title: Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
abstract: Malignant pleural mesothelioma is a highly aggressive cancer with poor prognosis and few treatment options following progression on platinum-containing chemotherapy. We assessed the safety and efficacy of pembrolizumab (an anti-programmed cell death receptor 1 [PD-1] antibody) in advanced solid tumours expressing programmed cell death ligand 1 (PD-L1) and report here on the interim analysis of the malignant pleural mesothelioma cohort.
  
  
  
  Previously treated patients with PD-L1-positive malignant pleural mesothelioma were enrolled from 13 centres in six countries. Patients received pembrolizumab (10 mg/kg every 2 weeks) for up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria included measurable disease, failure of standard therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1. PD-L1 positivity was defined as expression in 1% or more of tumour cells by immunohistochemistry. Response was assessed based on investigator review using the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Primary endpoints were safety and tolerability, analysed in the all-patients-as-treated population, and objective response, analysed for the full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT02054806, and is ongoing but not recruiting participants.
  
  
  
  As of June 20, 2016, 25 patients received pembrolizumab. 16 (64%) patients reported a treatment-related adverse event; the most common adverse event were fatigue (six [24%]), nausea (six [24%]), and arthralgia (five [20%]). Five (20%) patients reported grade 3 treatment-related adverse events. Three (12%) patients required dose interruption because of immune-related adverse events: one (4%) of 25 each had grade 3 rhabdomyolysis and grade 2 hypothyroidism; grade 3 iridocyclitis, grade 1 erythema multiforme, and grade 3 erythema; and grade 2 infusion-related reaction. No treatment-related deaths or discontinuations occurred. Five (20%) patients had a partial response, for an objective response of 20% (95% CI 6·8-40·7), and 13 (52%) of 25 had stable disease. Responses were durable (median response duration 12·0 months [95% CI 3·7 to not reached]); two patients remained on treatment at data cutoff.
  
  
  
  Pembrolizumab appears to be well tolerated and might confer anti-tumour activity in patients with PD-L1-positive malignant pleural mesothelioma. Response durability and efficacy in this patient population warrants further investigation.
  
  
  
  Merck.
authors.affiliation: Hematology and Oncology Division, Penn Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia, PA, USA. Electronic address: evan.alley@uphs.upenn.edu.
authors.forename: Evan W
authors.initials: EW
authors.lastname: Alley
authors.affiliation: Drug Development Unit, Institute of Cancer Research, London, UK.
authors.forename: Juanita
authors.initials: J
authors.lastname: Lopez
authors.affiliation: Humanitas Cancer Center, Humanitas University, Milan, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Merck, Kenilworth, NJ, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Morosky
authors.affiliation: Merck, Kenilworth, NJ, USA.
authors.forename: Sanatan
authors.initials: S
authors.lastname: Saraf
authors.affiliation: Merck, Kenilworth, NJ, USA.
authors.forename: Bilal
authors.initials: B
authors.lastname: Piperdi
authors.affiliation: Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Emilie
authors.initials: E
authors.lastname: van Brummelen
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018771:Arthralgia / Q000139:chemically induced; D060890:B7-H1 Antigen / Q000032:analysis; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000737:chemistry / Q000188:drug therapy*; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D065228:Non-Randomized Controlled Trials as Topic; D010997:Pleural Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D066066:Response Evaluation Criteria in Solid Tumors; D019233:Retreatment
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C582435:pembrolizumab