Phase 1 Open-Label, Multicenter Study of First-in-Class RORγ Agonist LYC-55716: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

PURPOSE: Transcription factor retinoic acid receptor-related orphan receptor g (RORg) 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, a first-in-class, oral, small-molecule RORg agonist in adults with relapsed/refractory metastatic cancer.

EXPERIMENTAL DESIGN: 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 (AEs) were primarily Grade 1-2 and included diarrhea (n=11), fatigue (n=7), anemia (n=4), decreased appetite (n=4), 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 RORg pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2-12 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.