Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+/HER2-locally advanced or metastatic breast cancer (ABC)

Abstract Background The SERD fulvestrant is a well-established therapy for ER+/HER2- ABC. However, its intramuscular route of administration may be painful and limits systemic exposure. G1T48 is a highly potent and efficacious oral SERD in both mutant and WT ESR1 preclinical models with the potential to achieve higher exposure and provide clinical benefit in patients with ER+ ABC. Methods Postmenopausal women with ER+/HER2- ABC following progression on endocrine therapy are eligible for this 3 + 3 dose escalation and expansion study. Patients receive G1T48 QD until disease progression or unacceptable toxicity. The objectives are to evaluate DLTs, safety, tolerability, PK, ER target engagement via [18F] FES-PET, and anti-tumor efficacy, and to determine the recommended phase 2 dose. Results Currently, 11 patients (mean age 64 years) have received G1T48 doses ranging from 200-800 mg QD for up to 7 months. Prior lines (median of 3) included chemotherapy in 45%, fulvestrant in 91%, and CDK4/6i in 54% of patients. G1T48 is well tolerated: no DLTs, G1T48-related SAEs, or withdrawals due to an AE have occurred. The most common Gr 1/2 G1T48-related TEAEs are diarrhea, headache, hot flush, and nausea (27% each) with a single Gr 3 TEAE (fatigue) and no Gr 4 TEAEs. G1T48 exposure increased with dose (200 to 800 mg), and minimum to moderate accumulation of G1T48 was observed following repeated doses. Median maximum standard tumor [18F] FES-PET uptake values decreased (ranging from 70% (200 mg) to 88% (600 mg)) after 4 weeks of treatment. Of 6 response evaluable patients (RECIST v1.1), 1 patient had a PR (600 mg, prior palbociclib/fulvestrant) and 1 patient had SD ≥ 24 weeks (200 mg, prior abemaciclib/fulvestrant). Conclusions The oral SERD G1T48 is well tolerated with no DLTs reported to date in patients with ER+/HER2- ABC. Early efficacy, safety, PK, and FES-PET data are encouraging, and support continued dose escalation followed by expansion. Updated safety, anti-tumor activity, and cfDNA data will be presented (NCT#03455270). Clinical trial identification NCT03455270. Legal entity responsible for the study G1 Therapeutics, Inc. Funding G1 Therapeutics. Disclosure E.C. Dees: Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): H3Biosciences; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Cerulean; Research grant / Funding (institution): Meryx; Advisory / Consultancy, Research grant / Funding (institution): Novartis. P.G. Aftimos: Advisory / Consultancy: Boehringer Ingleheim; Advisory / Consultancy: Macrogenics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Amcure; Honoraria (self), Research grant / Funding (institution): Synthon; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Radius; Research grant / Funding (institution): Servier. C.W. Menke-van der Houven van Oordt: Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy: Novartis. E.G..E. De Vries: Research grant / Funding (institution): G1 Therapeutics; Advisory / Consultancy: NSABP; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): CytomX Therapeutics; Research grant / Funding (institution): Nordic Nanovector; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Synthon. M.D. Pegram: Advisory / Consultancy: G1 Therapeutics. J. Xiao: Full / Part-time employment: G1 Therapeutics. C. Sipes: Full / Part-time employment: G1 Therapeutics. C. Li: Full / Part-time employment: G1 Therapeutics. J.A. Sorrentino: Full / Part-time employment: G1 Therapeutics. R. Malik: Full / Part-time employment: G1 Therapeutics. A.P. Beelen: Full / Part-time employment: G1 Therapeutics. All other authors have declared no conflicts of interest.