Phase 1 Open-Label, Multicenter Study Of First-In-Class Ror Gamma Agonist Lyc-55716 (Cintirorgon): Safety, Tolerability, And Preliminary Evidence Of Antitumor Activity

Purpose: Transcription factor retinoic acid receptor-related orphan receptor gamma (ROR gamma) regulates type 17 effector T-cell differentiation and function and is key to immune cell regulation. Synthetic RORg 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 RORg agonist in adults with relapsed/refractory metastatic cancer.Patients and Methods: 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.Results: 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 ROR gamma 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).Conclusions: 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.