Abstract
Transcription factor retinoic acid receptor-related orphan receptor γ (RORγ) regulates type 17 effector T-cell differentiation and function and is key to immune cell regulation. Synthetic RORγ agonists modulate immune cell gene expression to increase effector T-cell activity and decrease immune suppression. A phase 1 study evaluated the safety and tolerability of LYC-55716 (cintirorgon), a first-in-class, oral, small-molecule RORγ agonist in adults with relapsed/refractory metastatic cancer. Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate. No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AE) were primarily grade 1-2 and included diarrhea (n = 11), fatigue (n = 7), anemia (n = 4), decreased appetite (n = 4), and nausea (n = 4). Grade 3 AEs were anemia (n = 2), elevated gamma-glutamyl transferase (n = 1), and hypophosphatemia (n = 1). Pharmacokinetic concentrations achieved levels expected for target gene regulation. Pharmacodynamic results indicated RORγ pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2 to 12 months (6 received >4 months of treatment). These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.
Highlights
No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg twice a day (BID) to 450 mg BID
As a transcription factor agonist, receptor g (RORg) agonists affect a number of pathways and have multiple mechanisms of action
Men and non-pregnant women >18 years of age with at least 1 measurable lesion according to response evaluation criteria in solid tumors (RECIST) v1.1 criteria, histologic or cytologic confirmation of advanced unresectable solid tumors, Karnofsky Performance Status (KPS) score !70 or Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, adequate organ function, and life expectancy of at least 12 weeks [16, 17]
Summary
Differentiation and function of type 17 effector T cells such as CD4þ helper T (Th17) and CD8þ cytotoxic T (Tc17) cells [1, 2]. These cells are associated with improved outcomes in a variety of preclinical models as well as human cancers [3,4,5,6,7,8,9]. Synthetic RORg agonists modulate immune cell gene expression to enhance Th17 and Tc17 T-cell effector function and decrease immunosuppressive mechanisms [10,11,12]. The increased immune activity and decreased immune suppression can result in potent antitumor responses
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