Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer

Abstract

Purpose: To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC).

Methods: A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1-positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1.

Results: A total of 61 patients (40 PD-L1-positive, 21 PD-L1-negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1-positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1-negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks).

Conclusion: Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, many of whom were heavily pretreated.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2016 by American Society of Clinical Oncology.

Figures

Fig 1.

Representative photomicrographs of urinary bladder cancer biopsy specimens from patients, illustrating immunohistochemical staining for programmed cell death ligand-1 (PD-L1) on tumor cells (TC) and tumor-infiltrating immune cells (IC). (A) Tumor biopsy with ≥ 25% TC and ≥ 25% IC (TC-positive/IC-positive) PD-L1 staining; (B)

Fig 2.

(A) Best change from baseline in tumor size over time by programmed cell death ligand-1 (PD-L1) status; (B) tumor size change from baseline by PD-L1–positive status (response-evaluable population with one or more postbaseline scans); (C) tumor size change from baseline by PD-L1–negative status (response-evaluable population with one or more postbaseline scans). Note: PD-L1–positive was defined as either ≥ 25% of tumor cells or ≥ 25% of tumor-infiltrating immune cells expressing PD-L1, and PD-L1–negative was defined as both

Fig 3.

Time to response and duration of response. Note: programmed cell death ligand-1–positive was defined as either ≥ 25% of tumor cells or ≥ 25% of tumor-infiltrating immune cells expressing programmed cell death ligand-1. This figure includes only response-evaluable patients who had confirmed responses. Abbreviations: D/C, discontinued; TRT, treatment.