Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies

Abstract

Background: The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies.

Methods: MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20 mg/kg. Two cohorts received 20 mg/kg once a week for 2 or 4 weeks, then 20 mg/kg Q2W. All were treated for 12 months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics.

Results: Fifty-eight patients were treated. Median age was 62.5 years and 81% were male. Most had kidney cancer (n = 36) or melanoma (n = 9). There were no dose-limiting toxicities. Treatment-related adverse events occurred in 83% and were grade ≥ 3 in 21%. Objective clinical responses occurred in 8/58 patients (14%): 5 with kidney cancer, including 1 with a complete response, and 3 with melanoma. The relationship between dose and serum levels was predictable and linear, with apparent receptor saturation at 10 mg/kg Q2W and all 20 mg/kg cohorts.

Conclusions: MEDI0680 induced peripheral T-cell proliferation and increased plasma IFNγ and associated chemokines regardless of clinical response. CD8+ T-cell tumor infiltration and tumoral gene expression of IFNG, CD8A, CXCL9, and granzyme K (GZMK) were also increased following MEDI0680 administration.

Trial registration: NCT02013804 ; date of registration December 12, 2013.

Keywords: Immunotherapy; Kidney cancer; MEDI0680; Melanoma; PD-1.

Conflict of interest statement

Aung Naing: Research grants from NCI, EMD Serono, AstraZeneca, Healios Onc., Nutrition, Atterocor, Amplimmune, Karyopharm Therapeutics, Incyte, Regeneron, Merck, BMS, Pfizer, Neon Therapeutics, Calithera BioSciences, and TopAlliance BioSciences; grants and advisory board membership with ARMO BioSciences, Novartis, and CytomX Therapeutics; grants from Immune Deficiency Foundation (spouse).

Jeffrey Infante: Consultant for Armo Biosciences and Biomed Valley; employee of Janssen Oncology.

Sanjay Goel: Funding to conduct clinical trial from AstraZeneca.

Howard Burris: Consultant or advisor to Mersana, AstraZeneca, Bristol-Myers Squibb, FORMA Therapeutics, Janssen, Novartis, Roche/Genentech, and TG Therapeutics; research funding from Roche/Genentech, Bristol-Myers Squibb, Incyte, Tarveda Therapeutics, Mersana, AstraZeneca, Macrogenics, Novartis, Boehringer-Ingelheim, Eli Lilly, Seattle Genetics, AbbVie, Bayer, Celldex, Merck, Celgene, Agios, Jounce Therapeutics, Moderna Therapeutics, CytomX Therapeutics, GlaxoSmithKline, Verastem, Tesaro, Immunocore, Takeda, Millennium, BioMed Valley Discoveries, Pfizer, PTC Therapeutics, TG Therapuetics, Loxo, Vertex, eFFECTOR Therapetics, Janssen, Gilead Sciences, Valent Technologies, BioAtla, CicloMed, Harpoon Therapeutics, Jiangsu Hengrui Medicine, Revolution Medicines, Daiichi Sankyo, H3 Biomedicine, Neon Therapeutics, OncoMed, Regeneron, and Sanofi; expert testimony for Novartis.

Patricia LoRusso: Advisory boards for Genentech, AstraZeneca, Ipsen, AbbVie, Genmab, Roche, CytomX, and SOTIO; Data Safety Monitoring Boards for Agios, Five Prime, Halozyme, and Tyme.

Amy Weise: Speakers’ bureau for Array Biopharma.

Joseph Eder: No conflicts to disclose.

Brendan Curti: Institution receives research funding from AstraZeneca.

Chelsea Black, Shannon Marshall, Ikbel Achour, Rena May, Chris Morehouse, Kristen Pollizzi, Xuyang Song, Keith Steele, Nairouz Elgeioushi, Farzana Walcott, Joyson Karakunnel, and Michael Oberst are current or former employees of AstraZeneca and own stocks/shares in AstraZeneca. Susannah Barbee is a former employee of Amplimmune.

Figures

Fig. 1

Response to MEDI0680 therapy. a Tumor size change from baseline in the as-treated population. b The timing and duration of response and onset of progressive disease or new lesions in the responding population. Blue bars indicate treatment initiation to censoring date or progression date. One patient with kidney cancer and PR had an ongoing response but did not have a disease assessment at the time of the last dose

Fig. 2

Pharmacokinetic and receptor occupancy analysis of MEDI0680. a Pharmacokinetic analysis of MEDI0680 in patient serum. Data represent time points up to 150 days. Abbreviation: LLOQ lower limit of quantitation. b PD-1 receptor occupancy by MEDI0680 on CD45 RO+ CD3 T cells among patients treated at various drug doses and schedules, as indicated. Measurements were done at baseline, during the first cycle of MEDI0680 treatment, and on the first day after the completion of the first cycle

Fig. 3

Peripheral and intratumoral measures of MEDI0680 activity. a Peripheral CD4+ and CD8+ T-cell activation and proliferation among treatment groups, as indicated. Shown are the fold changes in the percentages of CD4+ and CD8+ Ki67+ and CD4+ TEM CD38high/HLA-DRhigh cells in whole blood post-treatment. Abbreviation: TEM effector memory T cells. b Change in plasma cytokines among treatment groups, as indicated. Shown are the fold change in the plasma levels of IFNγ, CXCL-9, CXCL-10, and CXCL-11 at day 8 post-treatment with MEDI0680. c Examples of PD-L1+ and CD8+ IHC images (20× magnification) from matched pre- and on-treatment biopsies from an RCC patient. The tumor at screening is characterized by abundant CD8+ TILs and PD-L1 on immune cells but not on tumor cells (* symbols on IHC images). The on-treatment tumor has greater CD8+ T-cell infiltration and PD-L1 immunoreactivity on both immune and tumor cells (*). d Levels of CD8+ TILs in tumor biopsies pre- and on-treatment at various dose levels. Abbreviation: hpf high power field. (e) Log2 fold change in on-treatment versus pretreatment CD8A, IFNG, CXCL9, and GZMK gene expression in RCC and melanoma tumor biopsies. A 1.5-fold change is indicated by the dotted line