TY - JOUR
T1 - Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer
AU - Garrido-Castro, Ana C.
AU - Saura, Cristina
AU - Barroso-Sousa, Romualdo
AU - Guo, Hao
AU - Ciruelos, Eva
AU - Bermejo, Begoña
AU - Gavilá, Joaquin
AU - Serra, Violeta
AU - Prat, Aleix
AU - Paré, Laia
AU - Céliz, Pamela
AU - Villagrasa, Patricia
AU - Li, Yisheng
AU - Savoie, Jennifer
AU - Xu, Zhan
AU - Arteaga, Carlos L.
AU - Krop, Ian E.
AU - Solit, David B.
AU - Mills, Gordon B.
AU - Cantley, Lewis C.
AU - Winer, Eric P.
AU - Lin, Nancy U.
AU - Rodon, Jordi
N1 - Funding Information:
This work was supported by NIH grants Breast SPORE P50 CA1P50CA168504 (PI: E.P.W.), R35 CA197588 (PI: L.C.C.), U54 U54CA210184 (PI: L.C.C.), the Gray Foundation (PI: L.C.C.), the Breast Cancer Research Foundation (PI: L.C.C.), Program of the Entertainment Industry Foundation (SU2C-AACR-DT0209; PI: L.C.C.), and Novartis Pharmaceuticals, Inc. The funding sources for the study were not involved in the collection, analysis, or interpretation of the data. Novartis was provided a draft of the manuscript prior to publication; however, they were not involved in the writing of the report or in the decision to submit the paper for publication. N.U.L. and J.R. had full access to all the data in the study and had final responsibility for the decision to submit for publication. Acknowledgements
Funding Information:
L.C.C. is a founder and member of the SAB and holds equity in Agios Pharmaceuticals and Petra Pharmaceuticals, companies developing drugs for treating cancer. The laboratory of L.C.C also receives funding from Petra.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - BKM120
KW - Buparlisib
KW - PI3K pathway
KW - Phase 1
KW - Triple-negative breast cancer
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U2 - 10.1186/s13058-020-01354-y
DO - 10.1186/s13058-020-01354-y
M3 - Article
C2 - 33138866
AN - SCOPUS:85094899381
SN - 1465-5411
VL - 22
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 120
ER -