Programmed cell death ligand-1 ( PD-L1 ) is widely expressed on antigen presenting cells ( APC ) and other immune cells. PD-L1 binds two important regulatory receptors on T-cells: programmed cell death-1 ( PD-1 ) and CD80/B7.
Targeting Programmed Death-1 ( PD-1 ) and its ligand, PD-L1, have demonstrated promising anti-tumor activity among other challenging solid tumors and growing data implicates PD-1/PD-L1 signaling as a significant contributor to immunosuppression in glioblastoma ( GBM ).
PD-1 is expressed by many GBM infiltrating lymphocytes while PD-L1 is expressed by 61-100% of GBM tumors. Furthermore, loss of the PTEN tumor suppressor gene, which occurs in 40-50% of GBM tumors, leads to increased transcription and expression of PD-L1 in glioblastoma.
These findings indicate that PD-L1 is an attractive and important therapeutic target in glioblastoma.
MEDI4736, a human IgG1κ blocking monoclonal antibody against PD-L1, represents a compelling immune-mediated anti-tumor treatment for glioblastoma.
Phase II, multicenter, open-label study is evaluating the clinical efficacy and safety of MEDI4736 in patients with glioblastoma.
Eligible patients include those who are newly diagnosed with unmethylated MGMT glioblastoma scheduled for standard radiotherapy ( Cohort A ); Bevacizumab-naïve patients with recurrent gliobastoma ( Cohort B ); and Bevacizumab-refractory patients with recurrent glioblastoma ( Cohort C ).
Cohort A patients will receive MEDI4736 at 10 mg/kg i.v. Q2W for up to 12 months beginning with standard radiotherapy. Cohort B will receive MEDI4736 at 10 mg/kg i.v. Q2W for up to 12 months as monotherapy.
Cohort C will receive MEDI4736 at 10 mg/kg i.v. Q2W for up to 12 months in combination with continued Bevacizumab at 10 mg/kg Q2W.
Primary endpoints include overall survival ( OS ) at 12 months ( cohort A ), progression free survival rate at 6 months ( PFS-6 ) ( cohort B ) and OS-6 ( cohort C ).
Secondary endpoints are safety / tolerability, progression-free survival, median overall survival, radiographic response, and quality of life ( QoL ) by EORTC QLQ-C30/BN20.
Exploratory endpoints are patient neurologic function using the Neurologic Assessment in Neuro-Oncology ( NANO ) scale, as well as immuno-correlative biomarkers and pharmacokinetics. ( Xagena )
Reardon DA et al, J Clin Oncol 33, 2015 ( suppl; abstr TPS2077 )