SYNERGY: A phase 1b/2 study of nenocorilant, a selective glucocorticoid receptor antagonist, plus nivolumab in patients with advanced solid malignancies.

Abstract

TPS2695 Background: Acting through the glucocorticoid receptor (GR), glucocorticoids (GCs) suppress the anticancer immune response by decreasing antigen presentation, exhausting CD8+ T-cell effector function, and increasing the immunosuppressive function of regulatory T cells and tumor-infiltrating myeloid cells. The use of GCs with anti-programmed death (ligand) 1 (anti-PD[L]1) therapy is associated with poor outcomes in several solid tumor types. Selective GR antagonists (SGRAs) inhibit the effects of GCs at the GR and show synergistic activity with cytotoxic chemotherapy, as demonstrated by the phase 3 ROSELLA study in patients with platinum-resistant ovarian cancer (Olawaiye Lancet 2025). SGRAs enhance tumor growth inhibition when combined with anti-PD1 therapy in syngeneic mouse tumor models that are refractory to immune checkpoint inhibition (Greenstein Int Immunopharmacol 2023). We hypothesize that GR antagonism with nenocorilant, an SGRA, may enhance or restore sensitivity to anti-PD(L)1 therapy and provide clinical benefit for patients with solid malignancies. Methods: This phase 1b/2, open-label, multicenter study (NCT07276373) is evaluating nenocorilant + nivolumab in patients with advanced solid malignancies. Key eligibility criteria for phase 1b include having received standard-of-care therapies, no prior immune-related adverse events (AEs) grade ≥3 or leading to anti-PD(L)1 discontinuation, no ongoing requirement for GCs, and evaluable disease (per Response Evaluation Criteria in Solid Tumors version 1.1). Treatment will continue until disease progression or discontinuation criteria are met. Nenocorilant will be given orally once daily in escalating doses (starting at 200 mg) across 3 cohorts of 10 patients each. Nivolumab 240 mg will be given intravenously once every 2 weeks. If ≤3 patients in a cohort experience dose-limiting toxicities (DLTs) during the 28-day evaluation period, enrollment will proceed to the next cohort at a higher dose of nenocorilant. Primary objectives include characterizing safety/tolerability (DLTs, AEs, serious AEs, dose modifications, and treatment discontinuations due to AEs) and determining the maximum tolerated dose and/or optimal dose/schedule. Secondary objectives are to characterize the anticancer activity, pharmacokinetics, and corrected QT interval effects of this combination. Safety endpoints will be summarized using descriptive statistics and time-to-event endpoints will be estimated using Kaplan-Meier methods. Data from the currently enrolling phase 1b part of the study will inform the dosing regimen for phase 2, which will further characterize the anticancer activity and safety of nenocorilant + nivolumab in specific solid malignancies. Clinical trial information: NCT07276373 .