Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC).

Abstract

Background: Metastatic UBC is associated with a poor prognosis and limited treatment options. PD-L1 expression is prevalent in this disease and may protect cancer cells from immune-mediated destruction by binding to its receptors PD-1 and B7.1. MPDL3280A is a human anti-PD-L1 mAb with an engineered Fc-domain designed for optimized efficacy and safety. Methods: In a Ph I study, UBC pts received MPDL3280A 15 mg/kg IV q3w for up to 1 y. Objective response rate (ORR; including unconfirmed responses) was assessed by RECIST v1.1. In parallel, tumor and circulating biomarkers were evaluated to study MPDL3280A immune correlates. Results: As of Sep 19, 2013, 31 UBC pts were treated with MPDL3280A. Pts were 84% male, had a median age of 66 y (42-86), 57% were ECOG PS 1 and 68% had visceral metastases. 71% received ≥ 2 prior therapies; 97% received prior platinum-based chemotherapy. Pts had received MPDL3280A for a median duration of 43 d (1-153); the majority remained on treatment as of the data cutoff. The G1-4 treatment-related AEs occurring in ≥ 2 pts were pyrexia, anemia, decreased appetite, fatigue and nausea. Related G3-4 AEs occurred in 3.2% of pts. There were no immune-related AEs. 20 PD-L1+ pts were evaluable for efficacy at time of analysis with a median follow up of 2.8 m (1.4-5). The ORR was 50% (1 CR and 9 PRs) with a median time to response of 43 d (39-82), corresponding to the first radiographic assessment. Responders included pts with visceral metastases at baseline. All responders were still responding at the time of clinical cutoff. Treatment resulted in transient increases in circulating CD8+Ki-67+ T cells and plasma proteins (eg, IL-18) upstream of IFN{gamma} signaling, representing pharmacodynamic biomarkers of activity. Gene expression data from pretreatment tumors showed that pts who progressed had a proportionally higher myeloid gene signature (eg, IL8, CCL2). Updated data will be presented, including data from PD-L1–neg pts. Conclusions: MPDL3280A was well tolerated in this pretreated UBC population. 50% of pts treated responded to treatment. Responses were rapid and on-going. Biomarker analysis revealed pharmacodynamic markers, as well as markers of potential mechanisms of resistance to therapy. Clinical trial information: NCT01375842.