Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer

Breast Cancer Research

Begoña Bermejo¹  Yisheng Li²  Ana C. Garrido-Castro³  Ian E. Krop³  Eric P. Winer³  Jennifer Savoie³  Nancy U. Lin³  Romualdo Barroso-Sousa⁴  Aleix Prat⁵  Jordi Rodon⁶  Cristina Saura⁷  Hao Guo⁸  Violeta Serra⁹  Joaquin Gavilá^1,10  Carlos L. Arteaga^1,11  Eva Ciruelos^1,12  Gordon B. Mills^1,13  David B. Solit^1,14  Patricia Villagrasa^1,15  Laia Paré^1,15  Pamela Céliz^1,15  Lewis C. Cantley^1,16  Zhan Xu^1,17 

[1] Clinic University Hospital, INCLIVA Biomedical Research Institute, CIBERONC-ISCIII, Valencia, Spain;Department of Biostatistics, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Medical Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, 02215, Boston, MA, USA;Department of Medical Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, 02215, Boston, MA, USA;Present Address: Hospital Sírio-Libanês, Brasilia, Brazil;Department of Medical Oncology, Translational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS, Hospital Clínic of Barcelona, Barcelona, Spain;Department of Medical Oncology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain;SOLTI Breast Cancer Research Group, Barcelona, Spain;Present Address: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Medical Oncology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain;Vall d’Hebron Institute of Oncology, VHIO, Barcelona, Spain;SOLTI Breast Cancer Research Group, Barcelona, Spain;Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA;Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain;Fundación Instituto Valenciano De Oncología, Valencia, Spain;Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA;Hospital 12 de Octubre, Madrid, Spain;Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA;Present Address: Division of Basic Science Research, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA;SOLTI Breast Cancer Research Group, Barcelona, Spain;Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, NY, USA;School of Communication, Northern Arizona University, Flagstaff, AZ, USA;

关键词: Buparlisib;    BKM120;    Triple-negative breast cancer;    PI3K pathway;    Phase 1;   

DOI  :  10.1186/s13058-020-01354-y

来源: Springer

【 摘 要 】

BackgroundTreatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer.MethodsThis was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies.ResultsFifty patients were enrolled. Median number of cycles was 2 (range 1–10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6–2.3). Median OS was 11.2 months (95% CI 6.2–25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease.ConclusionsBuparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer.Trial registrationNCT01790932. Registered on 13 February 2013; NCT01629615. Registered on 27 June 2012.

【 授权许可】

CC BY