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 cisplatin-ineligible 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 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.

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), diarrhea (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 Hoffmann-La Roche, Genentech.

LANCET. volume 389, issue 10064, P67-76, January  07, 2017 [Epub]

Dr Arjun V Balar, MD,1 Matthew D Galsky, MD,2 Jonathan E Rosenberg, MD,3 Thomas Powles, MD,4 Daniel P Petrylak, MD,5 Joaquim Bellmunt, MD,6 Yohann Loriot, MD,7 Andrea Necchi, MD,8 Jean Hoffman-Censits, MD,9 Jose Luis Perez-Gracia, MD,10 Nancy A Dawson, MD,11 Michiel S van der Heijden, MD,12 Robert Dreicer, MD,13 Sandy Srinivas, MD,14 Margitta M Retz, MD,15 Richard W Joseph, MD,16 Alexandra Drakaki, MD,17 Ulka N Vaishampayan, MD,18 Srikala S Sridhar, MD,19 David I Quinn, MD,20 Ignacio Durán, MD,21 David R Shaffer, MD,22 Bernhard J Eigl, MD,23 Petros D Grivas, MD,24 Evan Y Yu, MD, Shi Li, PhD,25 Edward E Kadel III, BS,26 Zachary Boyd, MSc,26 Richard Bourgon, PhD,26 Priti S Hegde, PhD,26 Sanjeev Mariathasan, PhD,26 AnnChristine Thåström, PhD,26 Oyewale O Abidoye, MD,26 Gregg D Fine, MD,26 Dean F Bajorin, MD3 for the IMvigor210 Study Group

1. Perlmutter Cancer Center, New York, New York
2. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
3. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
4. Barts Cancer Institute ECMC, Barts Health and the Royal Free NHS Trust, Queen Mary University of London, London, United Kingdom
5. Smilow Cancer Center, Yale University, New Haven, Connecticut
6. Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
7. Département de médecine oncologique, Université Paris-Saclay and Gustave Roussy, Villejuif, France
8. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
9. Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania
10. Department of Oncology, Clínica Universidad de Navarra, University of Navarra, Pamplona, Navarre, Spain
11. MedStar Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC
12. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands
13. Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, Virginia
14. Division of Oncology/Department of Medicine, Stanford University School of Medicine, Stanford, California
15. Department of Urology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
16. Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida
17. Department of Medicine, Division of Hematology and Oncology and Institute of Urologic Oncology, David Geffen School of Medicine, University of California, Los Angeles, California
18. Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
19. Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, Ontario, Canada
20. University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California
21. Department of Medical Oncology, Hospital Universitario Virgen del Rocío and Institute of Biomedicine of Seville, Seville, Spain
22. New York Oncology Hematology, Albany, New York
23. British Columbia Cancer Agency, British Columbia, Vancouver, Canada
24. Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
25. Division of Oncology, Department of Medicine, University of Washington and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
26. Genentech, South San Francisco, California

The Lancet| VOLUME 389, ISSUE 10064, P67-76, JANUARY 07, 2017; DOI:https://doi.org/10.1016/S0140-6736(16)32455-2
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