382MO - Updated results from the phase I/II study of OP-1250, an oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) in patients (pts) with advanced or metastatic ER-positive, HER2-negative breast cancer

Background

OP-1250 is a small molecule CERAN/SERD with antitumor activity in breast cancer (BC) xenograft models, including ESR1/PIK3CA mutations and brain metastasis. OP-1250 was administered at 30–300 mg daily (qd) in the dose-escalation part of a phase 1 study. Maximum tolerated dose was not reached and no dose-limiting toxicities occurred. OP-1250 at 60 mg and 120 mg was assessed in the dose-expansion part. Based on safety, pharmacokinetics, and preliminary antitumor activity, 120 mg qd was selected as the recommended phase 2 dose. Here we present the phase 1/2 study data (phase 2 is ongoing).

Methods

Pts with measurable and nonmeasurable disease were included. Eligible women (any menopausal status) and men had received ≤4 lines of endocrine therapy (ET) and ≤1 line of chemotherapy for metastatic disease. Pts with stable brain metastasis had to have ≥1 prior line of ET and ≤3 prior lines of chemotherapy (both for metastatic disease). Tumor assessment (RECIST v1.1) occurred every 8 weeks (NCT04505826).

Results

By March 17, 2023, of 86 pts on OP-1250 (120 mg), 66% had ≥2 prior lines of ET, 30% prior chemotherapy, 67% prior fulvestrant, and 98% prior cyclin-dependent kinase 4/6 inhibitors (CDK4/6i); 45% (34/75) of pts with available baseline ctDNA had ESR1 mutations. The most common (≥15% of pts) all-grade treatment-emergent adverse events (AEs) were nausea, vomiting, neutropenia, fatigue, headache, constipation, and diarrhea. The most common grade 3/4 treatment-related AEs were neutropenia (9%), nausea (3%), and vomiting (3%). Neutropenia was reversible; 3 pts with grade 4 neutropenia were rechallenged at a lower dose without recurrence. There were 4 partial responses (3 confirmed) with a clinical benefit rate of 40% (23/57). In pts with an ESR1 mutation, CBR was 50% (11/22). D[NZ1] [NZ2] ata continue to mature and updated data will be presented.

Conclusions

OP-1250 (120 mg qd) was well tolerated with promising efficacy in heavily pretreated pts, including pts progressing on fulvestrant and CDK4/6i. A phase 3 monotherapy study in metastatic BC (second/third line) is planned in 2023.

Clinical trial identification

NCT04505826.

Editorial acknowledgement

Legal entity responsible for the study

Olema Pharmaceuticals, Inc.

Funding

Olema Pharmaceuticals, Inc.

Disclosure

N.U. Lin: Financial Interests, Personal, Advisory Board, Ad board participation: Seattle Genetics, Daiichi Sankyo, Prelude Therapeutics; Financial Interests, Personal, Advisory Board, Ad board/Steering Committee participation; consultant: AstraZeneca; Financial Interests, Personal, Other, Consultant: Denali Therapeutics, Blueprint Medicines, Janssen, Affinia Therapeutics; Financial Interests, Personal, Advisory Board, Ad board/Steering committee participation: Olema Pharmaceuticals; Financial Interests, Personal, Other, High level Consulting: Artera Inc.; Financial Interests, Personal, Other, Steering committee: Stemline/Menarini; Financial Interests, Personal, Other, Consulting: Voyager Therapeutics; Financial Interests, Personal, Royalties, Royalties for book chapter(s): Up to Date; Financial Interests, Institutional, Funding, Trial funding to institute (and steering committee): Olema Pharmaceuticals, AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Funding, Trial funding to institute: Zion Pharmaceuticals; Financial Interests, Institutional, Funding, trial funding to institute: Pfizer, Genentech. V.F. Borges: Financial Interests, Personal, Speaker, Consultant, Advisor: Seagen, AstraZeneca, Gilead; Financial Interests, Institutional, Principal Investigator: Olema Pharmaceuticals, AstraZeneca, Gilead. M.R. Patel: Financial Interests, Personal, Leadership Role: ION Pharma; Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen Onocology; Financial Interests, Personal, Advisory Board: Olema Pharmaceuticals; Financial Interests, Institutional, Research Funding: Acerta Pharma, ADC Therapeutics, Agenus, Aileron Therapeutics, AstraZeneca, BioNTech AG, Boehringer Ingelheim, Celgene, CicloMed, Clovis Oncology, Cyteir Therapeutics, Daiichi Sankyo, Lilly, Evelo Therapeutics, Genentech/Roche, Gilead Sciences, GSK, H3 Biomedicine, Hengrui Therapeutics, Hutchinson MediPharma, Jacobio, Janssen, Klus Pharma, Kymab, Loxo, LSK Biopartners, Lycera, Macrogenics, Merck, Millennium, Mirati Therapeutics, Moderna Therapeutics, Pfizer, Prelude Therapeutics, Ribon Therapeutics, Seven and Eight Biopharmaceuticals, Syndax, Taiho Pharmaceutical, Tesaro, TopAlliance BioSciences Inc, Vigeo, ORIC, Artios, Treadwell, Mabspace, IgM Biosciences, Puretech, BioTheryX, Black Diamond Therapeutics, IgM Biosciences, NGM Biopharmaceuticals, Novartis, nurix, PureTech, Relay Therapeutics, Samumed, Silicon Therapeutics, TeneoBio, Zymeworks, Olema Pharmaceuticals, Adagene, Astellas, Accutar Biotech, Compugen, Immunogen, Blueprint Pharmaceuticals, Bayer, Bicycle Therapeutics, Cullinan Oncology, Erasca, Inc, Immune-Onc Therapeutics, Immunitas, Jazz Pharmaceuticals, Pionyr, Revolution Medicines, Step Pharma, Syndax, Synthorx, Xencor. M. Okera: Financial Interests, Institutional, Local PI, Institution receives payment for research activities conducted as per the clinical trial agreements: Cancer Research SA. J. Meisel: Financial Interests, Personal, Advisory Board: Pfizer, Puma; Financial Interests, Institutional, Research Grant: Pfizer, Seattle Genetics, Eli Lilly. R. Wesolowski: Financial Interests, Personal, Invited Speaker, Gave an update about targeted therapies for breast cancer with focus on antibody drug conjugates at Precision Oncology Forum in Cincinnati, OH organized by the company on 3/11/23: Innovative Healthcare Institute; Non-Financial Interests, Principal Investigator, Site Principal Investigator: Olema, Dragonfly Therapeutics, Celcuity, Bayer, Oncorus, Treadwell Therapeutics; Non-Financial Interests, Advisory Role, Scientific Steering Committee: Celcuity; Non-Financial Interests, Advisory Role, Tucatinib Advisory Board: Seagen. T. Pluard: Financial Interests, Personal, Speaker, Consultant, Advisor: Pfizer, MacroGenics, Genentech, Seattle Genetics, Novartis, H3 Biomedicine, AstraZeneca/Daiichi Sankyo, Gilead Sciences; Financial Interests, Institutional, Research Funding: Seattle Genetics, Zymeworks, HiberCell, Pfizer, H3 Biosciences, DAEHWA Pharmaceutical, G1 Therapeutics, Olema Pharmaceuticals, Dantari, AstraZeneca/Daiichi Sankyo, Orinove, Sanofi. K.D. Miller: Financial Interests, Personal, Other, IDMC member: Celcuity, Roche, AstraZeneca, Merck and Company, Inc.; Financial Interests, Institutional, Coordinating PI, Clinical trial funding: Pfizer, Astex; Financial Interests, Institutional, Local PI, Clinical trial funding: Olema. N.J. McCarthy: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Pfizer, Novartis, Lilly. A.K. Conlin: Financial Interests, Personal, Advisory Board: SeaGen, AstraZeneca. R. Mahtani: Financial Interests, Personal, Other, Consultant: Agendia, Amgen, Biotheranostics, Daiichi Sankyo, Genentech, Immunomedics, Lilly, Merck, Novartis, Pfizer, Puma, Sanofi, SeaGen; Financial Interests, Personal, Advisory Board, Consultant and served on advisory boards: AstraZeneca; Financial Interests, Personal, Advisory Board, Consultant: Eisai, Stemline. K.E. McCann: Financial Interests, Personal, Other, Speaker's bureau for abemaciclib: Eli Lilly; Financial Interests, Institutional, Local PI, Phase I/Ib trial: Olema; Non-Financial Interests, Advisory Role, Strategic council: Puma Biotech. E. Roesch: Financial Interests, Personal, Writing Engagement, I provide monthly expert commentary on journal articles related to breast cancer.: MDedge Hematology & Oncology. G. Mathauda-Sahota: Financial Interests, Personal, Full or part-time Employment: Olema Pharmaceuticals. J. Schroeder: Financial Interests, Personal, Full or part-time Employment: Olema Pharmaceuticals. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, AstraZeneca, Daiichi Sankyo, SeaGen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science, Theratechnologies; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Inst, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, Abbvie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics All other authors have declared no conflicts of interest.