title: Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.
abstract: BACKGROUND
  Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma.
  
  
  METHODS
  We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients.
  
  
  RESULTS
  Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39-0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment-related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy.
  
  
  CONCLUSIONS
  These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma.
  
  
  BACKGROUND
  Merck Sharp & Dohme.
authors.affiliation: University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu.
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authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
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authors.lastname: Puzanov
authors.affiliation: University of Zürich, Zürich, Switzerland.
authors.forename: Reinhard
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authors.affiliation: University Hospital Essen, Essen, Germany.
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authors.affiliation: Gustave Roussy and Paris-Sud University, Villejuif, France.
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authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
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authors.affiliation: University Medical Center, Mainz, Germany.
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authors.affiliation: Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA.
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authors.affiliation: Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, and Melanoma Institute Australia, Westmead, NSW, Australia.
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authors.initials: MS
authors.lastname: Carlino
authors.affiliation: St Luke's Cancer Center, Bethlehem, PA, USA; Temple University, Philadelphia, PA, USA.
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authors.affiliation: University of North Carolina, Chapel Hill, NC, USA.
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authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
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authors.affiliation: University of Zürich, Zürich, Switzerland.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Goldinger
authors.affiliation: Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Ronnie
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authors.lastname: Shapira-Frommer
authors.affiliation: University of Colorado Denver, Aurora, CO, USA.
authors.forename: Rene
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authors.lastname: Gonzalez
authors.affiliation: University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Gustave Roussy and Paris-Sud University, Villejuif, France.
authors.forename: Alexander
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authors.lastname: Eggermont
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Xiaoyun Nicole
authors.initials: XN
authors.lastname: Li
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Wei
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authors.lastname: Zhou
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
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authors.lastname: Zernhelt
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
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authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
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authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
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authors.affiliation: University of California, San Francisco, San Francisco, CA, USA.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; 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*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000074324:Ipilimumab; C582435:pembrolizumab