Buparlisib is a brain penetrable pan-PI3K inhibitor

Gooijer, Mark C. de; Zhang, Ping; Buil, Levi C.M.; Çitirikkaya, Ceren H.; Thota, Nishita; Beijnen, Jos H.; Tellingen, Olaf van

doi:10.1038/s41598-018-29062-w

Cited by 60 publications

(47 citation statements)

References 47 publications

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“…Notably, any grade anxiety and any grade depression were reported in 18% of patients. Buparlisib is one of the PI3K inhibitors with highest blood-brain barrier penetration [ 23 ]. However, the physiopathology of mood disorders associated with pan-PI3K inhibitors has not been well characterized, and it remains unclear whether the higher incidence of neuropsychiatric effects observed with buparlisib compared to isoform-selective PI3K inhibitors is due to its elevated CNS penetration or to other pharmacokinetic differences.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…The preliminary results showed that the overall response rate in DLBCL was 12% [61] . Another study showed that buparlisib had excellent brain penetration regardless of the influence of the blood-brain barrier, complete oral bioavailability, and efficient intracranial target inhibition at clinically achievable plasma concentrations [62] . These studies provide information that will aid the development of targeted therapeutic strategies for PCNSL patients.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Genomic Alteration in Primary Central Nervous System Lymphoma and the Expression of Some Related Genes

Zhou

Liu

et al. 2018

Neoplasia

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Primary central nervous system lymphoma (PCNSL) is a rare and special type of non-Hodgkin lymphoma. The treatment of PCNSL is comprehensive, combining surgery, radiotherapy, and chemotherapy. However, the outcome is poor because of its high invasiveness and rate of recurrence. We analyzed 22 cases of PCNSL using next-generation sequencing (NGS) to detect 64 candidate genes. We used immunohistochemical methods to analyze gene expression in 57 PCNSL samples. NGS showed that recurrent mutations in KMT2D and CD79B, components of the NF-κB pathway, accounted for 65% of total mutations in PCNSL samples. The most frequent mutated gene was PIM1 (77.27%, 17/22), followed by MYD88 (63.64%, 14/22), CD79B (69.09%, 13/22), and KMT2D (50.00%, 11/22). Mutations of the CD79B gene were associated with an inferior progression-free survival (PFS), and GNA13 gene mutations were associated with a shorter PFS and overall survival (OS) in PCNSL patients (P < .05). PIM1 and MYD88 were highly expressed in PCNSL patients and were related to their OS time. MYD88 overexpression might be an independent and poor prognostic predictor of OS time. In summary, we identified highly recurrent genetic lesions in CD79B and KMT2D, components of the NF-κB pathway, in PCNSL and validated the expression of PIM1 and MYD88 related to poor survival, thereby providing novel insights into the pathogenesis and precision medicine of PCNSL.

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“…19 Buparlisib has also been shown to cross the blood-brain barrier, accumulate in the brain tissue of non-tumour-bearing rats, and efficiently downregulate tissue phospho-S6 and phospho-AKT. 20 Buparlisib has also shown preclinical efficacy in various PI3K pathway-hyperactivated cancer models, including GBM. [21][22][23][24] Here, we report the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of buparlisib in combination with carboplatin or lomustine and the safety and preliminary antitumour activity of these combinations in patients with rGBM.…”

Section: Key Questionsmentioning

confidence: 99%

“… 19 Buparlisib has also been shown to cross the blood–brain barrier, accumulate in the brain tissue of non-tumour-bearing rats, and efficiently downregulate tissue phospho-S6 and phospho-AKT. 20 Buparlisib has also shown preclinical efficacy in various PI3K pathway-hyperactivated cancer models, including GBM. 21–24 …”

Section: Introductionmentioning

confidence: 99%

Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study

Rosenthal

Clément²,

Campone

et al. 2020

ESMO Open

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BackgroundGlioblastoma relapse is associated with activation of phosphatidylinositol 3-kinase (PI3K) signalling pathway. In preclinical studies, the pan-PI3K inhibitor buparlisib showed antitumour activity in glioma models.MethodsThis was a two-part, multicentre, phase Ib/II study in patients with recurrent glioblastoma pretreated with radiotherapy and temozolomide standard of care. Patients received buparlisib (80 mg or 100 mg once daily) plus carboplatin (area under the curve (AUC)=5 every 3 weeks), or buparlisib (60 mg once daily) plus lomustine (100 mg/m2 every 6 weeks). The primary endpoint was to determine the maximum tolerable dose (MTD) and/or recommended phase II dose of buparlisib plus carboplatin or lomustine.ResultsBetween 28 February 2014 and 7 July 2016, 35 patients were enrolled and treated with buparlisib plus carboplatin (n=17; buparlisib (80 mg) plus carboplatin, n=3; and buparlisib (100 mg) plus carboplatin, n=14), or buparlisib (60 mg) plus lomustine (n=18). The MTD of buparlisib was determined to be 100 mg per day in combination with carboplatin at an AUC of 5 every 3 weeks. The MTD of buparlisib in combination with lomustine could not be determined as it did not satisfy the MTD criteria per the Bayesian logistic regression model.ConclusionThe overall safety profile of buparlisib remained unchanged, and no new or unexpected safety findings were reported in this study. Preliminary assessment for both combinations did not demonstrate sufficient antitumour activity compared with historical data on single-agent carboplatin or lomustine.Trial registration numberNCT01934361.

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Buparlisib is a brain penetrable pan-PI3K inhibitor

Cited by 60 publications

References 47 publications

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

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

Analysis of Genomic Alteration in Primary Central Nervous System Lymphoma and the Expression of Some Related Genes

Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study

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