Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial

Abstract

Summary 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 mon...

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

“…Krop et al [24] assessed the efficacy of the pan-PI3K inhibitor pictilisib in luminal AI-resistant MBC in the phase II randomized FERGI trial. This study was divided into 2 parts, with part 1 including patients with or without PIK3CA mutations, and part 2 including only patients with PIK3CA mutations.…”

“…Furthermore, in part 1, the experimental arm was more toxic than the control arm with grade 3 or worse adverse events occurring in 61% compared with 28% of patients, respectively. Of note, the proportion of patients discontinuing the experimental treatment due to toxicity was quite high (18% in part 1 and 24% in part 2) and possibly contributed to the study failure [24]. More recently, the BELLE-2 trial evaluated another pan-PI3K inhibitor, named buparlisib, in association with fulvestrant in 1,147 patients with luminal HER2 -MBC pretreated with AI.…”

Pushing estrogen receptor around in breast cancer

“…The combination of everolimus with ER-directed therapies has approximately doubled the duration of progressionfree survival compared with ER-directed therapies alone (Bachelot et al 2012, Baselga et al 2012, Piccart et al 2014. Conversely, the addition of a pan-PI3K inhibitor to fulvestrant has demonstrated either no improvement in clinical outcome (Krop et al 2016) or a very modest overall effect with those patients with PIK3CA mutations detectable in cell-free DNA deriving the greatest benefit (Baselga et al 2016).…”

New Perspectives in Medical Oncology : Molecular Medicine and its Perspectives

“…De façon simpliste, l'amplification et/ou la mutation activatrice d'un gène dit « pilote fort » est à privilégier comme cible. A l'opposé, l'activation supposée d'une voie (par exemple PI3K/AKT/mTOR) offre des opportunités de traitement (inhibiteurs de PI3K, d'AKT ou de mTOR), mais n'est que rarement prédictive de l'efficacité de ces traitements (16)(17)(18). Dans les deux cas, hors indication approuvée formellement, les patients doivent être traités dans le cadre de protocoles de recherche clinique formalisés.…”