A phase Ib study of utomilumab (PF-05082566) in combination with mogamulizumab in patients with advanced solid tumors

Ezra E.W. Cohen, Michael J. Pishvaian, Dale R. Shepard, Ding Wang, Jared Weiss, Melissa L. Johnson, Christine H. Chung, Ying Chen, Bo Huang, Craig B. Davis, Francesca Toffalorio, Aron Thall, Steven F. Powell

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Expressed on activated T and natural killer cells, 4-1BB/CD137 is a costimulatory receptor that signals a series of events resulting in cytokine secretion and enhanced effector function. Targeting 4-1BB/CD137 with agonist antibodies has been associated with tumor reduction and antitumor immunity. C-C chemokine receptor 4 (CCR4) is highly expressed in various solid tumor indications and associated with poor prognosis. This phase Ib, open-label study in patients with advanced solid tumors assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of utomilumab (PF-05082566), a human monoclonal antibody (mAb) agonist of the T-cell costimulatory receptor 4-1BB/CD137, in combination with mogamulizumab, a humanized mAb targeting CCR4 reported to deplete subsets of regulatory T cells (Tregs). Methods: Utomilumab 1.2-5 mg/kg or 100 mg flat dose every 4 weeks plus mogamulizumab 1 mg/kg (weekly in Cycle 1 followed by biweekly in Cycles ≥2) was administered intravenously to 24 adults with solid tumors. Blood was collected pre- and post-dose for assessment of drug pharmacokinetics, immunogenicity, and pharmacodynamic markers. Baseline tumor biopsies from a subset of patients were also analyzed for the presence of programmed cell death-ligand 1 (PD-L1), CD8, FoxP3, and 4-1BB/CD137. Radiologic tumor assessments were conducted at baseline and on treatment every 8 weeks. Results: No dose-limiting toxicities occurred and the maximum tolerated dose was determined to be at least 2.4 mg/kg per the time-to-event continual reassessment method. No serious adverse events related to either treatment were observed; anemia was the only grade 3 non-serious adverse event related to both treatments. Utomilumab systemic exposure appeared to increase with dose. One patient with PD-L1-refractory squamous lung cancer achieved a best overall response of partial response and 9 patients had a best overall response of stable disease. No patients achieved complete response. Objective response rate was 4.2% (95% confidence interval: 0.1-21.1%) per RECIST 1.1. Depletion of Tregs in peripheral blood was accompanied by evidence of T-cell expansion as assessed by T-cell receptor sequence analysis. Conclusions: The combination of utomilumab/mogamulizumab was safe and tolerable, and may be suitable for evaluation in settings where CCR4-expressing Tregs are suppressing anticancer immunity. Trial registration: ClinicalTrials.gov identifier: NCT02444793.

Original languageEnglish (US)
Article number342
JournalJournal for immunotherapy of cancer
Volume7
Issue number1
DOIs
StatePublished - Dec 4 2019
Externally publishedYes

Keywords

  • 4-1BB
  • CD137
  • Mogamulizumab
  • Solid tumors
  • Utomilumab

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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