A Phase I/II Study of GSK525762 Combined With Fulvestrant in Patients With Hormone Receptor-Positive/HER2-Negative (HR+/HER2-) Advanced or Metastatic Breast Cancer.

Abstract

Endocrine-based therapy is the initial primary treatment option for HR+/HER2- mBC. However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of BET family proteins (BRD2, BRD3, BRD4, and BRDT). Pre-clinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy (ORR) of molibresib combined with fulvestrant in women with HR+/HER2- mBC. In this phase I/II dose-escalation and expansion study, patients received oral molibresib 60 mg or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2- BC with disease progression on prior treatment with an aromatase inhibitor, with or without a CDK4/6 inhibitor. The study included 123 patients. The most common treatment-related AEs were nausea (52%), dysgeusia (49%), and fatigue (45%). At molibresib 60 mg, >90% patients experienced treatment-related AEs. Grade 3 or 4 treatment-related AEs were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% (95% CI, 8-20), not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrolment, a strong association was observed between the detection of copy number amplification and poor progression-free survival (hazard ratio, 2.89; 95% CI, 1.73-4.83; P < 0.0001). Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.