A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor–positive/HER2-negative Advanced or Metastatic Breast Cancer

Author:

Cescon David W.1ORCID,Hilton John2ORCID,Morales Murilo Serafin3ORCID,Layman Rachel M.4ORCID,Pluard Timothy5ORCID,Yeo Belinda6ORCID,Park In Hae78ORCID,Provencher Louise9ORCID,Kim Sung-Bae10ORCID,Im Young-Hyuck11ORCID,Wyce Anastasia12ORCID,Krishnatry Anu Shilpa12ORCID,Hicks Kirsty12ORCID,Zhang Qu12ORCID,Barbash Olena12ORCID,Khaled Ahmed12ORCID,Horner Thierry12ORCID,Dhar Arindam12ORCID,Oliveira Mafalda13ORCID,Sparano Joseph A.14ORCID

Affiliation:

1. 1Princess Margaret Cancer Center, University Health Network and University of Toronto, Toronto, Ontario, Canada.

2. 2Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada.

3. 3Lleida Biomedical Research Institute, Lleida, Spain.

4. 4MD Anderson Cancer Center, Houston, Texas.

5. 5Saint Luke's Cancer Institute, Kansas City, Missouri.

6. 6Olivia Newton-John Cancer Research and Wellness Centre and Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia.

7. 7National Cancer Center, Goyang, Republic of South Korea.

8. 8Korea University Guro Hospital, Seoul, Republic of South Korea.

9. 9CHU de Québec-Laval University, Québec City, Québec, Canada.

10. 10Asan Medical Center, Seoul, Republic of South Korea.

11. 11Samsung Medical Center, Seoul, Republic of South Korea.

12. 12GSK, Collegeville, Pennsylvania.

13. 13Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

14. 14Icahn School of Medicine, Tisch Cancer Institute, New York, New York (formerly Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York).

Abstract

Abstract Purpose: Endocrine-based therapy is the initial primary treatment option for hormone receptor–positive and human epidermal growth factor receptor 2-negative (HR+/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 HR+/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. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2− breast cancer with disease progression on prior treatment with an 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.

Funder

N/A

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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