The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval.
To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC.
DESIGN, SETTING, AND PARTICIPANTS:
This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for or refused prior chemotherapy from 60 sites in 9 countries as reported herein.
Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects.
MAIN OUTCOMES AND MEASURES:
Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1).
A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] post platinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival was 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis).
CONCLUSIONS AND RELEVANCE:
Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC.
Trial Registration clinicaltrials.gov Identifier: NCT01693562
JAMA Oncol. 2017;3(9):e172411 [Epub]
Thomas Powles, MD,1 Peter H. O'Donnell, MD,2 Christophe Massard, MD, PhD,3 Hendrik-Tobias Arkenau, MD, PhD,4 Terence W. Friedlander, MD,5 Christopher J. Hoimes, DO,6 Jae Lyun Lee, MD,7 Michael Ong, MD,8 Srikala S. Sridhar, MD,9 Nicholas J. Vogelzang, MD,10 Mayer N. Fishman, MD, PhD,11 Jingsong Zhang, MD, PhD,11 Sandy Srinivas, MD,12 Jigar Parikh, MD,13 Joyce Antal, MS,14 Xiaoping Jin, PhD,14 Ashok K. Gupta, MD, PhD,14 Yong Ben, MD,15 Noah M. Hahn, MD16
1Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, England
2Department of Medicine, University of Chicago Comprehensive Cancer Center, Chicago, Illinois
3Department of Cancer Medicine, Institut Gustave Roussy Cancer Centre, Villejuif, France
4Drug Development Unit, Sarah Cannon Research Institute, University College London Cancer Centre, London, England
5Division of Genitourinary Medical Oncology, University of California, San Francisco Medical Center
6School of Medicine, Case Western Reserve University Seidman Cancer Center, Cleveland, Ohio
7Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
8Department of Medicine, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada
9Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
10Department of Medical Oncology, Comprehensive Cancer Centers of Nevada, Las Vega
11Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, Florida
12Division of Medical Oncology, Stanford University, Stanford, California
13Department of Medicine, Augusta University, Augusta, Georgia
14Immuno-Oncology Clinical Development, MedImmune, Gaithersburg, Maryland
15Immuno-Oncology Clinical Development, AstraZeneca, Gaithersburg, Maryland
16Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland