Abstract LB-288: A phase I study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors.
Authors: Gordon Michael S. , Hamid Omid , Powderly John , Anderson Maria , Fine Gregg , Mokatrin Ahmad , Kowanetz Marcin , Maya Leabman , Irving Bryan A. , Chen Daniel S. , Hodi F Stephen 
Published: August 2014

Background: Programmed Death-Ligand 1 (PD-L1) is the predominant ligand that binds Programmed Death-1 (PD-1), an inhibitory receptor expressed on T cells following T-cell activation. PD-L1 is highly expressed in many human tumors and elevated expression is often associated with a worse prognosis. PD-L1 exerts an immune suppressive signal through binding to PD-1 and B7.1, and tumor expression of PD-L1 can mediate tumor immune evasion. Therefore, inhibition of PD-L1 binding represents an attractive strategy to reinvigorate tumor-specific T-cell immunity. MPDL3280A is a human monoclonal antibody engineered to optimize efficacy and safety through a modification in the Fc region of the antibody. MPDL3280A targets PD-L1, inhibiting interaction with its receptors that include PD-1 and B7.1. In preclinical models, inhibition of PD-L1 can lead to durable antitumor activity.

Methods: A phase I, multicenter, open-label study was conducted to evaluate the safety, pharmacokinetics (PK), and antitumor activity of MPDL3280A administered intravenously every 3 weeks (q3w) in pts with locally advanced or metastatic solid tumors. The study includes 3+3 dose-escalation cohorts with a 21-day window to evaluate dose-limiting toxicity (DLT).

Results: As of September 14, 2012, results from the dose escalation include 30 patients (pts) (median age 66 years, range 39-80 years), all PS 0-1, with a median of 2 (range 1-3) prior treatments, received a median of 5.5 doses (range 2-16) of MPDL3280A in 8 dose-escalation cohorts (0.01-20 mg/kg). No DLTs or [Grade (G) ≥4 adverse events (AEs) attributed to MPDL3280A] have been reported; related G3 AEs were limited to rash in 1 pt. Pneumonitis was not observed in any of the patients in the dose-escalation cohorts. MPDL3280A exposure increased with dose; furthermore, PK was linear at doses ≥1 mg/kg q3w and consistent with that expected for an IgG1 in humans. RECIST-based responses were observed in a variety of different tumor types with ongoing responses in all responding patients.

Conclusions: MPDL3280A was well tolerated with an acceptable safety and efficacy profile in pts with a variety of advanced tumors. PK supports dosing intervals that include q2wk or q3wk administration. An expansion phase in numerous tumor types with biomarker assessments is ongoing.

Citation Format: Michael S. Gordon, Omid Hamid, John Powderly, Maria Anderson, Gregg Fine, Ahmad Mokatrin, Marcin Kowanetz, Leabman Maya, Bryan A. Irving, Daniel S. Chen, F Stephen Hodi. A phase I study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-288. doi:10.1158/1538-7445.AM2013-LB-288