Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial

Background: 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 cisplatinineligible patients.

Methods: 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 confi rmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecifi ed 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.

Findings: 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.

Interpretation: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.

Funding: F Hoff mann-La Roche, Genentech.

Authors: Arjun V Balar, Matthew D Galsky, Jonathan E Rosenberg, Thomas Powles, Daniel P Petrylak, Joaquim Bellmunt, Yohann Loriot, Andrea Necchi, Jean Hoffman-Censits, Jose Luis Perez-Gracia, Nancy A Dawson, Michiel S van der Heijden, Robert Dreicer, Sandy Srinivas, Margitta M Retz, Richard W Joseph, Alexandra Drakaki, Ulka N Vaishampayan, Srikala S Sridhar, David I Quinn, Ignacio Durán, David R Shaff er, Bernhard J Eigl, Petros D Grivas, Evan Y Yu, Shi Li, Edward E Kadel III, Zachary Boyd, Richard Bourgon, Priti S Hegde, Sanjeev Mariathasan, AnnChristine Thåström, Oyewale O Abidoye, Gregg D Fine, Dean F Bajorin, for the IMvigor210 Study Group*

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Author Affiliations: Genitourinary Cancers Program, Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA (A V Balar MD); The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA (M D Galsky MD); Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA (J E Rosenberg MD, D F Bajorin MD); Barts Cancer Institute ECMC, Barts Health and the Royal Free NHS Trust, Queen Mary University of London, London, UK (T Powles MD); Smilow Cancer Center, Yale University, New Haven, CT, USA (D P Petrylak MD); Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA (J Bellmunt MD); Département de médecine oncologique, Université Paris-Saclay and Gustave Roussy, Villejuif, France (Y Loriot MD); Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (A Necchi MD); Sidney Kimmel Cancer Center at Jefferson, Philadelphia, PA, USA (J Hoffman-Censits MD); Department of Oncology, Clínica Universidad de Navarra, University of Navarra, Pamplona, Navarre, Spain (J L Perez-Gracia MD); MedstarGeorgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC, USA (N A Dawson MD); Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands (M S van der Heijden MD); Division of Hematology/ Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA (R Dreicer MD); Division of Oncology/Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA (S Srinivas MD); Department of Urology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany (M M Retz MD); Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA (R W Joseph MD); 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 (A Drakaki MD); Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA (U N Vaishampayan MD); Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON, Canada (S S Sridhar MD); University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA (D I Quinn MD); Department of Medical Oncology, Hospital Universitario Virgen del Rocío and Institute of Biomedicine of Seville, Seville, Spain (I Durán MD); New York Oncology Hematology, Albany, NY, USA (D R Shaffer MD); British Columbia Cancer Agency, British Columbia, Vancouver, Canada (B J Eigl MD); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA (P D Grivas MD); Division of Oncology, Department of Medicine, University of Washington and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA (E Y Yu MD); and Genentech, South San Francisco, CA, USA (S Li PhD, E E Kadel III BS,Z Boyd MSc, R Bourgon PhD, P S Hegde PhD, S Mariathasan PhD, AC Thåström PhD, O O Abidoye MD, G D Fine MD)

Published Online December 7, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)32455-2
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