Development of LNS8801 for cutaneous melanoma patients who cannot tolerate immunotherapy

Project Summary: Although recent advances in immune and targeted therapies have dramatically improved outcomes for many patients with advanced cancer, durable responses are achieved in only a minority of patients, and treatment is frequently limited by significant side effects. These side effects include immune-related adverse events (irAEs), which often prevent patients from receiving further immunotherapeutic agents to treat their disease. There is an urgent need to identify new therapeutic targets and efficacious pharmacologic agents that selectively engage them. Orally deliverable, well-tolerated, and easily synthesized small molecule cancer therapeutics that work in combination with existing standard-of-care drugs are especially desired. Recent work by us and others established that many cancer types are inhibited by nonclassical estrogen signaling through a widely expressed surface receptor called G protein-coupled estrogen receptor (GPER). Linnaeus has used Small Business Technology Transfer (STTR) and Small Business Innovation Research (SBIR) awards (R41/R44 CA228695), along with venture capital funding, to advance a GPER agonist called LNS8801 to human trials. Preclinical work has established that (1) LNS8801 has potent antitumor effects across a wide range of malignancies and that this activity depends on GPER expression in the tumor cells; (2) LNS8801 has beneficial combinatorial effects with targeted therapies, chemotherapies, and immunotherapies; and (3) LNS8801 has a large safety window in rats and dogs. Linnaeus also developed an orally bioavailable and manufacturable formulation of LNS8801. Together, this work enabled us to receive clearance of an Investigational New Drug Application as well as Fast Track designation from the FDA in anti-PD1 refractory melanoma; Orphan Designation from the FDA in cutaneous melanoma; initiate a multisite phase 1 clinical trial (NCT04130516) and complete dose escalation at 10 cancer centers in the United States. LNS8801 has proven safe and well tolerated at all dose levels and the mechanism of action has been validated in humans. We also identified that consensus GPER, lacking a hypofunctional germline variant, serves as predictive biomarker. LNS8801 has demonstrated benefit in patients with multiple cancer types, particularly in cutaneous melanoma patients with prior irAEs. The purpose of this Phase II proposal is to expand upon the preliminary clinical data and complete a proof-of-concept study of LNS8801 in melanoma patients with prior irAEs. Success in this single arm cohort will define metrics and assumptions necessary to conduct a future randomized controlled trial to support registration in this setting, which represents a large unmet need.