Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/34332
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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/34332
DOI: 10.1158/1078-0432.CCR-23-0133
ORCID: 0000-0002-1080-0998
0000-0002-6280-8633
0000-0001-7445-4193
0000-0002-8663-0331
0000-0002-3640-3077
0000-0002-9218-9917
0000-0001-7894-8772
0009-0001-3463-8649
0000-0001-5588-8332
0000-0001-6459-8118
0000-0003-2294-3096
0000-0002-8768-9896
0009-0005-4966-7388
0000-0001-5220-2665
0000-0001-7144-5603
0000-0003-2233-3394
0000-0002-8248-6993
0000-0002-7929-0877
0000-0001-9152-8799
0000-0002-9031-2010
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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