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A phase II, randomised, double-blind study of neoadjuvant letrozole plus GDC-0032 versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative, early stage breast cancer

LORELEI is an international two-arm, randomised, double-blind, pre-operative study for postmenopausal women with oestrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) early stage, untreated, Stage I-III operable breast cancer whose primary tumours are > or = 2 cm.  The study aims to compare two treatments: letrozole, a drug blocking oestrogen receptor (ER) signaling, combined with GDC-0032 (also known as taselisib), an experimental drug blocking PI3K signaling, versus the combination letrozole and placebo.

Biological samples (blood, tumour tissue, RNA, and DNA) are being collected as part of the study.  The intention is to analyse these samples to see whether there are changes in proteins and the nucleic acids DNA or RNA in pathways that are known (or believed) to be important for the treatment of patients with breast cancer. In particular, scientists want to better understand how the drug GDC-0032 combined with letrozole works, and to identify if there are factors that can predict whether a patient will be sensitive or resistant to the treatment. This kind of research can help us better individualise breast cancer treatment in the future.

In ER+ breast cancer, patients can become resistant to endocrine treatments like letrozole, and this appears to be related to the activation of the PI3K pathway. Therefore, it is hypothesised that combining letrozole with the PI3K blocking drug GDC-0032 could be more effective than letrozole alone.

The purpose of LORELEI is to determine if combining GDC-0032 with letrozole in treatment of patients with previously untreated, postmenopausal ER+, HER-, Stage I-III breast cancer is better than giving letrozole alone. Both the response of tumors to the treatment and safety will be carefully evaluated.

LORELEI met its primary objective and showed that the addition of the PI3K inhibitor taselisib to the standard neoadjuvant endocrine treatment increased the objective response rate (ORR) from 38% to 56.2% in patients with PIK3CA mutations and from 39.3% to 50% across all patients in the study. No significant difference in the pathologic complete response (pCR) was observed between the two arms of the study (letrozole + taselisib vs letrozole alone). Tumour response was evaluated by using centrally assessed breast MRI. The patient safety profile was reported to be manageable.

The study results were presented by Dr Cristina Saura, study primary investigator, during an oral session at the 2017 ESMO Congress in Spain.

All patients screened for the study are required to provide tumour biopsies, which will be tested to see if the tumour has a PIK3CA gene mutation. The results of the test determine a patient’s eligibility to be enrolled into the study.
Eligible patients are randomly assigned to one of two treatments: either letrozole + taselisib or letrozole + placebo for 16 weeks (or until surgery), and then they are followed-up for 30 days for safety reasons.

334 postmenopausal women with breast cancer who meet the study’s eligibility criteria are taking part in this study.

Collaborative Partners: Austrian Breast & Colorectal Cancer Study Group- (ABCSG), SOLTI Breast Cancer Group and the Breast International Group-BIG (HQ).

Pharmaceutical partner and sponsor: Genentech/Roche.

The target recruitment of 334 patients was achieved in August 2016, 4 months ahead of schedule.

103 activated sites worldwide in 22 countries, including 8 BIG Groups, are participating in the study.

Genentech, Inc., a member of the Roche group, and study sponsor, is providing funding for this study, which is run according to BIG’s research principles.

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