title: Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma.
abstract: OBJECTIVE
  Nivolumab, a human immunoglobulin G4-blocking antibody against the T-cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma.
  
  
  METHODS
  In this phase I study, 90 patients with unresectable stage III or IV melanoma who were ipilimumab naive and had experienced progression after at least one prior therapy (cohorts 1 to 3, 34 patients) or experienced progression after prior ipilimumab (cohorts 4 to 6, 56 patients) received nivolumab at 1, 3, or 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine.
  
  
  RESULTS
  Nivolumab with vaccine was well tolerated and safe at all doses. The RECIST 1.1 response rate for both ipilimumab-refractory and -naive patients was 25%. Median duration of response was not reached at a median of 8.1 months of follow-up. High pretreatment NY-ESO-1 and MART-1-specific CD8(+) T cells were associated with progression of disease. At week 12, increased peripheral-blood T regulatory cells and decreased antigen-specific T cells were associated with progression. PD-L1 tumor staining was associated with responses to nivolumab, but negative staining did not rule out a response. Patients who experienced progression after nivolumab could respond to ipilimumab.
  
  
  CONCLUSIONS
  In patients with ipilimumab-refractory or -naive melanoma, nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks. Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab.
authors.affiliation: Jeffrey S. Weber, Ragini Reiney Kudchadkar, Bin Yu, Donna Gallenstein, Xiuhua Zhao, Alberto J. Martinez, Wenshi Wang, Geoffrey Gibney, Jodi Kroeger, Cabell Eysmans, Amod A. Sarnaik, and Y. Ann Chen, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and Christine E. Horak and H. David Inzunza, Bristol-Myers Squibb, Princeton, NJ.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
authors.forename: Ragini Reiney
authors.initials: RR
authors.lastname: Kudchadkar
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.forename: Donna
authors.initials: D
authors.lastname: Gallenstein
authors.forename: Christine E
authors.initials: CE
authors.lastname: Horak
authors.forename: H David
authors.initials: HD
authors.lastname: Inzunza
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Zhao
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Martinez
authors.forename: Wenshi
authors.initials: W
authors.lastname: Wang
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Gibney
authors.forename: Jodi
authors.initials: J
authors.lastname: Kroeger
authors.forename: Cabell
authors.initials: C
authors.lastname: Eysmans
authors.forename: Amod A
authors.initials: AA
authors.lastname: Sarnaik
authors.forename: Y Ann
authors.initials: YA
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D019496:Cancer Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005431:Florida; D006801:Humans; D007150:Immunohistochemistry; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D000077594:Nivolumab; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; D000074324:Ipilimumab; D000077594:Nivolumab