MADRID – Adding the investigational PI3K inhibitor taselisib to letrozole (Femara) significantly improved overall response rates, compared with neoadjuvant letrozole alone, in postmenopausal women with early estrogen receptor–positive, human epidermal growth factor receptor 2–negative (ER+/HER2–) breast cancer, results of the LORELEI trial show.
In this phase 2 trial, the overall response rate (ORR), the primary endpoint, was 50% for 166 patients assigned to letrozole plus taselisib, compared with 39.3% for 168 patients assigned to letrozole plus placebo, reported Cristina Saura, MD, of Vall d’Hebron University Hospital in Barcelona.
Dr. Christina Saura
Although the pathologic complete rate (pCR) was low in each study arm, this was not unexpected, due to the short course (4 months) of endocrine-based therapy, she said.
Taselisib is a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), with enhanced activity against the mutation isoform of the protein, labeled p110a. The PI3K alpha isoform, Taselisib degrades p110a by a mechanism of action that is different from other PI3K inhibitors, Dr. Saura said.
As monotherapy and in combination with endocrine therapy agents in phase 1 trials, taselisib elicited partial responses in patients with PIK3CA-mutated metastatic breast cancer, she noted.
In LORELEI, 334 postmenopausal women with previously untreated ER+/HER2– stage I-III operable breast cancer with tumors of 2 cm or greater on MRI were enrolled. The patients were stratified by tumor size and nodal status and then randomly assigned to letrozole 2.5 mg daily plus taselisib 4 mg taken in 2 mg doses twice daily for 5 days each week for 16 weeks, or letrozole plus placebo. Patients then went on to surgery, were followed for safety for 30 days, and then had adjuvant therapy consisting of endocrine therapy and/or chemotherapy and/or radiation therapy.
As noted, the ORR for patients assigned to the combination was 50%, consisting of 4.8% CR, and 45.2% partial responses (PR). Additionally, 40.4% of patients assigned to the taselisib arm had stable disease. The corresponding response rates for patients assigned to the letrozole/placebo arm were 1.8%, 37.5%, and 51.2%.
The odds ratio favoring the combination was 1.55 (P = .049).
For the subset of patients with PIK3CA-mutated tumors, the ORR was 56.2% for 73 patients in the taselisib arm, vs. 38% for 79 patients in the placebo arm (OR, 2.03; P = .033).
The pCRs in the overall population were 1.8% with taselisib vs. 0.6% with placebo. The corresponding pCRs in the PIK3CA-mutated population were 1.4% and 0%. None of the differences were statistically significant.
In all, 11.4% of patients assigned to taselisib required dose reductions, and 10.8% had to discontinue the drug.
The incidence of adverse events of any grade was 91% with letrozole/taselisib, and 83.2% with letrozole placebo.
Taselisib was associated with higher rates of gastrointestinal side effects, skin and subcutaneous disorders, metabolic and nutritional side effects and respiratory, thoracic, and mediastinal disorders. Patients in the taselisib arm had a lower incidence of musculoskeletal/connective tissue problems, vascular disorders, and psychiatric complaints.
The toxicities were generally manageable and consistent with that of other PI3K inhibitors, Dr. Saura said.
Dr. Nadia Harbeck
She said that although taselisib is more selective than other PI3K inhibitors and has a somewhat lower incidence of GI toxicities, “it’s still difficult to manage as a drug in the clinic, but I think if we can tell a patient there is a selection criterion which is a PIK3CA mutation, then patients are more willing and we as therapists are more willing to give those drugs.”
LORELEI provides the first clinical proof of efficacy of a specific PI3K inhibitor in early breast cancer, and “results of confirmatory phase 3 trials in metastatic breast cancer are eagerly awaited,” Dr. Harbeck added.
The study was supported by Genentech/F. Hoffman–La Roche. Dr. Saura disclosed consulting fees and institutional funding from Roche. Dr. Harbeck reported no disclosures relevant to the study.