1. Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer
- Author
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Yisheng Li, Violeta Serra, Lewis C. Cantley, Begoña Bermejo, Ana C. Garrido-Castro, Gordon B. Mills, Patricia Villagrasa, Ian E. Krop, Nan Lin, Zhan Xu, Aleix Prat, Cristina Saura, Hao Guo, Eva Ciruelos, Romualdo Barroso-Sousa, Carlos L. Arteaga, David B. Solit, Laia Paré, Eric P. Winer, Joaquín Gavilá, Jennifer Savoie, Pamela Céliz, Jordi Rodon, Institut Català de la Salut, [Garrido-Castro AC] Department of Medical Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA. [Saura C] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. SOLTI Breast Cancer Research Group, Barcelona, Spain. [Barroso-Sousa R] Department of Medical Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA. Hospital Sírio-Libanês, Brasilia, Brazil. [Guo H] Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA. [Ciruelos E] Hospital 12 de Octubre, Madrid, Spain. [Bermejo B] Clinic University Hospital, INCLIVA Biomedical Research Institute, CIBERONC-ISCIII, Valencia, Spain. [Serra V] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Rodon J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. SOLTI Breast Cancer Research Group, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
Oncology ,Proteomics ,Buparlisib ,Phases of clinical research ,Aminopyridines ,Medicaments antineoplàstics - Ús terapèutic ,Triple Negative Breast Neoplasms ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,chemistry.chemical_compound ,0302 clinical medicine ,Mama - Càncer ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Medicine ,Neoplasm Metastasis ,Triple-negative breast cancer ,0303 health sciences ,Neoplasms::Neoplastic Processes::Neoplasm Metastasis [DISEASES] ,High-Throughput Nucleotide Sequencing ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Metastatic breast cancer ,Survival Rate ,Treatment Outcome ,030220 oncology & carcinogenesis ,Neoplasms::Neoplasms by Site::Breast Neoplasms::Triple Negative Breast Neoplasms [DISEASES] ,Disease Progression ,Female ,Patient Safety ,Research Article ,Adult ,medicine.medical_specialty ,Class I Phosphatidylinositol 3-Kinases ,Morpholines ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Phase 1 ,lcsh:RC254-282 ,03 medical and health sciences ,Breast cancer ,Metàstasi ,Internal medicine ,Humans ,Adverse effect ,Protein Kinase Inhibitors ,Response Evaluation Criteria in Solid Tumors ,030304 developmental biology ,Aged ,business.industry ,medicine.disease ,BKM120 ,neoplasias::neoplasias por localización::neoplasias de la mama::neoplasias de mama triple negativos [ENFERMEDADES] ,PI3K pathway ,chemistry ,neoplasias::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES] ,business ,Progressive disease - Abstract
BackgroundTreatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss ofPTENand/orINPP4Bis 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 inPIK3CA/AKT1/PTENwere 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.
- Published
- 2020