title: Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors.
abstract: OBJECTIVE
  This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors.
  
  
  METHODS
  In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005-10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  
  
  RESULTS
  No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks.
  
  
  CONCLUSIONS
  Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, Texas. amita.patnaik@start.stoh.com.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: S Peter
authors.initials: SP
authors.lastname: Kang
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
authors.forename: Drew
authors.initials: D
authors.lastname: Rasco
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Elassaiss-Schaap
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
authors.forename: Ronald
authors.initials: R
authors.lastname: Drengler
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
authors.forename: Lon
authors.initials: L
authors.lastname: Smith
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Espino
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gergich
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Liliana
authors.initials: L
authors.lastname: Delgado
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Adil
authors.initials: A
authors.lastname: Daud
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Lindia
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Xiaoyun Nicole
authors.initials: XN
authors.lastname: Li
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Pierce
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Yearley
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Dianna
authors.initials: D
authors.lastname: Wu
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Omar
authors.initials: O
authors.lastname: Laterza
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Manfred
authors.initials: M
authors.lastname: Lehnert
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Robert
authors.initials: R
authors.lastname: Iannone
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab