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)
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)
Annals of Oncology