Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial
José Baselga,Seock–Ah –A Im,Hiroji Iwata,Javier Cortes,Michele De Laurentiis,Zefei Jiang,Carlos L. Arteaga,Walter Jonat,Mark Clemons,Yoshinori Ito,Ahmad Awada,Stephen Chia,Agnieszka Jagiełło-Gruszfeld,Barbara Pistilli,Ling Ming Tseng,Sara A. Hurvitz,Norikazu Masuda,Masato Takahashi,Peter Vuylsteke,Soulef Hachemi,Bharani Dharan,Emmanuelle di Tomaso,Patrick Urban,Cristian Massacesi,Mario Campone +24 more
TLDR
This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit.Abstract:
Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit Methods The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent) Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 11) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients Efficacy analyses were done in the intention-to-treat population Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received This trial is registered with ClinicalTrialsgov, number NCT01610284, and is currently ongoing but not recruiting participants Findings Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571) In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67–0·89]; one-sided p=0·00021) In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 [95% CI 0·68–0·94]; one-sided p=0·0033) In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 [0·60–0·97], one-sided p=0·014) The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [ vs none) Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [ vs one [ Interpretation The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting No further studies are being pursued because of the toxicity associated with this combination Funding Novartis Pharmaceuticals Corporationread more
Citations
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Journal ArticleDOI
The PI3K pathway in human disease
David A. Fruman,Honyin Chiu,Benjamin D. Hopkins,Shubha Bagrodia,Lewis C. Cantley,Robert T. Abraham +5 more
TL;DR: A perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions is provided, two topics closely intertwined with cancer biology.
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Alpelisib for PIK3CA-Mutated, Hormone Receptor–Positive Advanced Breast Cancer
Fabrice Andre,Eva Ciruelos,G. Rubovszky,Mario Campone,Sibylle Loibl,Hope S. Rugo,H. Iwata,Pierfranco Conte,Ingrid A. Mayer,Bella Kaufman,Toshinari Yamashita,Yen-Shen Lu,Kenichi Inoue,Masato Takahashi,Zsuzsanna Papai,Anne-Sophie Longin,David Mills,Celine Wilke,Samit Hirawat,Dejan Juric +19 more
TL;DR: Treatment with alpelisib–fulvestrant prolonged progression‐free survival among patients with PIK3CA‐mutated, HR‐positive, HER2‐negative advanced breast cancer who had received endocrine therapy previously.
Journal ArticleDOI
Targeting PI3K in cancer: mechanisms and advances in clinical trials
TL;DR: A critical review is performed to summarize the role of the PI3K pathway in tumor development, recentPI3K inhibitors development based on clinical trials, and the mechanisms of resistance to PI3k inhibition.
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Targeting the PI3K pathway in cancer: are we making headway?
TL;DR: Considering that oncogenic activation of the PI3K–AKT–mTOR pathway often occurs alongside pro-tumorigenic aberrations in other signalling networks, rational combinations are also needed to optimize the effectiveness of treatment.
Journal ArticleDOI
Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review.
TL;DR: The development of drugs targeting the PI3K/AKT/mTOR pathway for the treatment of TNBC is an evolving field that should take into account the efficacies and toxicities of new agents in addition to their interactions with different cancer pathways.
References
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Proceedings ArticleDOI
Abstract S4-07: BELLE-3: A phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2–, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment
A Di Leo,K Seok Lee,Eva Ciruelos,Per Eystein Lønning,Wolfgang Janni,Ruth O'Regan,M-A Mouret Reynier,D Kalev,Daniel Egle,Tibor Csoszi,Roberto Bordonaro,Thomas Decker,Vivianne C. G. Tjan-Heijnen,Sibel Blau,A Schirone,D Weber,M El-Hashimy,Bharani Dharan,Dalila Sellami,Thomas Bachelot +19 more
TL;DR: The BELLE-3 study, a phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2–, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment, met its primary endpoint.
Journal ArticleDOI
Test and power considerations for multiple endpoint analyses using sequentially rejective graphical procedures
TL;DR: This paper gives a coherent description of the methodology and illustrates it with a real clinical trial example and discusses suitable power measures for clinical trials with multiple primary and/or secondary objectives.
Proceedings ArticleDOI
Abstract PD5-2: Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer
Cristina Saura,Jasgit C. Sachdev,Manish R. Patel,Andrés Cervantes,Dejan Juric,Jeffrey R. Infante,Donald A. Richards,Sandra Sanabria,Xuyang Lu,Joseph A. Ware,Timothy R. Wilson,Hema Parmar,Jerry Y. Hsu,Mafalda Oliveira,Eric P. Winer,Daniel D. Von Hoff,José Baselga,Ian E. Krop +17 more
TL;DR: The combination of taselisib and letrozole is a well-tolerated regimen with promising preliminary efficacy in PIK3CA MT breast cancer patients, and promising efficacy data has been observed in these heavily pretreated patients.
Proceedings ArticleDOI
Abstract PD5-5: Phase I study of the PI3Kα inhibitor BYL719 plus fulvestrant in patients withPIK3CA-altered and wild type ER+/HER2- locally advanced or metastatic breast cancer
Filip Janku,Dejan Juric,Javier Cortes,H Rugo,Howard A. Burris,Martin Schuler,Barbara Deschler-Baier,Mark R. Middleton,M. Gil-Martin,Jordan Berlin,Eric P. Winer,Douglas Bootle,Lars Blumenstein,David Demanse,Christina Coughlin,Cornelia Quadt,José Baselga +16 more
TL;DR: Byl719+ fulvestrant was shown to be more effective in patients with PIK3CA-altered tumors compared to those with wild-type (WT) tumors.
Journal ArticleDOI
451PDPHASE I STUDY OF THE PI3Kα INHIBITOR BYL719, AS A SINGLE AGENT IN PATIENTS WITH ADVANCED SOLID TUMORS (AST)
Dejan Juric,H. A. Burris,Martin Schuler,J.H.M. Schellens,Jordan Berlin,R. Seggewiß-Bernhardt,M. Gil-Martin,Avinash Gupta,Jordi Rodon,J. Tabernero,Filip Janku,Hope S. Rugo,Douglas Bootle,Cornelia Quadt,Christina Coughlin,David Demanse,Lars Blumenstein,J. Baselga +17 more
TL;DR: ByL719 is the first a isoform-specific PI3K inhibitor to show single-agent responses in tumors with activating mutations and the safety profile was favorable with mostly on-target effects.
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