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Clinical Trial
. 2020 Nov 2;22(1):120.
doi: 10.1186/s13058-020-01354-y.

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

Ana C Garrido-Castro  1 , Cristina Saura  2   3   4 , Romualdo Barroso-Sousa  1   5 , Hao Guo  6 , Eva Ciruelos  7 , Begoña Bermejo  8 , Joaquin Gavilá  9 , Violeta Serra  10 , Aleix Prat  11 , Laia Paré  4 , Pamela Céliz  4 , Patricia Villagrasa  4 , Yisheng Li  12 , Jennifer Savoie  1 , Zhan Xu  13 , Carlos L Arteaga  14 , Ian E Krop  1 , David B Solit  15 , Gordon B Mills  16   17 , Lewis C Cantley  18 , Eric P Winer  1 , Nancy U Lin  19 , Jordi Rodon  2   4   20
Affiliations
Clinical Trial

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

Ana C Garrido-Castro et al. Breast Cancer Res. .

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.

Keywords: BKM120; Buparlisib; PI3K pathway; Phase 1; Triple-negative breast cancer.

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Conflict of interest statement

C.S. reports the following personal financial interests: C.S. has served as consultant, participated in advisory boards or received travel grants from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann-La Roche Ltd., Genomic Health, Merck, Sharp and Dhome España SA, Novartis, Pfizer, Philips Healthwork, Pierre Fabre, prIME Oncology, Puma, Synthon, and Sanofi Aventis. C.S. reports the following institutional financial interests, paid directly to Institution: AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck, Sharp and Dhome España S.A., Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Synthon and Zenith Pharma.

R.B-S. has served as an advisor/consultant to Eli Lilly and Roche and has received honoraria from Eli Lilly, Roche, Bristol-Myers Squib, Novartis, Pfizer, and travel, accommodations, or expenses from Roche.

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.

D.B.S. has consulted with and received honoraria from Pfizer, Loxo Oncology, Lilly Oncology, Illumina, and Vivideon Therapuetics.

B.B. has participated in advisory boards for MSD, Mylan, Roche, and Novartis.

V.S. has received non-commercial support from Novartis.

C.A. serves or has served as an advisor to Novartis, Lilly, Sanofi, RADIUS, ABBVIE, TAIHO Oncology, PUMA Biotechnology, Merck, H3Biomedicine, Symphogen, OrigiMed, Immunomedics, Petra Pharma, G1 Therapeutics, Athenex, and Daiichi Sankyo. C.A. receives or has received research grant support from Pfizer, Lilly, RADIUS, Bayer, Takeda, PUMA Biotechnology, and Symphogen. C.A. holds stock options in Provista and Y-TRAP and serves in the Scientific Advisory Board of the Komen Foundation.

N.U.L. receives or has received research support paid directly to the Institution from Genentech, Pfizer, Merck, and Seattle Genetics. N.U.L. has served as a consultant or participated in advisory boards for Puma, Seattle Genetics, Daiichi Sankyo, Denali Therapeutics, and California Institute for Regenerative Medicine. N.U.L. has received travel expense reimbursement from Puma and Seattle Genetics.

All other authors declare no relevant conflicts of interest.

Figures

Fig. 1
Fig. 1
Kaplan-Meier curves for progression-free survival (a) and overall survival (b) in patients with metastatic, triple-negative breast cancer treated with buparlisib. Median PFS was 1.8 months (95% confidence interval [CI] 1.6–2.3) and median OS was 11.2 months (95% CI 6.2–25)
Fig. 2
Fig. 2
Co-mutation/CNV plot of tumor samples analyzed with targeted next-generation sequencing. Co-mutation and copy number variation plot for samples analyzed with MSK-IMPACT panel testing (n = 27 samples; n = 27 patients). Included here are genes related to PI3K pathway and drug resistance with at least one identified alteration in the cohort. Best overall response is displayed for each patient. Six samples harbored an alteration in PIK3CA (E542K mutation, n = 1), AKT1 (E17K mutation, n = 1; AKT1 amplification, n = 1), or PTEN (D24H mutation, n = 1; K237fs mutation, n = 1; PTEN deep deletion, n = 1). Alterations in PIK3CA, AKT1, or PTEN were observed in 3 of 8 patients (37.5%) who achieved SD, and in 2 of 9 (22.2%) patients with progressive disease as best overall response
Fig. 3
Fig. 3
Unsupervised clustering and PI3K signature score based on the RBN dataset. Heatmap depicting protein levels after unsupervised hierarchical clustering of 826 TCGA samples plus 6 baseline SU2C samples and 128 antibodies. Protein levels are indicated on a low-to-high scale (green-black-red). Annotation bars include the PAM50 intrinsic subtype classification. The PI3K score is shown in the lower panel. SU2C samples (black) are located in close proximity to triple-negative breast cancer samples from TCGA (red)
Fig. 4
Fig. 4
Unsupervised clustering based on the delta values of the paired samples. Heatmap depicting the delta values in the paired samples of the PI3K signature-related proteins ordered from upstream (top) to downstream (bottom). Protein levels are indicated on a low-to-high scale (green-black-red)
See this image and copyright information in PMC

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