TY - JOUR
T1 - A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor–positive/ HER2-negative Advanced or Metastatic Breast Cancer
AU - Cescon, David W.
AU - Hilton, John
AU - Murilo, Serafin Morales
AU - Layman, Rachel M.
AU - Pluard, Timothy
AU - Yeo, Belinda
AU - Park, In Hae
AU - Provencher, Louise
AU - Kim, Sung Bae
AU - Im, Young Hyuck
AU - Wyce, Anastasia
AU - Krishnatry, Anu Shilpa
AU - Hicks, Kirsty
AU - Zhang, Qu
AU - Barbash, Olena
AU - Khaled, Ahmed
AU - Horner, Thierry
AU - Dhar, Arindam
AU - Oliveira, Mafalda
AU - Sparano, Joseph A.
N1 - Publisher Copyright:
© 2023 The Authors; Published by the American Association for Cancer Research.
PY - 2024/1/15
Y1 - 2024/1/15
N2 - aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor. Results: The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (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 enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73–4.83; P < 0.0001). Conclusions: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study. Purpose: Endocrine-based therapy is the initial primary treatment option for hormone receptor–positive and human epidermal growth factor receptor 2-negative (HRþ/HER2-) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical 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 [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HRþ/HER2- mBC. Patients and Methods: In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant.
AB - aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor. Results: The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (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 enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73–4.83; P < 0.0001). Conclusions: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study. Purpose: Endocrine-based therapy is the initial primary treatment option for hormone receptor–positive and human epidermal growth factor receptor 2-negative (HRþ/HER2-) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical 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 [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HRþ/HER2- mBC. Patients and Methods: In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant.
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U2 - 10.1158/1078-0432.CCR-23-0133
DO - 10.1158/1078-0432.CCR-23-0133
M3 - Article
C2 - 37992310
AN - SCOPUS:85182740506
SN - 1078-0432
VL - 30
SP - 334
EP - 343
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -