Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study

Vuylsteke, Peter; Huizing, Manon; Petráková, Katarína; Roylance, Rebecca; Laing, Robert; Chan, Stephen; Abell, F.; Gendreau, Steven; Rooney, Isabelle; Apt, Doris; Zhou, Jing; Singel, Stina Mui; Fehrenbacher, Louis

doi:10.1093/annonc/mdw320

Cited by 91 publications

(76 citation statements)

References 15 publications

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“…could dominate the negative clinical outcome. This seems currently to be in agreement with the phase II PEGGY-study in HER2 − patients, where paclitaxel was combined with the non-brain penetrable pan-PI3K inhibitor pictilisib (GDC-0941) or placebo, and also did not reveal a significant benefit of the combinatorial treatment22. The active molecules in the BELLE-4 and PEGGY-study are, however, structurally unrelated and have different physico-chemical properties.…”

Section: Discussionsupporting

confidence: 77%

Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

et al. 2017

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BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K. Crystal structures of BKM120 and derivatives in complex with tubulin and PI3K provide insights into the selective mode of action of this class of drugs. Our results raise concerns over BKM120's generally accepted mode of action, and provide a unique mechanistic basis for next-generation PI3K inhibitors with improved safety profiles and flexibility for use in combination therapies.

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Section: Discussionsupporting

confidence: 77%

Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

et al. 2017

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“…Addition of pictilisib to anastrozole in patients with ER-positive, HER2-negative early breast cancer in the OPPORTUNE study significantly decreased tumor cell proliferation [32]. The randomized phase II PEGGY trial (NCT01740336) did not show any benefit from the addition of pictilisib to paclitaxel in patients with hormone receptor-positive, HER2-negative locally recurrent or metastatic breast cancer [33]. Moreover, a randomized phase II trial (FERGI; NCT01437566) in patients with ER-positive, HER2-negative, endocrine-resistant breast cancer found that the addition of pictilisib to fulvestrant did not significantly improve PFS [34].…”

Section: Discussionmentioning

confidence: 99%

“…Although the phase III BELLE-2 study (NCT01610284) reported modest improvements in median PFS (1.9 months) in patients with hormone receptor-positive metastatic breast cancer treated with the pan-PI3K inhibitor buparlisib (BKM120) in combination with fulvestrant (versus placebo plus fulvestrant) [35], combining a PI3K inhibitor with different therapies is challenging. In both the PEGGY and FERGI studies, efficacy was likely limited by the higher incidence of AEs and dose reductions/discontinuations owing to AEs with pictilisib treatment [33, 34]. As a result, further development of pictilisib by the sponsor is not planned.…”

Section: Discussionmentioning

confidence: 99%

A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer

et al. 2018

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BackgroundThis phase Ib study (NCT00960960) evaluated pictilisib (GDC-0941; pan-phosphatidylinositol 3-kinase inhibitor) plus paclitaxel, with and without bevacizumab or trastuzumab, or in combination with letrozole, in patients with locally recurrent or metastatic breast cancer.MethodsThis was a three-part multischedule study. Patients in parts 1 and 2, which comprised 3 + 3 dose escalation and cohort expansion stages, received pictilisib (60–330 mg) plus paclitaxel (90 mg/m2) with and without bevacizumab (10 mg/kg) or trastuzumab (2–4 mg/kg). In part 3, patients received pictilisib (260 mg) plus letrozole (2.5 mg). Primary objectives were evaluation of safety and tolerability, identification of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of pictilisib, and recommendation of a phase II dosing regimen. Secondary endpoints included pharmacokinetics and preliminary antitumor activity.ResultsSixty-nine patients were enrolled; all experienced at least one adverse event (AE). Grade ≥ 3 AEs, serious AEs, and AEs leading to death were reported in 50 (72.5%), 21 (30.4%), and 2 (2.9%) patients, respectively. Six (8.7%) patients reported a DLT, and the MTD and recommended phase II pictilisib doses were established where possible. There was no pictilisib–paclitaxel drug–drug interaction. Two (3.4%) patients experienced complete responses, and 17 (29.3%) patients had partial responses.ConclusionsCombining pictilisib with paclitaxel, with and without bevacizumab or trastuzumab, or letrozole, had a manageable safety profile in patients with locally recurrent or metastatic breast cancer. The combination had antitumor activity, and the additive effect of pictilisib supported further investigation in a randomized study.Trial registrationClinicalTrials.gov, NCT00960960. Registered on August 13, 2009.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1015-x) contains supplementary material, which is available to authorized users.

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“…Pictilisib binds to the ATP-binding pocket of PI3K p110, prevents activation of PI3K and formation of PIP3, and phosphorylation of downstream targets such as AKT (14,15). Pictilisib is now in advanced stages of clinical trials (16–18). In a phase I, open-label dose-escalation clinical trial of patients with advanced solid tumors, pictilisib was found to have anti-tumor activity, on-target pharmacodynamics activity, and an acceptable safety profile at doses of ≥100 mg. Additionally, pictilisib was well tolerated at doses up to 330 mg with mild to moderate adverse effects and no treatment related deaths (16).…”

Section: Introductionmentioning

confidence: 99%

The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

Zeng

Zhu

Hong

et al. 2017

Clinical Cancer Research

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Purpose Activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action and resistant mechanisms of drugs targeting the PI3K pathway. Experimental Design Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine. Potential predictive biomarkers for pictilisib were evaluated and RNA-sequencing was performed to explore drug resistance mechanisms. Results The bladder cancer cell line TCCSUP, which harbors a PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild type PIK3CA. Pictilisib exhibited stronger anti-tumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, significantly delayed tumor growth and prolonged survival compared with single drug treatment in the PDX models. The phosphorylation of ribosomal protein S6 correlated with response to pictilisib both in vitro and in vivo, and could potentially serve as biomarker to predict response to pictilisib. Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance. Conclusion These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer.

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Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study

Cited by 91 publications

References 15 publications

Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer

The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

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