title: Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma.
abstract: OBJECTIVE
  The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients.
  
  
  METHODS
  HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies.
  
  
  RESULTS
  Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4(+)/CD4(+), CD25(+)Treg/CD4(+), and tetramer specific CD8(+) T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25(+)Treg/CD4(+) populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS.
  
  
  CONCLUSIONS
  Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study.
authors.affiliation: Department of Cutaneous Oncology and Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida. Department of Oncologic Sciences, University of South Florida, Tampa, Florida. geoffrey.gibney@moffitt.org.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Gibney
authors.affiliation: Division of Oncology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Ragini R
authors.initials: RR
authors.lastname: Kudchadkar
authors.affiliation: Department of Cutaneous Oncology and Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida. Department of Oncologic Sciences, University of South Florida, Tampa, Florida.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: DeConti
authors.affiliation: Department of Cutaneous Oncology and Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Thebeau
authors.affiliation: Department of Cutaneous Oncology and Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Czupryn
authors.affiliation: Department of Cutaneous Oncology and Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Leticia
authors.initials: L
authors.lastname: Tetteh
authors.affiliation: Division of Oncology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Cabell
authors.initials: C
authors.lastname: Eysmans
authors.affiliation: Department of Cutaneous Oncology and Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Allison
authors.initials: A
authors.lastname: Richards
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schell
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Fisher
authors.affiliation: Bristol-Myers Squibb, Early Clinical and Translational Research, Princeton, New Jersey.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Horak
authors.affiliation: Bristol-Myers Squibb, Early Clinical and Translational Research, Princeton, New Jersey.
authors.forename: H David
authors.initials: HD
authors.lastname: Inzunza
authors.affiliation: Department of Cutaneous Oncology and Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of Cutaneous Oncology and Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Martinez
authors.affiliation: Department of Clinical Pharmacology, College of Medicine, Minufiya University, Minufiya, Egypt. Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Younos
authors.affiliation: Department of Cutaneous Oncology and Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida. Department of Oncologic Sciences, University of South Florida, Tampa, Florida.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D017024:Chemotherapy, Adjuvant / Q000379:methods; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D000077594:Nivolumab; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D000077594:Nivolumab