title: Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.
abstract: BACKGROUND
  Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC.
  
  
  METHODS
  In this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs ≥1%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion of patients who achieved an objective response, defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent central review, in the intention-to-treat population, defined as all patients who were allocated to study treatment. Significance threshold was p<0·025 (one sided). Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned study treatment. This trial, which is closed for enrolment but continuing for follow-up, is registered with ClinicalTrials.gov, number NCT02039674.
  
  
  RESULTS
  Between Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42-68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18-41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9-42%]; p=0·0016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia.
  
  
  CONCLUSIONS
  Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study.
  
  
  BACKGROUND
  Merck & Co.
authors.affiliation: Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: corey.langer@uphs.upenn.edu.
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.affiliation: Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA.
authors.forename: Shirish M
authors.initials: SM
authors.lastname: Gadgeel
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Borghaei
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Papadimitrakopoulou
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, TX, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Sanford Cancer Center, Sioux Falls, SD, USA.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Powell
authors.affiliation: University of Virginia, Charlottesville, VA, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Gentzler
authors.affiliation: University of Washington and Seattle Cancer Care Alliance, Seattle, WA, USA.
authors.forename: Renato G
authors.initials: RG
authors.lastname: Martins
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Stevenson
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Shadia I
authors.initials: SI
authors.lastname: Jalal
authors.affiliation: Sanford Roger Maris Cancer Center, Fargo, ND, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Panwalkar
authors.affiliation: National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.affiliation: University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gubens
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Awad
authors.affiliation: Merck & Co Inc, Kenilworth, NJ, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Fiore
authors.affiliation: Merck & Co Inc, Kenilworth, NJ, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Merck & Co Inc, Kenilworth, NJ, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Raftopoulos
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Leena
authors.initials: L
authors.lastname: Gandhi
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed / Q000008:administration & dosage
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068437:Pemetrexed; D016190:Carboplatin; C582435:pembrolizumab