G, Kosty MP, Langer CJ, Martincic D, Masri M, Mohebtash M, Panwalker A, Parsons B, Patel R, Peguero JA, Quejada M, Rao SB, Rybkin II, Santos E, Schreiber AO, Seetharamu N, Mocherla D, Singh T, Sleckman BG, Stampleman L, Stevenson J, Stilwill J, Sukari A, Walsh WV, Wrangle J, Wrzesinski SH, Bunn P, Johnson D, Pirker R, Shih WJ.

Author information

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.).



First-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.


In 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.


After 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.


In 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 number, NCT02578680 .).

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