Journal Article
. 2019 Aug;20(9).
doi: 10.1016/S1470-2045(19)30334-1.

Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Cristina Saura 1 Dominik Hlauschek 2 Mafalda Oliveira 3 Dimitrios Zardavas 4 Anita Jallitsch-Halper 2 Lorena de la Peña 5 Paolo Nuciforo 3 Alberto Ballestrero 6 Peter Dubsky 7 Janine M Lombard 8 Peter Vuylsteke 9 Carlos A Castaneda 10 Marco Colleoni 11 Giuliano Santos Borges 12 Eva Ciruelos 13 Monica Fornier 14 Katalin Boer 15 Aditya Bardia 16 Timothy R Wilson 17 Thomas J Stout 17 Jerry Y Hsu 17 Yi Shi 17 Martine Piccart 18 Michael Gnant 19 José Baselga 20 Evandro de Azambuja 21 
Affiliations
  • PMID: 31402321
  •     15 citations

Abstract

Background: Endocrine therapy-based neoadjuvant treatment for luminal breast cancer allows efficient testing of new combinations before surgery. The activation of the phosphatidylinositol-3-kinase (PI3K) pathway is a known mechanism of resistance to endocrine therapy. Taselisib is an oral, selective PI3K inhibitor with enhanced activity against PIK3CA-mutant cancer cells. The LORELEI trial tested whether taselisib in combination with letrozole would result in an increased proportion of objective responses and pathological complete responses.

Methods: In this multicentre, randomised, double-blind, parallel-cohort, placebo-controlled phase 2, study, we enrolled postmenopausal women (aged ≥18 years) with histologically confirmed, oestrogen receptor (ER)-positive, HER2-negative, stage I-III, operable breast cancer, from 85 hospitals in 22 countries worldwide. To be eligible, patients had have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1, adequate organ function, and had to have evaluable tumour tissue for PIK3CA genotyping. Patients were randomly assigned (1:1) by means of a permuted block algorithm (block size of four) via an interactive voice or web-based response system, to receive letrozole (2·5 mg/day orally, continuously) with either 4 mg of oral taselisib or placebo (on a 5 days-on, 2 days-off schedule) for 16 weeks, followed by surgery. Randomisation was stratified by tumour size and nodal status. Site staff, patients, and the sponsor were masked to treatment assignment. Coprimary endpoints were the proportion of patients who achieved an objective response by centrally assessed breast MRI and a locally assessed pathological complete response in the breast and axilla (ypT0/Tis, ypN0) at surgery in all randomly assigned patients and in patients with PIK3CA-mutant tumours. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02273973, and is closed to accrual.

Findings: Between Nov 12, 2014, and Aug 12, 2016, 334 participants were enrolled and randomly assigned to receive letrozole and placebo (n=168) or letrozole and taselisib (n=166). Median follow-up was 4·9 months (IQR 4·7-5·1). The study met one of its primary endpoints: the addition of taselisib to letrozole was associated with a higher proportion of patients achieving an objective response in all randomly assigned patients (66 [39%] of 168 patients in the placebo group vs 83 [50%] of 166 in the taselisib group; odds ratio [OR] 1·55, 95% CI 1·00-2·38; p=0·049) and in the PIK3CA-mutant subset (30 [38%] of 79 vs 41 [56%] of 73; OR 2·03, 95% CI 1·06-3·88; p=0·033). No significant differences were observed in pathological complete response between the two groups, either in the overall population (three [2%] of 166 in the taselisib group vs one [1%] of 168 in the placebo group; OR 3·07 [95% CI 0·32-29·85], p=0·37) or in the PIK3CA-mutant cohort (one patient [1%) vs none [0%]; OR not estimable, p=0·48). The most common grade 3-4 adverse events in the taselisib group were gastrointestinal (13 [8%] of 167 patients), infections (eight [5%]), and skin-subcutaneous tissue disorders (eight [5%]). In the placebo group, four (2%) of 167 patients had grade 3 or worse vascular disorders, two (1%) had gastrointestinal disorders, and two (1%) patients had grade 3 or worse infections and infestations. There was no grade 4 hyperglycaemia and grade 3 cases were asymptomatic. Serious adverse events were more common in the taselisib group (eight [5%] patients with infections and seven [4%] with gastrointestinal effects) than in the placebo group (one [1%] patient each with grade 3 postoperative wound and haematoma infection, grade 4 hypertensive encephalopathy, grade 3 acute cardiac failure, and grade 3 breast pain). One death occurred in the taselisib group, which was not considered to be treatment-related.

Interpretation: The increase in the proportion of patients who achieved an objective response from the addition of taselisib to endocrine therapy in a neoadjuvant setting is consistent with the clinical benefit observed in hormone receptor-positive, HER2-negative, metastatic breast cancer.

Funding: Genentech and F Hoffmann-La Roche.

Efficacy of PI3K inhibitors in advanced breast cancer.
B Verret, J Cortes, +2 authors, M Arnedos.
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ER+ metastatic breast cancer: past, present, and a prescription for an apoptosis-targeted future.
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Review.
TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer.
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Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments.
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Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.
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Science, 2019 Nov 09; 366(6466). PMID: 31699932    Free PMC article.
Cellular Plasticity in Breast Cancer Progression and Therapy.
Deguang Kong, Connor J Hughes, Heide L Ford.
Front Mol Biosci, 2020 May 12; 7. PMID: 32391382    Free PMC article.
Review.
The Predictive Role of PIK3CA Mutation Status on PI3K Inhibitors in HR+ Breast Cancer Therapy: A Systematic Review and Meta-Analysis.
Mingming Wang, Jin Li, Jiangsheng Huang, Mei Luo.
Biomed Res Int, 2020 May 29; 2020. PMID: 32461963    Free PMC article.
Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer.
Benjamin D Hopkins, Marcus D Goncalves, Lewis C Cantley.
Nat Rev Endocrinol, 2020 Mar 05; 16(5). PMID: 32127696    Free PMC article.
Review.
Neoadjuvant Endocrine Therapy in Breast Cancer: Current Knowledge and Future Perspectives.
Giacomo Barchiesi, Marco Mazzotta, +14 authors, Patrizia Vici.
Int J Mol Sci, 2020 May 21; 21(10). PMID: 32429381    Free PMC article.
Review.
Neoadjuvant endocrine therapy in locally advanced estrogen or progesterone receptor-positive breast cancer: determining the optimal endocrine agent and treatment duration in postmenopausal women-a literature review and proposed guidelines.
Lauren I Madigan, Phuong Dinh, J Dinny Graham.
Breast Cancer Res, 2020 Jul 22; 22(1). PMID: 32690069    Free PMC article.
Review.
How Effective is Neoadjuvant Endocrine Therapy (NET) in Downstaging the Axilla and Achieving Breast-Conserving Surgery?
Giacomo Montagna, Varadan Sevilimedu, +3 authors, Melissa L Pilewskie.
Ann Surg Oncol, 2020 Aug 26; 27(12). PMID: 32839900    Free PMC article.
Targeting the PI3K/AKT/mTOR Pathway in Hormone-Positive Breast Cancer.
Sara E Nunnery, Ingrid A Mayer.
Drugs, 2020 Sep 08; 80(16). PMID: 32894420    Free PMC article.
Review.
Correlative studies investigating effects of PI3K inhibition on peripheral leukocytes in metastatic breast cancer: potential implications for immunotherapy.
Carly Bess Williams, Caroline A Nebhan, +8 authors, Ann Richmond.
Breast Cancer Res Treat, 2020 Aug 09; 184(2). PMID: 32767201    Free PMC article.
Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer.
Kyung-Min Lee, Angel L Guerrero-Zotano, +13 authors, Carlos L Arteaga.
Nat Commun, 2020 Nov 01; 11(1). PMID: 33127913    Free PMC article.