Phase 2 study of glesatinib or sitravatinib with nivolumab in non-small cell lung cancer (NSCLC) after checkpoint inhibitor therapy.
Nemunaitis J, Borghaei H, Akerley W, Gadgeel S, Spira A, Rybkin I, Faltaos D, Chen I, Christensen J, Potvin D, Velastegui K, Levisetti M, and Husain H. Phase 2 study of glesatinib or sitravatinib with nivolumab in non-small cell lung cancer (NSCLC) after checkpoint inhibitor therapy. J Thorac Oncol 2017; 12(1):S1078.
J Thorac Oncol
Background: Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant NSCLC. Glesatinib, a tyrosine kinase inhibitor (TKI), which targets Axl, MER and MET RTKs expressed on macrophages and antigen-presenting-cells within the tumor microenvironment (TME), may reverse the immunosuppressive TME and enhance anti-tumor T and NK cell responses by enhancing antigen presentation and T cell effector function. Sitravatinib, also a TKI, which targets VEGFR2 and KIT as well as Axl, MER and MET, may further enhance anti-tumor activity by VEGFR2 and KIT inhibition mediated reduction of regulatory T cells and myeloid-derived suppressor cells (MDSCs). Given these pleiotropic immune activating effects, the combination of glesatinib or sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC. Methods: This open-label Phase 2 study evaluates the tolerability and clinical activity of the investigational agents, glesatinib or sitravatinib in combination with nivolumab in separate cohorts of patients with nonsquamous NSCLC who have experienced progression of disease on or after treatment with CIT. The study begins with a limited dose escalation evaluation of each investigational agent in combination with nivolumab to determine the dose levels to be used in Phase 2. The primary objective is to assess the clinical activity of the combination regimens using the Objective Response Rate (ORR) by RECIST 1.1. Other objectives include safety, tolerability, pharmacokinetics and changes in circulating and tumor cell PD-L1, circulating and tumor infiltrating immune cell populations, cytokines and gene expression signatures. Enrollment into each Phase 2 treatment arm is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤ 12 weeks). The investigational agents are administered orally in continuous regimens; nivolumab is administered intravenously, 3 mg/kg every 2 weeks. The sample sizes for the treatment arms are based on two-stage Simon Optimal Designs.