Adding taselisib, a selective PI3-kinase (PI3K) inhibitor with enhanced activity against PIK3CA mutant cancer cells, to letrozole improved the objective response rate (ORR) in postmenopausal women with early breast cancer overall and in a subset of women with PIK3CA mutant tumours, researchers reported during ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Previously, confirmed partial responses had been demonstrated in PIK3CA mutated metastatic breast cancer with taselisib, administered either as a single agent or combined with endocrine therapy.
Cristina Saura, Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology in Barcelona, Spain presented findings from the phase II LORELEI (NCT02273973) trial of neoadjuvant letrozole plus taselisib compared to letrozole plus placebo in postmenopausal patients with oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer.
LORELEI is a phase II randomised, double-blind study that enrolled 334 patients in 90 sites worldwide with operable early breast cancer, stages I to III, and evaluable tumour tissue for centralised PIK3CA genotyping. The patients were randomised to receive letrozole plus either taselisib at 4 mg in a 5 days on - 2 days off weekly cycle or placebo for 16 weeks, followed by surgery.
The ORR by centrally assessed breast MRI and pathologic complete response (pCR) defined as the rate of tumour eradication from both breast and lymph nodes (ypT0/is N0) at date of surgery in all randomised patients and in patients with PIK3CA mutated tumours were the co-primary endpoints.
The sample size was calculated to detect an absolute increase of 24% in ORR (from 40% to 64%, minimal detectable difference [MDD] 15%; 2-sided α 16%, 80% power), or 18% in pCR (from 1% to 19%; MDD 13%; 2-sided α 4%, 80% power) in patients with PIK3CA mutant tumours.
The LORELEI study met the primary endpoint
With the taselisib/letrozole combination, the ORR was increased from 38% to 56.2% in the PIK3CA mutated subset, odds ratio [OR] 2.03; 95% confidence interval [CI] 1.06, 3.88 (p = 0.033).
The ORR was also increased from 39.3% to 50%, in the overall cohort of all randomised patients that included women without tumours having mutated PIK3CA as well, OR 1.55; 95%CI 1.00, 2.38 (p = 0.049).
Neither the overall patients nor the patients in the PIK3CA mutated subset demonstrated significant differences in the pCR rate with the taselisib/letrozole combination compared to letrozole/placebo.
The investigators reported that the toxicity with taselisib was manageable. The most common serious (grade 3 and 4) adverse events associated with the drug included gastrointestinal disorders (7.8%), infections (4.8%), and skin / subcutaneous tissue disorders (4.8%), vascular disorders (3.6%), and metabolism and nutrition disorders (3.6%) including hyperglycemia (1.2%).
One sudden death occurred in the taselisib arm that was considered unrelated to study treatment.
Dose reductions were made in 11.4% of patients and 10.8% of patients discontinued taselisib.
The authors noted that LORELEI is the first randomised study to demonstrate a significant increase in ORR as measured by MRI following treatment with a PI3K selective inhibitor in combination with letrozole in patients with ER-positive/HER2-negative early breast cancer.
They are performing comprehensive biomarker analyses to provide further insight into the antitumour responses observed with the taselisib/letrozole combination.
Commenting on the results of the study, Nadia Harbeck of the Breast Center, Department of Obstetrics and Gynecology, University of Munich (LMU), Munich, Germany said that it is about first clinical proof of efficacy of a specific PI3K inhibitor (taselisib) in early breast cancer. The results of confirmatory phase III trials in metastatic breast cancer are eagerly awaited.
This trial was funded by Genentech Inc.
LBA10_PR – Saura C, et al. Primary results of LORELEI: a phase II randomized, double-blind study of neoadjuvant letrozole (LET) plus taselisib versus LET plus placebo (PLA) in postmenopausal patients (pts) with ER+/HER2-negative early breast cancer (EBC).