title: Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study.
abstract: BACKGROUND
  In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination.
  
  
  METHODS
  This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+) or CD45RA(+) T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status.
  
  
  RESULTS
  Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in 'memory' but not in 'naïve' T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points. BRAF status did not correlate with clinical outcome.
  
  
  CONCLUSIONS
  Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab.
  2010-019356-50.
  
  
  BACKGROUND
  NCT01654692.
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena.
authors.forename: A M
authors.initials: AM
authors.lastname: Di Giacomo
authors.affiliation: Medical Oncology and Innovative Therapies, Fondazione 'G. Pascale', National Cancer Institute, Naples.
authors.forename: P A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Medical Oncology 2, IRCCS, AOU San Martino, Genoa.
authors.forename: P
authors.initials: P
authors.lastname: Queirolo
authors.affiliation: Melanoma Unit, San Raffaele Scientific Institute, Milan.
authors.forename: L
authors.initials: L
authors.lastname: Pilla
authors.affiliation: Immunotherapy and Somatic Cell Therapy Unit, Scientific Institute of Romagna, Meldola.
authors.forename: R
authors.initials: R
authors.lastname: Ridolfi
authors.affiliation: Melanoma and Sarcoma Unit, National Institute for Cancer Research, Milan.
authors.forename: M
authors.initials: M
authors.lastname: Santinami
authors.affiliation: Dermatoncological Division, Istituto Europeo di Oncologia, Milan.
authors.forename: A
authors.initials: A
authors.lastname: Testori
authors.affiliation: Medical Oncology and Innovative Therapies, Fondazione 'G. Pascale', National Cancer Institute, Naples.
authors.forename: E
authors.initials: E
authors.lastname: Simeone
authors.affiliation: Immunotherapy and Somatic Cell Therapy Unit, Scientific Institute of Romagna, Meldola.
authors.forename: M
authors.initials: M
authors.lastname: Guidoboni
authors.affiliation: Melanoma and Sarcoma Unit, National Institute for Cancer Research, Milan.
authors.forename: A
authors.initials: A
authors.lastname: Maurichi
authors.affiliation: Medical Oncology 2, IRCCS, AOU San Martino, Genoa.
authors.forename: L
authors.initials: L
authors.lastname: Orgiano
authors.affiliation: Dermatoncological Division, Istituto Europeo di Oncologia, Milan.
authors.forename: G
authors.initials: G
authors.lastname: Spadola
authors.affiliation: Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan.
authors.forename: M
authors.initials: M
authors.lastname: Del Vecchio
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena.
authors.forename: R
authors.initials: R
authors.lastname: Danielli
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena.
authors.forename: L
authors.initials: L
authors.lastname: Calabrò
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena.
authors.forename: D
authors.initials: D
authors.lastname: Annesi
authors.affiliation: Statistical Unit, Regina Elena National Cancer Institute, Rome.
authors.forename: D
authors.initials: D
authors.lastname: Giannarelli
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena; Italian Network for Tumor Biotherapy (NIBIT), Siena, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Maccalli
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena.
authors.forename: E
authors.initials: E
authors.lastname: Fonsatti
authors.affiliation: Melanoma Unit, San Raffaele Scientific Institute, Milan.
authors.forename: G
authors.initials: G
authors.lastname: Parmiani
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena. Electronic address: mmaiocro@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Maio
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001691:Biological Therapy / Q000401:mortality*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D009607:Nitrosourea Compounds / Q000008:administration & dosage; D009943:Organophosphorus Compounds / Q000008:administration & dosage; D011379:Prognosis; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate
chemical_list: D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; C054368:fotemustine
keywords: CTLA-4; fotemustine; immunotherapy; ipilimumab; metastatic melanoma