9543 Background: LNS8801 is an oral, selective, small molecule agonist of the G-protein coupled estrogen receptor (GPER). LNS8801 treatment results in increased melanocytic differentiation, reduced c-Myc protein levels in cancer cells, inhibition of proliferation, suppression of invasion, and enhancement of immune recognition. In preclinical models, LNS8801 has demonstrated increased activity in combination with immune checkpoint inhibitors (ICIs). In the first-in-human dose escalation study, LNS8801 was safe and tolerable alone and in combination with pembrolizumab in patients with advanced solid tumors (NCT04130516). Methods: Patients with measurable metastatic uveal melanoma (mUM) received LNS8801 (125 mg, QD, PO) alone or with pembrolizumab (200 mg, Q3W, IV) (NCT04130516). The primary objective was safety and tolerability assessed according to NCI CTCAE v5.0. Secondary endpoints include pharmacokinetic, pharmacodynamics, objective response rate (ORR) and disease control rate (DCR, CR+PR+SD) per RECIST v1.1. Presence of a consensus, fully-functional, germline GPER coding sequence was assessed via Sanger sequencing on DNA extracted from blood as a potential predictive biomarker. Results: As of 1/25/23, 15 patients with mUM were treated with LNS8801 alone (n = 8) or a combination of LNS8801 and pembrolizumab (n = 7). Patients were previously treated with a median of 2 prior lines of systemic therapy. 4 of 8 monotherapy patients had AEs potentially related to study drug (all grade 1), with no AEs occurring in more than one patient. 6 of 7 combination patients had AEs potentially related to study drugs (grades 1-2), with fatigue occurring in more than one patient. Of the 14 patients evaluable for efficacy (7 mono, 7 combo), 7 had disease control (4 mono, 3 combo) resulting in a disease control rate of 50%. 1 patient treated with combination achieved a confirmed partial response. Consensus germline GPER was present in 2 of 12 sequenced patients (1 mono, 1 combo), and both of these patients have ongoing disease control lasting longer than 24 weeks. Conclusions: LNS8801 alone and in combination with pembrolizumab is tolerable without unanticipated toxicities and demonstrates encouraging anti-tumor activity in patients with mUM. The hypofunctional germline GPER variant appears over-represented in this cohort compared to the normal population, suggesting a potential significant role for GPER in the development of mUM. These data support further development of LNS8801 alone and in combination with pembrolizumab as a therapeutic approach to treat mUM patients, especially for patients with consensus germline GPER. Clinical trial information: NCT04130516 .