title: Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma.
abstract: Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death-1 protein, were suggested in previous phase 1 studies. The present phase 2, single-arm study (JAPIC-CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression-free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3-4 drug-related adverse events were observed in 31.4% of patients. Pretreatment serum interferon-γ, and interleukin-6 and -10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy.
authors.affiliation: Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Naoya
authors.identifier: http://orcid.org/0000-0002-9638-0428
authors.initials: N
authors.lastname: Yamazaki
authors.affiliation: Dermatology Division, Shizuoka Cancer Center Hospital, Shizuoka, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kiyohara
authors.affiliation: Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Uhara
authors.affiliation: Department of Dermatology, Asahikawa Medical University, Hokkaido, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Iizuka
authors.affiliation: Department of Dermatology, Asahikawa Medical University, Hokkaido, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Uehara
authors.affiliation: Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Fujio
authors.initials: F
authors.lastname: Otsuka
authors.affiliation: Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujisawa
authors.affiliation: Department of Dermatology, Niigata Cancer Center Hospital, Niigata, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takenouchi
authors.affiliation: Department of Dermatology, Kansai Medical University, Osaka, Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Isei
authors.affiliation: Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Iwatsuki
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchi
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
authors.affiliation: Department Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Hyogo, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.affiliation: Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hideaki
authors.identifier: http://orcid.org/0000-0002-1735-5372
authors.initials: H
authors.lastname: Tahara
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000077594:Nivolumab; D015996:Survival Rate
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015415:Biomarkers; D016207:Cytokines; D015850:Interleukin-6; D016753:Interleukin-10; D000077594:Nivolumab; D007371:Interferon-gamma
keywords: Antibody therapy; biomarker; check-point inhibitor; clinical trial; programmed cell death-1