Phase 1b results from OP-1250-001, a dose escalation and dose expansion study of OP-1250, an oral CERAN, in subjects with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer (NCT04505826)

Background: OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) that binds the ligand binding domain of the ER and completely blocks ER driven transcriptional activity. OP-1250 potently inactivates both wild-type ER and mutant forms of ER that confer ligand independent activity and resistance to standard of care endocrine therapies. OP-1250 inhibits estrogen-driven breast cancer cell growth and induces degradation of the ER. In preclinical models, OP-1250 is active in the presence of wild-type ER, mutant ER (ESR1 activating mutations), and brain metastasis. OP-1250 is being developed for ER+, HER2- metastatic breast cancer (MBC) patients (pts). We previously reported Phase 1a (dose escalation) results, here we present data from the Phase 1b expansion portion of the clinical trial. Methods: Following Phase 1a dose escalation of OP-1250 from 30 mg to 300 mg QD, a recommended phase 2 dose (RP2D) range was defined of 60 to 120 mg QD. Sixty pts are planned for Phase 1b enrollment, with 30 pts at each dose level (60 and 120 mg). In Phase 1b eligibility included measurable disease, 1–4 prior lines of hormonal therapy, and £1 prior line of chemotherapy in the advanced setting. Pts were monitored for adverse events (AE) and tumor assessments (RECIST 1.1) were conducted every two 28-day cycles. Results: As of May 13, 2022, 37 patients were assigned to either 60 mg or 120 mg dose levels. Pts were heavily pretreated: 62% had received 2 or more prior endocrine therapies in the advanced setting, 32% received chemotherapy, and 97% had received a prior CDK 4/6 inhibitor. More than half (57%) of pts who had ctDNA evaluated had an ESR1 mutation. At 60 mg and 120 mg, OP-1250 demonstrated high oral bioavailability and dose proportional exposure. The most common treatment emergent adverse events reported (≥10%) in Phase 1b in the 60 mg/120 mg cohorts were nausea (28%/21%), vomiting (17%/16%), fatigue (17%/5%) and headache (11%/ 11%). Adverse events were Grade 1/2, with the exception of two Grade 3 events at 60 mg (diarrhea and anemia); no Grade 3 events occurred at 120 mg. There were no dose reductions or discontinuations due to an AE. Across Phase 1b, among pts eligible for at least one post-baseline scan (n = 24), 1 confirmed PR (cPR) was observed at 60 mg and 1 uPR was observed at 120 mg. Data continues to mature and updated data will be presented. Conclusions: OP-1250 was well tolerated and showed promising safety and efficacy in Phase 1b pts treated at 60 mg and 120 mg daily. Based on safety and pharmacokinetic data, a RP2D will be selected. A Phase 2 evaluation will be initiated, and a Phase 3 monotherapy study is planned for 2023. Conflict of interest: Corporate-sponsored Research: Erika Hamilton: Abbvie, Acerta Pharma, Accutar Biotechnology, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, Black Diamond, Bliss BioPharmaceuticals, Boehringer Ingelheim, Cascadian Therapeutics, Clovis, Compugen, Cullen-Florentine, Curis, CytomX, Daiichi Sankyo, Dana Farber Cancer Inst, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Ellipses Pharma, Elucida Oncology, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, InvestisBio, Jacobio, Karyopharm, Leap Therapeutics, Lilly, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millennium, Molecular Templates, Myraid Genetic Laboratories, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Pfizer, Pharma Mar, Pieris Pharmaceuticals Pionyr, Immunotherapeutics, Plexxikon, Radius Health, Regeneron, Relay Therapeutics, Repertoire, Immune Medicine, Rgenix, Roche/Genentech, SeaGen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, Zymework Other Substantive Relationships: Erika Hamilton: Consulting Advisory Role (all to institution only): Arcus, Arvinas, AstraZeneca, Black Diamond, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Dantari, Deciphera Pharmaceuticals, Eisai, Greenwich LifeSciences, H3 Biomedicine iTeosJanssen, Lilly, Loxo, Merck, Mersana, Novartis, Orum Therapeutics, Pfizer, Propella Therapeutics, Puma Biotechnology, Relay Therapeutics, Roche/Genentech, SeaGen, Silverback Therapeutics