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.

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) < 25% TC and ≥ 25% IC (TC-negative/IC-positive) PD-L1 staining; (C) ≥ 25% TC and < 25% IC (TC-positive/IC-negative) PD-L1 staining; and (D) < 25% TC and < 25% IC (TC-negative/IC-negative) PD-L1 staining.

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 < 25% of tumor cells and < 25% of tumor-infiltrating immune cells expressing PD-L1. *Unconventional response. †Unconfirmed response at data cutoff, awaiting confirmation (with the exception of patients with unconventional responses, all other patients with best tumor shrinkage ≥ 30% had confirmed responses).

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.