Background: LYC-55716 is a first-in-class, oral, small-molecule agonist of the retinoic acid receptor–related orphan receptor γ (RORγ) under development as a novel immuno-oncology agent for solid tumors. Preclinical evidence suggests that LYC-55716 alters immune cell anti-tumor effector functions and immunosuppressive mechanisms, leading to reduced tumor growth and enhanced survival. In the Phase 1 portion of an ongoing Phase 1/2A trial, LYC-55716 was well tolerated with no dose-limiting toxicities. Evidence of pharmacodynamic target engagement was demonstrated and disease stabilization with tumor reduction was noted in patients after failure of PD-1 therapy. The Phase 2A trial (NCT02929862) is underway in patients with advanced non–small cell lung, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers. Methods: The Phase 2A portion of the trial will enroll ~70 adult patients who will receive 28-day treatment cycles of LYC-55716 administered twice daily. The primary endpoint is to determine the objective response rate (ORR). Secondary endpoints will include duration of response, progression-free survival, overall survival, safety, and pharmacokinetics. As an exploratory endpoint, immune-related biomarkers will be assessed in blood samples from all patients, taken at screening and every 2-4 weeks through treatment cycle 4, and in tissue biopsy samples of selected patients, taken at screening and 4-12 weeks after beginning cycle 1. Immune markers of interest will be evaluated using a NanoString platform and immunohistochemistry. Results will be analyzed using descriptive and summary statistics. Clinical trial information: NCT02929862