ESMO 2017 Press Release: LORELEI: Taselisib Boosts Breast Tumor Shrinkage

LUGANO-MADRID – Adding taselisib to letrozole before surgery significantly improved outcomes for patients with early breast cancer that was both estrogen receptor positive and HER2-negative (ER+/HER2-) according to results of the LORELEI trial, presented at the ESMO 2017 Congress in Madrid. (1)

“We were able to detect a reduction in tumor size after only 16 weeks of treatment, compared to patients who received letrozole plus placebo,” said study investigator Dr. Cristina Saura, from Vall d’Hebron University Hospital in Barcelona, Spain. “Any decrease in tumor measurements is something positive for patients because this means the drug has had activity against their tumor in a short period of time.”

LORELEI is the first randomized study to demonstrate a significant increase in objective response rate (ORR) upon treatment with a PI3K selective inhibitor in this population of patients, noted the authors of the study, which was conducted in 85 sites across the world.

Taselisib is an alpha specific PI3K inhibitor which blocks a signalling pathway known as PIK3 that promotes cancer growth.

“The alpha-specific story is important, because other PI3K inhibitors have had only a small effect, and the benefit-risk ratio was less favourable,” noted Prof. Sibylle Loibl, Chair of the German Breast Group, who was not involved in the study but provided comment for ESMO. “In general it is believed that alpha specific inhibitors will be more efficacious and less toxic than others”.

LORELEI included 334 postmenopausal patients with ER+/HER2-, stage I-III, operable early breast cancer.

All of them had tissue analysed for PIK3CA mutant cancer cells, and were randomised to receive letrozole plus either a placebo (n=168) or taselisib (n=166) for 16 weeks in order to shrink their tumour before surgery.

The study had two co-primary endpoints: one was ORR which was assessed by measuring the tumour size with magnetic resonance imaging; the second was the pathologic complete response (pCR) rate, which is a measure of the presence of cancer cells at the site after the tumour is surgically removed.

The study, carried out in collaboration with the Breast International Group (BIG), SOLTI Breast Cancer Research Group, and the Austrian Breast & Colorectal Cancer Study Group (ABCSG), showed that ORR was better in patients who received taselisib compared to placebo (50% versus 39.3%, odds ratio [OR] 1.55, 95% CI 1.00–2.38, P=0.049), but there was no significant difference between the groups for pCR.

Among the 152 patients who had PIK3CA mutant cancer cells detected at baseline, taselisib worked particularly well, with 56.2% showing an ORR compared to 38% of patients who received placebo (odds ratio [OR] 2.03, 95%CI 1.06-3.88, p = 0.033).

“For me, the main message is that even though all patients seems to derive some benefit from taselisib, those who had this mutation seemed to derive more benefit,” said Saura.

Discontinuation and reduced dosing of taselisib occurred in 10.8% and 11.4% of patients, respectively. The most common serious (grade 3 and 4) adverse events associated with the drug included gastrointestinal disorders (7.8%), infections (4.8%), skin / subcutaneous tissue disorders (4.8%), vascular disorders (3.6%), and metabolism and nutrition disorders (3.6%) including hyperglycemia (1.2%).

Although there was one sudden death in the taselisib-treated group, the study investigators considered it unrelated to the drug.

Loibl concluded that “these are the first data indicating that the addition of an alpha specific PI3K inhibitor might work in addition to an endocrine therapy in HER2-/Hr+ breast cancer. More data from LORELEI as well as data from the Phase III studies in metastatic breast cancer need to be awaited for evaluating the role of PIK3 Kinase inhibitors in breast cancer.”

-END-

Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress

References

  1. Abstract LBA10_PR ‘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)’ will be presented by Dr. Saura during Proffered Paper Session ‘Breast cancer, early stage’ on Friday, 8 September 2017, 14:00 to 15:30 (CEST) in Pamplona Auditorium.

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Abstract LBA10_PR

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)

C. Saura1, E. de Azambuja2, D. Hlauschek3, M. Oliveira1, D. Zardavas4, A. Jallitsch-Halper3, L. de la Pena5, P. Nuciforo6, A. Ballestrero7, M.N. Fornier8, K. Boer9, E. Ciruelos10, V. Valero11, T.R. Wilson12, T.J. Stout12, J.Y. Hsu12, Y. Shi12, M. Piccart2, M. Gnant13, J. Baselga14
1Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain, 2Medical Oncology, Institute Jules Bordet, Brussels, Belgium, 3ABCSG, Austrian Breast & Colorectal Cancer Study Group, Vienna, Austria, 4Brussels, Breast International Group, Brussels, Belgium, 5SOLTI, SOLTI BREAST CANCER RESEARCH, Barcelona, Spain, 6Molecular oncology group, Vall d´Hebron Institute of Oncology, Barcelona, Spain, 7& GOIRC, University of Genoa-IRCCS AOU San Martino IST, Genova, Italy, 8Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 9Medical Oncology, St. Margit Hospital, Budapest, Hungary, 10Medical Oncology, University Hospital 12 De Octubre, Madrid, Spain, 11Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA, 12--, Genentech Inc. - Roche - USA, South San Francisco, CA, USA, 13Department of Surgery and Comprehensive Cancer Center  , Medical University of Vienna, Vienna, Austria, 14--, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

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.

Keywords: neoadjuvant, ER-positive, HER2-negative, Early stage breast cancer, taselisib