title: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
abstract: BACKGROUND
  Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.
  
  
  METHODS
  We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0.00825 (one-sided) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657.
  
  
  RESULTS
  Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38-0.77; p=0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36-0.70; p<0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44-0.78; p=0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45-0.78; p<0.0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel).
  
  
  CONCLUSIONS
  Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.
  
  
  BACKGROUND
  Merck & Co.
authors.affiliation: Yale School of Medicine, Yale Cancer Center, and Smilow Cancer Hospital, New Haven, CT, USA. Electronic address: roy.herbst@yale.edu.
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.affiliation: The Netherlands Cancer Institute and The Academic Medical Hospital Amsterdam, Amsterdam, Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Baas
authors.affiliation: Seoul National University Hospital, Seoul, South Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Vall D'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.affiliation: Clinica Universidad de Navarra, Pamplona, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Pérez-Gracia
authors.affiliation: National Cancer Center, Goyang, South Korea.
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Han
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Molina
authors.affiliation: CHA Bundang Medical Center, CHA University, Gyeonggi-do, South Korea.
authors.forename: Joo-Hang
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Centre François Baclesse, Caen, France.
authors.forename: Catherine Dubos
authors.initials: CD
authors.lastname: Arvis
authors.affiliation: Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Majem
authors.affiliation: Rush University Medical Center, Chicago, IL, USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Fidler
authors.affiliation: Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: de Castro
authors.affiliation: Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Garrido
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lubiniecki
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shentu
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Ellie
authors.initials: E
authors.lastname: Im
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Dolled-Filhart
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Garon
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D018579:Patient Selection; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D043823:Taxoids; D000077143:Docetaxel; C582435:pembrolizumab