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)

Background: Taselisib is an oral, potent, and selective PI3-kinase (PI3K) inhibitor with enhanced activity against PIK3CA mutant (MUT) cancer cells. Confirmed partial responses were observed in pts with PIK3CA MUT metastatic breast cancer treated with taselisib as a single agent and combined with endocrine therapy (ET). Methods: 334 postmenopausal pts with ER+/HER2-, Stage I-III, operable EBC and evaluable tumor tissue for centralized PIK3CA genotyping were randomized (1:1) in 90 sites worldwide to receive LET with either taselisib (4mg 5 days on/2 days off) or PLA for 16 weeks, followed by surgery. Co-primary endpoints: objective response rate (ORR) by centrally assessed breast MRI and pathologic complete response (pCR, ypT0/is N0) rate at surgery, in all randomized pts and in pts with PIK3CA MUT tumors. The sample size was calculated to detect in the PIK3CA MUT subset an absolute increase of 24% in ORR (from 40% to 64%, minimal detectable difference [MDD] 15%; 2-sided α 16%, 80% power), and 18% in pCR (from 1% to 19%; MDD 13%; 2-sided α 4%, 80% power). Results: The study met its primary endpoint: the addition of taselisib to LET increased the ORR from 38% to 56.2% in the PIK3CA MUT subset (N = 152; Odds ratio [OR] 2.03, 95%CI 1.06-3.88, p = 0.033) and in all randomized pts (from 39.3% to 50%, OR 1.55, 95%CI 1.00-2.38, p = 0.049). No significant difference was observed for pCR rate overall or in the PIK3CA MUT subset. Most common G3-4 adverse events in the taselisib arm: gastrointestinal disorders (7.8%), infections (4.8%), and skin/subcutaneous tissue disorders (4.8%). G3-4 hyperglycemia occurred in 1.2% of pts. One sudden death occurred in the taselisib arm, but was considered unrelated to study treatment. Taselisib discontinuation (10.8%) and dose reductions (11.4%) were infrequent. Conclusions: LORELEI is the first randomized study to demonstrate a significant increase in ORR measured by MRI upon treatment with a PI3K selective inhibitor + ET in ER+/HER2- EBC pts. Toxicity was manageable. Ongoing comprehensive biomarker analyses will provide further insight into the antitumor responses observed with this combination. Clinical trial identification: NCT02273973 Legal entity responsible for the study: Colead partnership between Genentech (Sponsor) - BIG (Governance & coordination) - ABCSG (data center) - SOLTI (biosamples) Funding: Genentech Inc. Disclosure: T.R. Wilson, Y. Shi: Employed by Genentech Inc., stocks in Roche. T.J. Stout: Employed by Genentech Inc. J.Y. Hsu: Employed by Genentech Inc., M. Piccart: Consultant (honoraria) from Roche-Genentech, Research grants to my Institute from Roche-Genentech. M. Gnant: Honoraria: Roche Research Funding: Roche. All other authors have declared no conflicts of interest.