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)

E.C. Dees, P.G. Aftimos, C. W. Menke, E.G.E. De Vries, P Neven, M.D. Pegram, R Iqbal, J. Boers, J. Xiao, C. Sipes, C. Li, J.A. Sorrentino, R Malik, A.P. Beelen

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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.

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.

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).

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).
Original languageEnglish
JournalAnnals of Oncology
Issue numberSupplement 5
Publication statusPublished - 1 Oct 2019

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