BACKGROUND: Inhibition of phosphatidylinositol 3-kinase (PI3K) is a promising approach to overcome resistance to endocrine therapy in breast cancer. Pictilisib is an oral inhibitor of multiple PI3K isoforms. The aim of this study is to establish if addition of pictilisib to fulvestrant can improve progression-free survival in oestrogen receptor-positive, endocrine-resistant breast cancer. METHODS: In this two-part, randomised, double-blind, placebo-controlled, phase 2 study, we recruited postmenopausal women aged 18 years or older with oestrogen receptor-positive, HER2-negative breast cancer resistant to treatment with an aromatase inhibitor in the adjuvant or metastatic setting, from 123 medical centres across 21 countries. Part 1 included patients with or without PIK3CA mutations, whereas part 2 included only patients with PIK3CA mutations. Patients were randomly allocated (1:1 in part 1 and 2:1 in part 2) via a computer-generated hierarchical randomisation algorithm to daily oral pictilisib (340 mg in part 1 and 260 mg in part 2) or placebo starting on day 15 of cycle 1, plus intramuscular fulvestrant 500 mg on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles in both groups. In part 1, we stratified patients by presence or absence of PIK3CA mutation, primary or secondary aromatase inhibitor resistance, and measurable or non-measurable disease. In part 2, we stratified patients by previous aromatase inhibitor treatment for advanced or metastatic disease or relapse during or within 6 months of an aromatase inhibitor treatment in the adjuvant setting and measurable or non-measurable disease. All patients and those administering treatment and assessing outcomes were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population for both parts 1 and 2 and also separately in patients with PIK3CA-mutated tumours in part 1. Tumour assessment (physical examination and imaging scans) was investigator-assessed and done at screening and after 8 weeks, 16 weeks, 24 weeks, and 32 weeks of treatment from day 1 of cycle 1 and every 12 weeks thereafter. We assessed safety in as-treated patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT01437566. FINDINGS: In part 1, between Sept 27, 2011, and Jan 11, 2013, we randomly allocated 168 patients to the pictilisib (89 [53%]) or placebo (79 [47%]) group. In part 2, between March 18, 2013, and Jan 2, 2014, we randomly allocated 61 patients to the pictilisib (41 [67%]) or placebo (20 [33%]) group. In part 1, we found no difference in median progression-free survival between the pictilisib (6·6 months [95% CI 3·9-9·8]) and placebo (5·1 months [3·6-7·3]) group (hazard ratio [HR] 0·74 [95% CI 0·52-1·06]; p=0·096). We also found no difference when patients were analysed according to presence (pictilisib 6·5 months [95% CI 3·7-9·8] vs placebo 5·1 months [2·6-10·4]; HR 0·73 [95% CI 0·42-1·28]; p=0·268) or absence (5·8 months [3·6-11·1] vs 3·6 months [2·8-7·3]; HR 0·72 [0·42-1·23]; p=0·23) of PIK3CA mutation. In part 2, we also found no difference in progression-free survival between groups (5·4 months [95% CI 3·8-8·3] vs 10·0 months [3·6-13·0]; HR 1·07 [95% CI 0·53-2·18]; p=0·84). In part 1, grade 3 or worse adverse events occurred in 54 (61%) of 89 patients in the pictilisib group and 22 (28%) of 79 in the placebo group. 19 serious adverse events related to pictilisib treatment were reported in 14 (16%) of 89 patients. Only one (1%) of 79 patients reported treatment-related serious adverse events in the placebo group. In part 2, grade 3 or worse adverse events occurred in 15 (36%) of 42 patients in the pictilisib group and seven (37%) of 19 patients in the placebo group. Four serious adverse events related to pictilisib treatment were reported in two (5%) of 42 patients. One treatment-related serious adverse event occurred in one (5%) of 19 patients in the placebo group. INTERPRETATION: Although addition of pictilisib to fulvestrant did not significantly improve progression-free survival, dosing of pictilisib was limited by toxicity, potentially limiting its efficacy. For future assessment of PI3K inhibition as an approach to overcome resistance to hormonal therapy, inhibitors with greater selectivity than that of pictilisib might be needed to improve tolerability and potentially increase efficacy. No further investigation of pictilisib in this setting is ongoing. FUNDING: F Hoffmann-La Roche.

Barts Cancer Institute Queen Mary University of London London UK

Dana Farber Cancer Institute Boston MA USA

Genentech South San Francisco CA USA

Herlev University Hospital Copenhagen Denmark

Hospital Arnau de Vilanova Lleida Spain

Institut Jules Bordet Université Libre de Bruxelles Brussels Belgium

Masaryk Memorial Cancer Institute Brno Czech Republic

Mayo Clinic Jacksonville FL USA

Memorial Sloan Kettering Cancer Center New York NY USA

National University Hospital Singapore

Palacky University Medical School and Teaching Hospital Olomouc Czech Republic

Peninsula Oncology Centre Melbourne VIC Australia

Royal Melbourne Hospital Parkville VIC Australia

Sarah Cannon Research Institute and Tennessee Oncology Nashville TN USA

The Royal Marsden Hospital London UK

University of Alabama Birmingham AL USA

Vanderbilt Ingram Cancer Center Nashville TN USA

Washington University School of Medicine St Louis MO USA

Lancet Oncol. 2016 Jun;17(6):696-697. doi: 10.1016/S1470-2045(16)00148-0. PubMed

Zobrazit více v PubMed

Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer. 2004;11:643–58. PubMed

Johnston SR. New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res. 2010;16:1979–87. PubMed

Miller TW, Hennessy BT, González-Angulo AM, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120:2406–13. PubMed PMC

Shou J, Massarweh S, Osborne CK, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96:926–35. PubMed

Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27:2630–37. PubMed

Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30:2718–24. PubMed

Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–29. PubMed PMC

Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 2014;25:2357–62. PubMed PMC

Maruyama N, Miyoshi Y, Taguchi T, Tamaki Y, Monden M, Noguchi S. Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res. 2007;13:408–14. PubMed

Kalinsky K, Jacks LM, Heguy A, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009;15:5049–59. PubMed

Miller TW, Pérez-Torres M, Narasanna A, et al. Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 2009;69:4192–201. PubMed PMC

Abramson VG, Cooper Lloyd M, Ballinger T, et al. Characterization of breast cancers with PI3K mutations in an academic practice setting using SNaPshot profiling. Breast Cancer Res Treat. 2014;145:389–99. PubMed PMC

Loi S, Haibe-Kains B, Majjaj S, et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA. 2010;107:10208–13. PubMed PMC

Loi S, Michiels S, Baselga J, et al. PIK3CA genotype and a PIK3CA mutation-related gene signature and response to everolimus and letrozole in estrogen receptor positive breast cancer. PLoS One. 2013;8:e53292. PubMed PMC

Sabine VS, Crozier C, Brookes CL, et al. Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. J Clin Oncol. 2014;32:2952–58. PubMed

Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, et al. Correlation of molecular alterations with efficacy of everolimus in hormone receptor-positive, HER2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol. 2013;31(suppl) abstract LBA509.

Fu X, Creighton C, Biswal NC, et al. Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase. Breast Cancer Res. 2014;16:430. PubMed PMC

O’Brien C, Wallin JJ, Sampath D, et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3′ kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res. 2010;16:3670–83. PubMed

Sarker D, Ang JE, Baird R, et al. First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2015;21:77–86. PubMed PMC

von Hoff DD, LoRusso P, Demetri GD, et al. A phase I dose-escalation study to evaluate GDC-0941, a pan-PI3K inhibitor, administered QD or BID in patients with advanced or metastatic solid tumors. J Clin Oncol. 2011;29(suppl) abstract 3052.

Robertson JF, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer. 2003;98:229–38. PubMed

Mayer IA, Abramson VG, Balko JM, et al. SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER+/HER2- metastatic breast cancer (MBC) J Clin Oncol. 2012;30(suppl) abstract 510.

Schmid P, Pinder SE, Wheatley D, et al. Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study) Cancer Res. 2015;75 abstract S2-03.

Slamon DJ, Hurvitz SA, Chen D, et al. Predictive biomarkers of everolimus efficacy in HER2+ advanced breast cancer: combined exploratory analysis from BOLERO-1 and BOLERO-3. J Clin Oncol. 2015;33(suppl) abstract 512.

Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45:1446–51. PubMed PMC

Ross-Innes CS, Stark R, Teschendorff AE, et al. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature. 2012;481:389–93. PubMed PMC

Juric D, Argiles G, Burris HA, et al. Phase I study of BYL719, an alpha-specific PI3K inhibitor, in patients with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC) Cancer Res. 2012;72 abstract 610-07.

Olivero AG, Heffron TP, Baumgardner M, et al. Discovery of GDC-0032: a beta-sparing PI3K inhibitor active against PIK3CA mutant tumors. Cancer Res. 2013;73 abstract DDT02-01.

Saura C, Sachdev J, Patel MR, et al. Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer. Cancer Res. 2015;75 abstract D5-2.

Juric D, Krop I, Ramanathan RK, et al. GDC-0032, a beta isoform-sparing PI3K inhibitor: results of a first-in-human phase Ia dose escalation study. Cancer Res. 2013;73 abstract LB-64.

Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)

mTOR inhibition amplifies the anti-lymphoma effect of PI3Kβ/δ blockage in diffuse large B-cell lymphoma

Zobrazit více v PubMed

ClinicalTrials.gov
NCT01437566