title: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial.
abstract: Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen.
  
  
  
  In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still ongoing.
  
  
  
  Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96-8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0-24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9-39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5-32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5-23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3-4 treatment-related adverse events occurred in 48 (18%) of 270 patients-most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure).
  
  
  
  Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma.
  
  
  
  Bristol-Myers Squibb.
authors.affiliation: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA; 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 Urology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Margitta
authors.initials: M
authors.lastname: Retz
authors.affiliation: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: Arlene
authors.initials: A
authors.lastname: Siefker-Radtke
authors.affiliation: Department of Medicine, California Pacific Medical Center, San Francisco, CA, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Baron
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Necchi
authors.affiliation: Department of Urology, University of Tübingen, Tübingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Bedke
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.affiliation: Division of Hematology, Oncology, and Bone Marrow Transplantation/Department of Medicine and Urology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vaena
authors.affiliation: Department of Urology, Jena University Hospital, Jena, Germany.
authors.forename: Marc-Oliver
authors.initials: MO
authors.lastname: Grimm
authors.affiliation: Department of Oncology and Medical Oncology Unit, Ospedale San Donato, Azienda USL Toscana Sud-Est, Istituto Toscano Tumori, Arezzo, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bracarda
authors.affiliation: Genitourinary and Gynecologic Section, Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: José Ángel
authors.initials: JÁ
authors.lastname: Arranz
authors.affiliation: Kidney Cancer Program, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Sumanta
authors.initials: S
authors.lastname: Pal
authors.affiliation: Department of Urology, Hirosaki University, Hirosaki, Aomori, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Ohyama
authors.affiliation: Exploratory Clinical & Translational Research Department, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Abdel
authors.initials: A
authors.lastname: Saci
authors.affiliation: Translational Bioinformatics Department, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Qu
authors.affiliation: Biometrics Department, Bristol-Myers Squibb, Braine-l'Alleud, Belgium.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lambert
authors.affiliation: Global Clinical Research Oncology Department, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Suba
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Global Clinical Research Oncology Department, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Azrilevich
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai/Tisch Cancer Institute, New York, NY, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000556:secondary; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D000077594:Nivolumab; D010984:Platinum / Q000494:pharmacology*; D011379:Prognosis; D015996:Survival Rate; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077594:Nivolumab; D010984:Platinum