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 Cancer Immunology and Immunotherapy
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.