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Breast Cancer Research
Published in: Breast Cancer Research 1/2020

Open Access 01-12-2020 | Breast Cancer | Research article

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

Authors: Ana C. Garrido-Castro, Cristina Saura, Romualdo Barroso-Sousa, Hao Guo, Eva Ciruelos, Begoña Bermejo, Joaquin Gavilá, Violeta Serra, Aleix Prat, Laia Paré, Pamela Céliz, Patricia Villagrasa, Yisheng Li, Jennifer Savoie, Zhan Xu, Carlos L. Arteaga, Ian E. Krop, David B. Solit, Gordon B. Mills, Lewis C. Cantley, Eric P. Winer, Nancy U. Lin, Jordi Rodon

Published in: Breast Cancer Research | Issue 1/2020

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Abstract

Background

Treatment 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.

Methods

This 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.

Results

Fifty 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.

Conclusions

Buparlisib 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 registration

NCT01790932. Registered on 13 February 2013; NCT01629615. Registered on 27 June 2012.
Appendix
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Metadata
Title
Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer
Authors
Ana C. Garrido-Castro
Cristina Saura
Romualdo Barroso-Sousa
Hao Guo
Eva Ciruelos
Begoña Bermejo
Joaquin Gavilá
Violeta Serra
Aleix Prat
Laia Paré
Pamela Céliz
Patricia Villagrasa
Yisheng Li
Jennifer Savoie
Zhan Xu
Carlos L. Arteaga
Ian E. Krop
David B. Solit
Gordon B. Mills
Lewis C. Cantley
Eric P. Winer
Nancy U. Lin
Jordi Rodon
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-020-01354-y

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