title: Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy.
abstract: BACKGROUND
  An anti-programmed cell death protein 1 monoclonal antibody, nivolumab, is one of the most effective drugs for advanced melanoma. Tumor cell-derived or immune cell-derived markers and clinical predictors such as serum lactate dehydrogenase (LDH) and cutaneous adverse events, have already been described as prognostic factors for advanced melanoma treated with nivolumab. We sought to identify further clinical predictors that can be determined in routine clinical practice.
  
  
  METHODS
  We retrospectively analyzed clinical findings of 98 consecutive patients with unresectable stage III or IV melanoma treated with nivolumab, at the National Cancer Center Hospital or at Keio University Hospital, in Tokyo, Japan, between July 2014 and July 2016. These patients had been administered nivolumab at a dose of 2mg/kg every 3 weeks.
  
  
  RESULTS
  As for pretreatment prognostic factors, ECOG performance status (PS) ≥1, maximum tumor diameters of ≥30mm, elevated LDH and elevated C-reactive protein were significantly associated with poor overall survival (OS) (hazard ratio [HR] 0.29 [P<0.001], HR 0.40 [p=0.003], HR 0.29 [P<0.001], HR 0.42 [P=0.004], respectively) on univariate analysis. Among these factors, PS and LDH were identified as independent variables by multivariate analysis. As for early markers examined during therapy, patients with absolute lymphocyte count (ALC) ≥ 1000/μl (Week3: HR 0.40 [P=0.004], Week6: HR 0.33 [P=0.001]) and absolute neutrophil count (ANC) <4000/μl (Week3: HR 0.46 [P=0.014], Week6: HR 0.51 [P=0.046]) had significantly better OS.
  
  
  CONCLUSIONS
  ALC≥1000/μl and ANC<4000/μl during treatment appear to be early markers associated with OS. Nivolumab might have minimal efficacy in patients with a massive tumor burden.
authors.affiliation: Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.|Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Kitano
authors.affiliation: Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Tsutsumida
authors.affiliation: Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Namikawa
authors.affiliation: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanese
authors.affiliation: Department of Preventive Medicine and Public Health, Biostatistics Unit at Clinical Translational Research Center, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Funakoshi
authors.affiliation: Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amagai
authors.affiliation: Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yamazaki
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging; D000077594:Nivolumab; D011379:Prognosis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D000077594:Nivolumab
keywords: absolute lymphocyte count; absolute neutrophil count; early markers for outcome; metastatic melanoma; nivolumab