title: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial.
abstract: BACKGROUND
  The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma.
  
  
  METHODS
  In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ≥18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827.
  
  
  RESULTS
  173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses--21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0·96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient.
  
  
  CONCLUSIONS
  The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options.
  
  
  BACKGROUND
  Merck Sharp and Dohme.
authors.affiliation: Gustave Roussy and INSERM U981, Paris-Sud, France. Electronic address: caroline.robert@gustaveroussy.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.affiliation: University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Angeles Clinic and Research Institute, Los Angeles, CA, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.affiliation: Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Kefford
authors.affiliation: H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Joshua
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wen-Jen
authors.initials: WJ
authors.lastname: Hwu
authors.affiliation: Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Tara C
authors.initials: TC
authors.lastname: Gangadhar
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, TX, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Roxana
authors.initials: R
authors.lastname: Dronca
authors.affiliation: University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hassane
authors.initials: H
authors.lastname: Zarour
authors.affiliation: Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Joseph
authors.affiliation: Angeles Clinic and Research Institute, Los Angeles, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Boasberg
authors.affiliation: University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.affiliation: Gustave Roussy and INSERM U981, Paris-Sud, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Mateus
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Postow
authors.affiliation: Merck, Whitehouse Station, NJ, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gergich
authors.affiliation: Merck, Whitehouse Station, NJ, USA.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Elassaiss-Schaap
authors.affiliation: Merck, Whitehouse Station, NJ, USA.
authors.forename: Xiaoyun Nicole
authors.initials: XN
authors.lastname: Li
authors.affiliation: Merck, Whitehouse Station, NJ, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Iannone
authors.affiliation: Merck, Whitehouse Station, NJ, USA.
authors.forename: Scot W
authors.initials: SW
authors.lastname: Ebbinghaus
authors.affiliation: Merck, Whitehouse Station, NJ, USA.
authors.forename: S Peter
authors.initials: SP
authors.lastname: Kang
authors.affiliation: University of California San Francisco, San Francisco, CA, USA.
authors.forename: Adil
authors.initials: A
authors.lastname: Daud
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions / Q000209:etiology; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D011537:Pruritus / Q000139:chemically induced; D012878:Skin Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000074324:Ipilimumab; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab