Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial

Abstract

Purpose: Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.

Methods: This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.

Results: Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKT^S473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6^S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]).

Conclusion: Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

Trial registration: ClinicalTrials.gov NCT01339052.

FIG 1.

Study flow. PD, pharmacodynamics; PFS6, 6-month progression free survival; PK, pharmacokinetics.

FIG 2.

Buparlisib pharmacokinetics and phosphatidylinositol 3-kinase pathway modulation as a result of buparlisib in tumor tissue in cohort 1. (A) Box plots of buparlisib concentration in non–contrast-enhancing (NCE) and contrast-enhancing (CE) tumor tissue assessed by liquid chromatography-tandem mass spectrometry. Difference between groups was calculated using the Mann-Whitney U test. (B) Histopathologic and matrix-assisted laser desorption/ionization-mass spectrometry imaging drug analysis on stereotactically registered specimens collected from a patient in cohort 1 treated with buparlisib. Image on the left demonstrates location of buparlisib (green) and vessels as measured by heme (red). Hematoxylin and eosin (HE) staining of the corresponding tissue. Outlined area delineates tumor and adjacent infiltrated brain parenchyma. (C) Representative microscopy images of the HE staining and PTEN, phosphorylated AKT (pAKT), and phosphorylated S6 (pS6) in tumor samples collected at baseline and on buparlisib treatment from a patient in cohort 1. (D) Quantification of pAKT immunohistochemistry (IHC) staining intensity in the surgical cohort. Data are mean ± SEM (n = 5 to 7 replicates for each sample). (E) Box plots of mean pAKT IHC staining intensity in the archival and resected tissues from the surgical cohort (n = 14). Difference between groups was calculated using the Wilcoxon test (See Appendix).

FIG 3.

Relationship between mutations in phosphatidylinositol 3-kinase (PI3K) pathway members and response to buparlisib. Patient outcomes, including best overall response (BOR), median progression-free survival (PFS), and median overall survival (OS), are shown in the top rows; tumor genotyping and immunohistochemistry (IHC) results are shown in the middle rows; and integrative biomarker analysis for PI3K/PTEN signaling is shown in the bottom rows. Missense mutations are displayed in green, amplifications in orange, and deletions in blue. All mutations were reviewed by a molecular diagnostician to confirm that they were deemed pathogenic/hotspot mutations and were not commonly identified in normal databases as germline single nucleotide polymorphisms.

FIG A1.

Treatment schema. CR, complete response; GBM, glioblastoma; IHC, immunohistochemistry; MRI, magnetic resonance imaging; pAKT, phosphorylated AKT; PD, progressive disease; PI3K, phosphatidylinositol 3-kinase; PR, partial response; SD, stable disease.

FIG A2.

Phosphatidylinositol 3-kinase pathway modulation as a result of buparlisib in tumor tissue in the control cohort. Quantification of (A and B) phosphorylated AKT^S473 (pAKT^S473) and (C and D) phosphorylated S6 S235/236 (pS6_S235/236) immunohistochemistry staining in the surgical cohort. The control cohort consisted of seven patients treated with standard of care for whom surgical resection of tumor tissue was performed at initial diagnosis and recurrence. (B and D) Differences between groups were calculated using the paired Wilcoxon test.

FIG A3.

Phosphatidylinositol 3-kinase pathway modulation and changes in tumor cell proliferation as a result of buparlisib in tumor tissue in cohort 1. (A and B) Quantification of phosphorylated S6 S235/236 (pS6_S235/236) immunohistochemistry staining and (C and D) tumor cell proliferation as assessed by the IHC proliferation marker Ki-67 in the surgical cohort. (B and D) Differences between groups were calculated using the paired Wilcoxon test.

FIG A4.

Kaplan-Meier curves of (A) overall survival (OS) and (B) progression-free survival (PFS) in cohorts 1 and 2. IQR, interquartile range.

FIG A5.

Kaplan-Meier curves of overall survival (OS) and progression-free survival (PFS) by (A and B) IDH1/2 status, (C and D) PIK3CA/PIK3R1 status, and (E and F) PFS by PTEN status. Differences between groups were evaluated using the log-rank test. IQR, interquartile range.