Taselisib, Letrozole Combination Active for ER+, HER2- Early Breast Cancer

Taselisib added to standard letrozole (Femara) improved the objective response rate (ORR) compared to letrozole with a placebo in postmenopausal women with estrogen receptor-positive (ER+) and HER2-negative (HER2-) early breast cancer, according to findings from the LORELEI study presented at the 2017 ESMO Congress in Madrid, Spain.

The ORR was increased from 39.3% with letrozole and a placebo to 50% with taselisib added to letrozole in the overall cohort of patients, which included women who had tumors with and without mutated PIK3CA (odds ratio [OR], 1.55; 95% CI,1.00-2.38; P = 0.049). Eight (4.8%) patients achieved complete response (CR) versus 3 (1.8%) patients in the placebo group, and 75 (40.4%) versus 63 (51.2%) patients had a partial response (PR) in the combination group versus the placebo group, respectively. One patient in the placebo group had stable disease (SD), and 10 (6.0%) patients in each treatment arm experienced progressive disease (PD).

A significant response to the combination was also observed in the subset of 152 women with PIK3CA-mutant tumors, where the ORR was increased from 38% to 56.2% with letrozole plus placebo or taselisib, respectively (OR, 2.03; 95% CI, 1.06-3.88 P = 0.033). In this group, 5 (6.8%) versus 2 (2.5%) patients, and 36 (49.3%) versus 39 (49.4%) patients achieved CR and PR, respectively. One (1.3%) patient had SD, and 1 (1.4%) versus 3 (3.5%) patients in the respective arms had SD and PD. The median drug exposure was 15.7 weeks.

“LORELEI is the first randomized study to demonstrate a significant increase in objective response rate upon treatment with a PI3K selective inhibitor in this population of patients,” said Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology in Barcelona, Spain, who presented findings from the phase II LORELEI trial (NCT02273973) of neoadjuvant letrozole plus taselisib compared to letrozole plus placebo in postmenopausal patients with ER+/HER2- early breast cancer.

LORELEI enrolled 334 patients at 85 sites worldwide with operable early breast cancer, stages I to III, and with evaluable tumor tissue for centralized PIK3CA genotyping.

The primary endpoints were the ORR by centrally assessed breast MRI and pathologic complete response (pCR), defined as the rate of tumor eradication from both breast and lymph nodes (ypT0/is N0) at date of surgery, in all randomized patients and in patients with PIK3CA mutated tumours. The study was considered positive if either of the endpoints was met.

“Breast MRI is more accurate than clinical palpitation, ultrasound, or mammogram for prediction of residual disease,” according to Saura.

The trial, which aimed achieving at tumor shrinkage prior to surgery, randomized 166 patients letrozole plus taselisib at 4 mg given on 5 days with 2 days off in a weekly cycle, and 168 to letrozole plus placebo for 16 weeks.

“We were able to detect a reduction in tumor size after only 16 weeks of treatment, compared to patients who received letrozole plus placebo. 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,” Saura commented.

No significant differences in the pCR rate with the taselisib/letrozole combination compared to letrozole/placebo were observed in the overall patient population or in the PIK3CA mutated subset, respectively (OR, 3.07; P = 0.370; and OR, NE; P = 0.480, respectively).

“The low pCR rate with taselisib was not unexpected with only 4 months of endocrine-based therapy in patients with ER+/HER2- early breast cancer,” said Saura.

Taselisib differs from other PI3K inhibitors since it degrades mutated p110 alpha by a unique mechanism of action and provides enhanced activity against PIK3CA-mutant cancer cells.

“The alpha-specific story is important, because other PI3K inhibitors have had only a small effect, and the benefit-risk ratio was less favorable,” noted Sibylle Loibl, MD, Chair of the German Breast Group and an ESMO commentator. “In general, it is believed that alpha-specific inhibitors will be more efficacious and less toxic than others”.

The investigators considered that toxicity with taselisib was manageable. The most common serious adverse events grades 3/4 associated with the drug were gastrointestinal disorders, which occurred in 7.8% of patients, infections in 4.8%, skin/subcutaneous tissue disorders in 4.8%, vascular disorders in 3.6%, and metabolism and nutrition disorders in 3.6% of patients that included hyperglycemia in 1.2% of patients overall.

One sudden death occurred in the taselisib arm that was considered unrelated to the study treatment. Dose reductions were made in 11.4% of patients, and 10.8% of patients discontinued taselisib.

“The main message is that LORELEI met its primary endpoint and, even though all patients seem to derive some benefit from taselisib, those who had PIK3CA mutation seemed to derive more benefit,” Saura pointed out. “We are performing comprehensive biomarker analyses to provide further insight into the antitumor responses observed with the taselisib/letrozole combination.”

This trial was funded by Genentech Inc.

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: 2017 ESMO Congress; September 8-12; Madrid, Spain. Abstract LBA10_PR.

<<< View more from the 2017 ESMO Congress