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Title: 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.
Austin Authors: Cescon, David W;Hilton, John;Morales Murilo, Serafín;Layman, Rachel M;Pluard, Timothy;Yeo, Belinda ;Park, In Hae;Provencher, Louise;Kim, Sung-Bae;Im, Young-Hyuck;Wyce, Anastasia;Krishnatry, Anu Shilpa;Hicks, Kirsty;Zhang, Qu;Barbash, Olena;Khaled, Ahmed;Horner, Thierry;Dhar, Arindam;Oliveira, Mafalda;Sparano, Joseph A
Affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
University of Ottawa, Ottawa, ON, Canada.
Hospital Universitàri Arnau de Vilanova, Lleida, Spain.
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
Saint Luke's Cancer Institute, Kansas City, MO, United States.
Olivia Newton-John Cancer Research Institute
Korea university Guro hospital, Seoul, Korea (South), Republic of.
CHU de Québec-Laval University, Québec City, Québec, Canada.
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (South), Republic of.
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (South), Republic of.
GlaxoSmithKline (United States), Collegeville, PA, United States.
GlaxoSmithKline (United States), United States.
GlaxoSmithKline (United States), Collegeville, Pennsylvania, United States.
GlaxoSmithKline (United States), Collegeville, United States.
GlaxoSmithKline, Collegeville, United States.
GlaxoSmithKline (United States), Collegeville, PA, United States.
Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Barcelona, Spain.
Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Issue Date: 17-Jan-2024
Date: 2023
Publication information: Clinical Cancer Research: an Official Journal of the American Association for Cancer Research 2024-01-17; 30(2)
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.
DOI: 10.1158/1078-0432.CCR-23-0133
ORCID: 0000-0002-1080-0998
Journal: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
PubMed URL: 37992310
ISSN: 1557-3265
Type: Journal Article
Appears in Collections:Journal articles

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