Elsevier

The Lancet Oncology

Volume 20, Issue 9, September 2019, Pages 1226-1238
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(19)30334-1Get rights and content

Summary

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.

Introduction

Oestrogen receptor (ER)-positive, HER2-negative breast cancer accounts for about 70% of all diagnosed breast cancer cases, and endocrine therapy is its cornerstone treatment, both in the early and advanced disease settings. However, not all ER-positive breast cancer responds optimally to endocrine therapy. Upregulation of the PI3K–AKT–mTOR pathway is one of the mechanisms that can lead to primary or secondary endocrine resistance, or both.1 Genes in the PI3K–AKT–mTOR pathway are frequently mutated or amplified in breast cancer, especially in the ER-positive subtype. PIK3CA (encoding p110α, the catalytic subunit of PI3Kα) is mutated in about 35% of all breast cancers, and is more frequent in ER-positive tumours.2

Targeting the PI3K–AKT–mTOR pathway in ER-positive breast cancer has proved beneficial both in the neoadjuvant and in the advanced settings.3, 4 In the BOLERO-2 trial, the addition of everolimus to exemestane improved progression-free survival in patients with hormone receptor-positive disease, but efficacy was not increased in those with PIK3CA-mutant tumours,4, 5 suggesting that direct inhibitors of PI3K could be a preferred option in these patients. In line with this hypothesis, a phase 3 trial testing the pan-PI3K inhibitor buparlisib in combination with fulvestrant showed increased activity in those patients with a PIK3CA mutation detected in circulating tumour DNA (ctDNA).6 Although these results were encouraging, pan-PI3K inhibitors were frequently associated with hyperglycaemia, dermatological and gastrointestinal adverse events, fatigue, and pneumonitis.6, 7, 8 Mood disorders were reported in nearly a third of patients and a higher proportion of patients receiving buparlisib showed suicidal ideations and attempts,6, 7 which discouraged its approval. Conversely, PI3K isoform-specific agents, such as taselisib and alpelisib, have shown a better safety profile and their most common adverse events (eg, hyperglycaemia, rash, diarrhoea, and mucositis) are amenable to medical management if early interventions are indicated.9, 10, 11

Taselisib (GDC-0032) inhibits the PI3K-β isoform 30 times less potently than the α-isoform and shows enhanced activity against PIK3CA-mutant versus wild-type forms.12 Taselisib as single agent is well tolerated and has shown antitumour activity across multiple tumour types.13 The combination of taselisib with letrozole or fulvestrant induced several partial responses in heavily pretreated patients with metastatic, ER-positive breast cancer, especially in tumours harbouring a PIK3CA mutation,14 suggesting that the addition of taselisib to hormone therapy might be a potential therapeutic choice for patients with PIK3CA-mutant breast cancer.15

The neoadjuvant setting provides a unique opportunity to identify predictive biomarkers of response to novel therapeutic agents. Pretreatment biopsies are easily accessible, on-treatment biopsies can monitor treatment response at a biological level and, if a pathological complete response is not achieved, the surgical specimen can be examined for mechanisms of resistance to therapy. The biological information obtained from all specimens can be correlated with clinical data, such as objective response and pathological complete response, a surrogate endpoint that strongly associates with disease-free and overall survival in patients with some subtypes of breast cancer.16

Research in context

Evidence before this study

We searched PubMed for publications between Jan 1, 2001, and Sept 30, 2017, with the search terms “PIK3CA mutation”, “PI3K alpha-specific inhibitors”, “neoadjuvant endocrine”, and “ER+/HER2-negative early breast cancer”. We also searched PubMed for publications in the same period describing assessment of taselisib using the terms “taselisib” or “GDC-0032”. No previous randomised trials had investigated the targeting of PI3K specifically in oestrogen receptor (ER)-positive, HER2-negative early breast cancer. Analyses of preclinical studies and single-group phase 1 or phase 2 studies in ER-positive, HER2-negative, metastatic breast cancer have suggested a more pronounced effect of isoform selective inhibitors in cell lines, preclinical models, and patients harbouring a PIK3CA mutation.

Added value of this study

Our results suggest that taselisib increases the efficacy of letrozole in postmenopausal women with hormone receptor-positive, HER2-negative, operable breast cancer, because this combination results in a higher proportion of patients who achieved an objective response, especially in patients harbouring PIK3CA-mutant tumours. The safety profile of taselisib was consistent with previous reports and related toxicities were tolerable and manageable with early medical interventions.

Implications of all the available evidence

Targeting the mTOR–PI3K pathway combined with endocrine therapy is an active treatment option in this setting for hormone receptor-positive, HER2-negative, advanced breast cancer. The efficacy of taselisib in the neoadjuvant setting is consistent with the clinical benefit reported in the SANDPIPER trial in which taselisib plus fulvestrant resulted in longer progression-free survival than fulvestrant alone in patients with PIK3CA-mutant metastatic cancer. Our results and available data from phase 1–3 trials of taselisib in advanced disease, although limited by differences in sample sizes, tissues analysed, and populations included, suggest that PIK3CA mutations might help in selecting patients who benefit from targeting PI3K. Further studies are required to identify response and resistant biomarkers for these agents.

However, MRI has been shown to be more accurate than clinical palpation, ultrasound, and mammogram for measuring residual tumour size after neoadjuvant therapy in several prospective trials.17 In the I-SPY1 trial,18 breast functional tumour volume by MRI (tumour volume enhancement >70% after neoadjuvant chemotherapy) was a strong predictor of relapse-free survival in patients with ER-positive, HER2-negative breast cancer. In another study including ER-positive, HER2-negative tumours, absolute tumour size by MRI after neoadjuvant chemotherapy and radiological complete response but not pathological complete response was associated with relapse-free survival.19

In the LORELEI trial, we aimed to assess the efficacy and safety of neoadjuvant taselisib and letrozole in the treatment of patients with ER-positive, HER2-negative, early breast cancer and investigated the presence of a PIK3CA mutation as a biomarker for response.

Section snippets

Study design and participants

LORELEI is a multicentre, randomised, double-blind, parallel cohort, placebo-controlled, phase 2 trial. Patients were enrolled at 85 hospitals in 22 countries worldwide (appendix p 16). Eligible patients were women aged 18 years or older who were postmenopausal (by bilateral oophorectomy or 12 months of amenorrhoea plus follicle-stimulating hormone and oestradiol amounts in the postmenopausal range) with histologically confirmed, operable stage I–III, invasive breast cancer, defined as

Results

From Nov 12, 2014, to Aug 12, 2016, 501 patients were assessed for eligibility and 334 patients were enrolled and randomly assigned to treatment with letrozole plus taselisib (166 patients) or placebo (168 patients; figure 1). PIK3CA mutation was detected in 152 (46%) patients, 73 (44%) of 166 randomly assigned to taselisib and 79 (47%) of 168 assigned to placebo. Of the 181 (54%) patients without a PIK3CA mutation detected, 92 (55%) were randomly assigned to taselisib and 89 (53%) to placebo.

Discussion

The LORELEI study met one of its coprimary endpoints by showing that the addition of taselisib to letrozole significantly increased the proportion of patients achieving an objective response measured by centrally assessed MRI in ER-positive, HER2-negative postmenopausal patients with early breast cancer. The taselisib effect seemed to be more pronounced in patients whose tumour harboured a PIK3CA mutation, however, the 95% CIs overlap to a substantial degree and therefore further research is

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