The PD-1/PD-L1 pathway is a key regulator of T-cell activation and a promising target for cancer treatment. MEDI0680 (M) is a humanized IgG4κ mAb specific for human PD-1 that blocks interaction with PD-L1 and programmed cell death ligand-2 (PD-L2). Durvalumab (D; MEDI4736) is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Blocking both the PD-1 receptor and its ligand by combining M + D offers the potential for complete PD-1/PD-L1 axis inhibition.
This ongoing Phase 1 open-label, dose-escalation and expansion study is evaluating M + D in patients (pts) ≥18 years with relapsed/refractory advanced solid malignancies and ECOG performance status 0-1 (NCT02118337). The primary objectives are safety and maximum tolerated dose (MTD). Secondary objectives include antitumor activity.
As of 2 November 2015, 30 pts across various histologies were treated in 6 dose cohorts (Table) with 50% remaining on study. 1 dose-limiting toxicity occurred (Cohort 5; Grade 3 elevated AST/ALT). The MTD has not been reached. The most common drug-related AEs were pruritus (17%); diarrhea and fatigue (both 13%); and flushing, peripheral edema, and pyrexia (each 10%). Immune-related AEs were similar to those seen with other checkpoint blockade agents. No drug-related AEs led to death. 2 pts (7%) discontinued due to drug-related AEs. Of 26 evaluable pts, 1 had a complete response (CR; Cohort 5; bladder cancer), 3 had a partial response (PR) and 9 had stable disease (SD). Increased Ki67+ (proliferating) CD4+ and CD8+ T cells and elevated circulating IFNɣ, CXCL9, CXCL10, and CXCL11 levels were observed with M + D, indicating pharmacodynamic activity of PD-1/PD-L1 pathway blockade. Updated clinical data will be presented.
|Dose every 2 weeks (Q2W) (mg/kg), M + D||0.1 + 3||0.1 + 10||0.5 + 10||2.5 + 10||10 + 10||20 + 10|
|Patients with drug-related AEs, n (%)|
|All grades||2 (50)||3 (60)||3 (100)||2 (67)||8 (89)||3 (50)||21 (70)|
|Grade ≥3||1 (25)||0||1 (33)||0||3 (33)||0||5 (17)|
|All grades leading to discontinuation||1 (25)||1 (20)||1 (33)||1 (33)||2 (22)||0||6 (20)|
|Objective response rate (CR + PR), n/N (%)||1/4 (25)||0||0||0||3/8 (38)||0||4/26 (15)|
|Disease control (CR + PR + SD ≥8 weeks), n/N (%)||2/4 (50)||1/5 (20)||1/3 (33)||0||5/8 (63)||0||9/26 (35)|
*Response evaluable population
M 10 mg/kg + D 10 mg/kg Q2W appears to be well-tolerated and active in this population.
Clinical trial identification
Legal entity responsible for the study
O. Hamid: Consulting/Advisory: Merck, Merck Serono, Pfizer, Amgen, Novartis, Roche, BMS, Genentech Speakers Bureau: BMS, Genentech, Novartis Research funding: None. L.Q. Chow: Honoraria: Astellas Consulting/Advisory: Novartis, Amgen, Emergent Research funding: Novartis, BMS, Eli Lilly/Imclone Advisory board; travel & accommodations/Research funding: Merck. R.E. Sanborn: Consulting/Advisory: Amgen Research funding: BMS, Medimmune. S. Marshall: Employment: MedImmune, Amplimmune Stock options: MedImmune. C. Black: Employment: MedImmune Stock/ownership: AZ. M. Gribbin: Employment: Medimmune Stock ownership: MedImmune. J. McDevitt: Employment: MedImmune Stock/ownership: MedImmune (AZ). J.J. Karakunnel: Employee of MedImmune and own stock or options in AstraZeneca. JJK is also an employee of MedStar Montgomery Medical Center and Fauquier Hospital. J.E. Gray: Consulting/Advisory: AZ Travel, accommodation, expenses: AZ.