title: Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial.
abstract: BACKGROUND
  Few effective treatments exist for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy. We assessed the activity and safety of nivolumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after previous platinum-based chemotherapy.
  
  
  METHODS
  In this phase 1/2, multicentre, open-label study, we enrolled patients (age ≥18 years) with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1 membrane expression was assessed retrospectively. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or treatment discontinuation because of unacceptable toxicity or other protocol-defined reasons, whichever occurred later. The primary endpoint was objective response by investigator assessment. All patients who received at least one dose of the study drug were included in the analyses. We report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394.
  
  
  RESULTS
  Between June 5, 2014, and April 24, 2015, 86 patients with metastatic urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78 received at least one dose of treatment. At data cutoff (March 24, 2016), the minimum follow-up was 9 months (median 15·2 months, IQR 12·9-16·8). A confirmed investigator-assessed objective response was achieved in 19 (24·4%, 95% CI 15·3-35·4) of 78 patients. Grade 3-4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four [5%]), elevated amylase (three [4%]), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two [3%] each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died.
  
  
  CONCLUSIONS
  Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma.
  
  
  BACKGROUND
  Bristol-Myers Squibb.
authors.affiliation: Department of Genitourinary Medical Oncology, Department of Immunology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA. Electronic address: padsharma@mdanderson.org.
authors.forename: Padmanee
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Callahan
authors.affiliation: Department of Oncology, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Bono
authors.affiliation: Prostate and Urologic Cancers Program and Early Drug Development Program, Yale Cancer Center, New Haven, CT, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: Pavlina
authors.initials: P
authors.lastname: Spiliopoulou
authors.affiliation: Medical Oncology Division, START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Department of Hematology and Oncology, Emory Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Rathi N
authors.initials: RN
authors.lastname: Pillai
authors.affiliation: Melanoma Center, Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.affiliation: Department of Medical Oncology, Istituto Nazionale dei Tumori-Università degli Studi di Milano, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Morse
authors.affiliation: Division of Oncology-Gastrointestinal Cancer, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Dung T
authors.initials: DT
authors.lastname: Le
authors.affiliation: National Center for Tumor Diseases, Department of Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jaeger
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.affiliation: NIVO/IPI LCM Biomarkers, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Harbison
authors.affiliation: Clinical Biostatistics, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Chen-Sheng
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Global Clinical Research/Oncology, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Tschaika
authors.affiliation: Global Clinical Research/Oncology, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Azrilevich
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D000077594:Nivolumab; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077594:Nivolumab