LORELEI study: Taselisib improves outcomes, boosts breast tumor shrinkage in early breast cancer

By Liz Meszaros, MDLinx
Published September 14, 2017

Key Takeaways

Preoperative treatment that includes the addition of taselisib—an investigational PI3K inhibitor currently in clinical development based on its potential selectivity for the PI3Kα isoform—to letrozole before surgery may significantly improve outcomes in postmenopausal women with early estrogen receptor positive (ER+) and HER2-negative early breast cancer, according to results from the LORELEI trial, presented at the European Society for Medical Oncology 2017 Congress in Madrid, Spain.    

The LORELEI study was conducted in 85 sites worldwide, and is the first randomized study to show a significant increase in objective response rates (ORR) to treatment with a PI3K selective inhibitor in this population.

“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.”

Dr. Saura and colleagues randomized 334 postmenopausal women with ER+/HER2-, stage I-III, operable early breast cancer to treatment with letrozole plus either a placebo (n=168) or taselisib (n=166) for 16 weeks. The aim was to induce tumor shrinkage prior to surgery. They analyzed biopsied tissue for PIK3CA mutant cancer cells.

The two co-primary endpoints of the study were objective response rate (ORR), assessed via MRI to measure tumor size, and pathological complete response (pCR) rate.

Researchers found better ORR in patients treated with taselisib compared with placebo (50% vs 39.3%; OR: 1.55; 95% CI: 1.00, 2.38; P=0.049). They found no significant difference, however, in pCR between the two groups.

Results were especially good in the 152 patients with PIK3CA mutant cancer cells detected at baseline, of whom 56.2% had ORR, compared with 38% of placebo patients (OR: 2.03; 95% CI: 1.06, 3.88; P=0.033).

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

The need for treatment discontinuation occurred in 10.8% of taselisib patients, and dose reduction was necessary in 11.4%. The most common grade 3/4 adverse events associated with taselisib 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%).

In commenting on these results, Professor Sibylle Loibl, Chair of the German Breast Group, who was not involved in the study, noted: “The alpha-specific story is important, because other PI3K inhibitors have had only a small effect, and the benefit-risk ratio was less favourable. 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.”

This study was conducted in collaboration with the Breast International Group (BIG), SOLTI Breast Cancer Research Group, and the Austrian Breast & Colorectal Cancer Study Group (ABCSG).

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