Phase 1b study of the novel first-in-class G protein-coupled estrogen receptor (GPER) agonist, LNS8801, in combination with pembrolizumab in patients with immune checkpoint inhibitor (ICI)-relapsed and refractory solid malignancies and dose escalation update.
Authors: Muller Carolyn , Chaney Marya F. , Cohen Justine Vanessa , Garyantes Tina , Lin Jessica Jiyeong , LoRusso Patricia , Mita Alain C. , Mita Monica M. , Natale Christopher , Orloff Marlana M. , Papadopoulos Kyriakos P. , Patel Sapna Pradyuman , Rodon Ahnert Jordi 
Published: June 2022

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Background: LNS8801 is an oral, highly selective, small molecule 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. In preclinical models, LNS8801 has demonstrated increased activity with ICIs. In the first-in-human dose escalation study, LNS8801 was safe and tolerable alone and in combination with pembrolizumab in patients with metastatic solid tumors (NCT04130516). Methods: Patients who are relapsed and refractory (r/r) to PD-1/L1 ICIs and have measurable disease are enrolling in a Phase 1b cohort and receive LNS8801 (125 mg, QD, PO) and pembrolizumab (200 mg, Q3W, IV) (NCT04130516). The primary objective is safety and tolerability assessed according to NCI CTCAE v5.0. Secondary endpoints include pharmacokinetic, pharmacodynamics (eg., increase in serum prolactin over the initial 10 hours of dosing to assess GPER engagement), objective response rate and clinical benefit rate per RECIST v1.1. Results: Updates from the dose escalation portion of the study include long term benefit in a monotherapy patient with cutaneous melanoma on treatment for 2 years with RECIST stable, metabolically inactive disease by PET; a metastatic uveal melanoma patient on therapy for a year, and growing confidence in LNS8801’s favorable safety profile and predictive systemic biomarkers. As of 2/1/22, 13 ICI r/r patients were treated with LNS8801 and pembrolizumab, including those who entered the study directly after confirmed progression on ICIs. Cancer types include lung (3), colorectal, vaginal, nasopharyngeal, neuroendocrine, uterine, and pancreatic cancer, mesothelioma (2), and cutaneous and uveal melanoma. 46% of patients had AEs possibly related to study drugs (31% grades 1-2 and 31% grade 3), with colitis (15%) and fatigue (23%) appearing in more than 10% of patients. Of the 10 evaluable patients, 7 had stable disease (SD), with 4 patients demonstrating tumor regression. At the data cut-off, duration of treatment ranged from 0.7–7.5 months with 4 patients treated between 4.8 and 7.5 months and 4 patients continuing on treatment. All evaluated patients with SD had a prolactin response indicative of systemic target engagement. Conclusions: The combination of LNS8801 and pembrolizumab is tolerable without unanticipated toxicities and demonstrates encouraging anti-tumor activity in patients that are r/r to ICIs, including patients who enrolled immediately after confirmed progression on pembrolizumab alone. These data, as well as continued follow-up on patients with long-term benefit from dose escalation, support further development of LNS8801 as a cancer therapeutic. Clinical trial information: NCT04130516.