Abstract 2130
Background
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.
Methods
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.
Results
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.
| Cohort | 1 | 2 | 3 | 4 | 5 | 6 | Total |
|---|---|---|---|---|---|---|---|
| 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 | |
| N | 4 | 5 | 3 | 3 | 9 | 6 | 30 |
| 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) |
| Responses* | |||||||
| 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
Conclusions
M 10 mg/kg + D 10 mg/kg Q2W appears to be well-tolerated and active in this population.
Clinical trial identification
NCT02118337
Legal entity responsible for the study
MedImmune
Funding
MedImmune
Disclosure
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.