title: Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
abstract: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.
  
  
  
  For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652.
  
  
  
  Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.
  
  
  
  Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.
  
  
  
  F Hoffmann-La Roche, Genentech.
authors.affiliation: Genitourinary Cancers Program, Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA. Electronic address: arjun.balar@nyumc.org.
authors.forename: Arjun V
authors.initials: AV
authors.lastname: Balar
authors.affiliation: The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.affiliation: Barts Cancer Institute ECMC, Barts Health and the Royal Free NHS Trust, Queen Mary University of London, London, UK.
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authors.lastname: Powles
authors.affiliation: Smilow Cancer Center, Yale University, New Haven, CT, USA.
authors.forename: Daniel P
authors.initials: DP
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authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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authors.affiliation: Département de médecine oncologique, Université Paris-Saclay and Gustave Roussy, Villejuif, France.
authors.forename: Yohann
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authors.lastname: Loriot
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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authors.affiliation: Sidney Kimmel Cancer Center at Jefferson, Philadelphia, PA, USA.
authors.forename: Jean
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authors.lastname: Hoffman-Censits
authors.affiliation: Department of Oncology, Clínica Universidad de Navarra, University of Navarra, Pamplona, Navarre, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Perez-Gracia
authors.affiliation: Medstar Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Dawson
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Michiel S
authors.initials: MS
authors.lastname: van der Heijden
authors.affiliation: Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Robert
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authors.lastname: Dreicer
authors.affiliation: Division of Oncology/Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
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authors.lastname: Srinivas
authors.affiliation: Department of Urology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Margitta M
authors.initials: MM
authors.lastname: Retz
authors.affiliation: Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.
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authors.initials: RW
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authors.affiliation: Department of Medicine, Division of Hematology and Oncology and Institute of Urologic Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
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authors.lastname: Drakaki
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Ulka N
authors.initials: UN
authors.lastname: Vaishampayan
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON, Canada.
authors.forename: Srikala S
authors.initials: SS
authors.lastname: Sridhar
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.affiliation: Department of Medical Oncology, Hospital Universitario Virgen del Rocío and Institute of Biomedicine of Seville, Seville, Spain.
authors.forename: Ignacio
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authors.lastname: Durán
authors.affiliation: New York Oncology Hematology, Albany, NY, USA.
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authors.initials: DR
authors.lastname: Shaffer
authors.affiliation: British Columbia Cancer Agency, British Columbia, Vancouver, Canada.
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Eigl
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Petros D
authors.initials: PD
authors.lastname: Grivas
authors.affiliation: Division of Oncology, Department of Medicine, University of Washington and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Yu
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Li
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Kadel
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Boyd
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bourgon
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Priti S
authors.initials: PS
authors.lastname: Hegde
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Sanjeev
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authors.lastname: Mariathasan
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: AnnChristine
authors.initials: A
authors.lastname: Thåström
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Oyewale O
authors.initials: OO
authors.lastname: Abidoye
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Fine
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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authors.initials: DF
authors.lastname: Bajorin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood; D002295:Carcinoma, Transitional Cell / Q000097:blood / Q000188:drug therapy* / Q000556:secondary*; D002945:Cisplatin; D000075202:Contraindications; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D066066:Response Evaluation Criteria in Solid Tumors; D014571:Urologic Neoplasms / Q000097:blood / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C000594389:atezolizumab; D002945:Cisplatin