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.

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

“…In a study of pembrolizumab in patients with advanced NSCLC, IRRs were monitored using a single preferred term; any‐grade IRRs occurred in 3% of patients (grade 3‐5 in <1%) 21. Similarly, a study of durvalumab in patients with metastatic UC also reported IRRs using a single preferred term; any‐grade IRRs occurred in 3.3% of patients (grade 3 in 1 patient [1.6%]) 22. Despite using an expanded definition of IRRs in the current analysis, the incidence of grade ≥3 IRRs was similar to that in studies that used limited or single‐term definitions of IRR (ie, <1%).…”

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

“…PD-L2's contribution to T cell immunity is controversial, as both in vitro 17,20 and knockout mouse 56,57 studies have demonstrated both positive and negative influences on T cell activation, while two studies with human PBMC have favored the notion that PD-L2 serves as a negative regulator of T cell activation and function. 58,59 However, anti-PD-L1 mAbs do not interfere with PD-1/PD-L2 interactions but have had similar impact on clinical outcome in patients with lung cancer and bladder cancer in comparison with anti-PD-1 mAb, 4,[60][61][62] suggesting that the PD-1/PD-L2 interaction plays a lesser role in adaptive resistance to tumor immunity than PD-1/PD-L1. As PD-L2 expression also positively correlated with lymphocytic infiltration, we hypothesize that, in vivo, PD-L2-mediated stimulation results in a different outcome than observed with human PBMC studies in vitro.…”

Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology

“…97 Early results from a phase I/II multicenter study of durvalumab for 61 patients with PD-L1-positive inoperable or metastatic urothelial bladder cancer whose tumor had progressed during or after one standard platinum-based regimen showed that 46.4% of patients who were PD-L1-positive had disease that responded to treatment; no response was seen in patients who were PD-L1-negative. 98 A 2017 update on this study (N=103) showed a 29.5% ORR for PD-L1-high disease and a 7.7% ORR for PD-L1-low/negative disease. The OS rate at 6 months was 68.4% for the PD-L1-high group and 44.7% for the PD-L1-low/negative group.…”