The PI3K inhibitor taselisib increases the response rate when added to neoadjuvant endocrine therapy in patients with ER+/HER2- early breast cancer

Adding the alpha specific PI3K inhibitor taselisib to letrozole before surgery significantly improves the outcome of patients with estrogen receptor positive (ER+) and HER2 negative (ER+/HER2-) early breast cancer. The randomized, phase II LORELEI trial met its primary endpoint by demonstrating that the addition of taselisib to letrozole significantly increased the objective response rate (ORR) from 39.3% to 50% (OR[95%CI]: 1.55[1.00-2.38]; p = 0.049). As such, LORELEI is the first randomized study demonstrating a significant increase in ORR upon treatment with a PI3K selective inhibitor in this population of patients.

Taselisib is an oral, potent, and selective PI3K inhibitor with enhanced activity against PI3KCA mutant cancer cells. In previous studies assessing PI3K inhibitors, only small effects were seen, and the benefit-risk ratio was less favorable. In theory, alpha specific inhibitors, like taselisib, will be more efficacious and less toxic than others. In earlier studies, confirmed partial responses were observed in patients with PI3KCA mutant metastatic breast cancer treated with taselisib as a single agent and combined with endocrine therapy (ET).

In LORELEI, 334 postmenopausal patients with ER+/HER2-, Stage I-III, operable early breast cancer and evaluable tumor tissue for centralized PI3KCA genotyping were randomized (1:1) to receive letrozole with either taselisib (4mg 5 days on/ 2 days off) or placebo for 16 weeks, followed by surgery. The co-primary endpoints of the study were ORR by centrally assessed breast MRI and pathologic complete response (pCR, ypT0/is N0) rate at surgery, in all randomized patients and in patients with PI3KCA mutant tumors.

The study showed a better ORR among patients who received taselisib compared to placebo (50% versus 39.3%, OR[95%CI]: 1.55[1.00–2.38]; p = 0.049). Taselisib worked particularly well among the 152 patients who had PI3KCA mutant cancer cells detected at baseline, with an ORR of 56.2% compared to 38% for patients who received placebo (OR[95%CI]: 2.03[1.06-3.88], p= 0.033). No significant differences were observed for pCR rate overall (1.8% versus 0.6%), or in the PI3KCA mutant subset (1.4% versus 0%).

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 1 sudden death in the taselisib-treated group, the study investigators considered it unrelated to the drug.

In summary, LORELEI is the first randomized study to demonstrate a significant increase in ORR measured by MRI upon treatment with a PI3K selective inhibitor combined with endocrine therapy in ER+/HER2- early breast cancer patients. The toxicity associated with the drug was manageable. 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 PI3K inhibitors in breast cancer.

Reference

Saura C, de Azambuja E, Hlauschek D, 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). Presented at ESMO 2017; Abstract LBA10_PR.