A phase 1 study of nivolumab in combination with interferon-gamma for patients with advanced solid tumors

Matthew Zibelman, Alexander W. MacFarlane, Kimberly Costello, Thomas McGowan, John O’Neill, Rutika Kokate, Hossein Borghaei, Crystal S. Denlinger, Efrat Dotan, Daniel M. Geynisman, Angela Jain, Lainie Martin, Elias Obeid, Karthik Devarajan, Karen Ruth, R. Katherine Alpaugh, Essel Al Saleem Dulaimi, Edna Cukierman, Margret Einarson, Kerry S. CampbellElizabeth R. Plimack

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/m2, however based on a composite of safety, clinical, and correlative factors the RP2D is 50 mcg/m2. Exploratory analyses of efficacy in the phase I cohorts demonstrate one patient with a complete response, and five have achieved stable disease. Pre-planned correlative assessments of circulating immune cells demonstrate intermediate monocytes with increased PD-L1 expression correlating with IFN-γ dose and treatment duration. Interestingly, post-hoc analysis shows that IFN-γ induction increases circulating chemokines and is associated with an observed paucity of irAEs, warranting further evaluation. ClinicalTrials.gov Trial Registration: NCT02614456.

Original languageEnglish
Article number4513
Pages (from-to)4513
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Jun 27 2023

Keywords

  • Antineoplastic Combined Chemotherapy Protocols/adverse effects
  • Humans
  • Interferon-gamma
  • Neoplasms/pathology
  • Nivolumab/therapeutic use

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