1050PD - Combination of MEDI0680, an anti-PD-1 antibody, with durvalumab, an anti-PD-L1 antibody: A phase 1, open-label study in advanced malignancies

Date 10 October 2016
Event ESMO 2016 Congress
Session Immunotherapy of cancer
Topics Immunotherapy
Therapy
Presenter Omid Hamid
Citation Annals of Oncology (2016) 27 (6): 359-378. 10.1093/annonc/mdw378
Authors O. Hamid1, L.Q. Chow2, R.E. Sanborn3, S. Marshall4, C. Black5, M. Gribbin6, J. McDevitt4, J.J. Karakunnel4, J.E. Gray7
  • 1Melanoma Therapeutics, The Angeles Clinic and Research Institute, CA 90025 - Los Angeles/US
  • 2Department Of Medicine, Division Of Medical Oncology, University of Washington, Seattle/US
  • 3Department Of Medical Oncology, Earle A. Chiles Research Institute, Providence Cancer Center, Portland/US
  • 4Clinical Development, MedImmune, Gaithersburg/US
  • 5Translational Medicine, MedImmune, Gaithersburg/US
  • 6Biostatistics, MedImmune, Gaithersburg/US
  • 7Department Of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa/US

Abstract

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.