LNS8801 is an oral, highly selective agonist of the G protein-coupled estrogen receptor (GPER). LNS8801 normalizes c-Myc levels in cancer cells, inhibits proliferation, suppresses invasion, and enhances immune recognition. LNS8801 is being advanced through clinical trials (NCT04130516) for the treatment of advanced solid tumors. GPER is a widely expressed across tumor types as well as normal tissues, including the pituitary gland. Estrogens are endogenous ligands of GPER, and it is known that exogenous estrogen exposures can induce prolactin secretion that is detectable systemically. GPER signaling is both sufficient and necessary to mediate this effect. Due to circadian rhythms, systemic prolactin levels typically decrease throughout the day. However, we hypothesize that prolactin will increase with LNS8801 treatment.
Circulating prolactin levels were measured on the first day of treatment in patients with advanced solid tumors. Prolactin levels were measured before dosing LNS8801 and at 0.5, 1, 2, 4, 7 and 10 hours after dosing. Tumor responses were measured every 8 weeks for the 1st year and then every 12 weeks.
In up to 70% of patients treated with LNS8801, systemic prolactin increased over the first 10 hours after treatment. A retrospective analysis correlated this change in prolactin with exposure to LNS8801 and anti-tumor benefit from LNS8801 treatment. The kinetics of plasma prolactin levels immediately follows and tightly trends with LNS8801 plasma exposure. A progression-free survival (PFS) analysis comparing patients with a robust prolactin response to those with a weak/nonresponse was performed. Patients with a robust prolactin response had a statistically significant increase in PFS (p<0.01).
These data suggest that prolactin induction may serve as a surrogate-systemic biomarker of pharmacodynamic engagement of GPER. This biomarker will continue to be assessed in the ongoing clinical studies of LNS8801 for the treatment of cancer. Prolactin induction may be used prior to randomization to identify patients most likely to benefit from LNS8801 therapy in future studies.
Clinical trial identification
Legal entity responsible for the study
Linnaeus Therapeutics, Inc.
J. Cohen: Non-Financial Interests, Personal, Invited Speaker: Sanofi Genzyme, Regeneron. C.A. Natale: Financial Interests, Personal, Invited Speaker: Linnaeus Therapeutics. M. Orloff: Financial Interests, Personal, Invited Speaker: Immunocore, Ideaya, Delcath; Non-Financial Interests, Personal, Invited Speaker: Trisalus. T.K. Garyantes: Financial Interests, Personal, Invited Speaker: Linnaeus Therapeutics. All other authors have declared no conflicts of interest.