Dr Goetz on the Early Pharmacokinetic Data With Neoadjuvant (Z)-endoxifen in ER+/HER2– Breast Cancer

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses pharmacokinetic data for neoadjuvant (Z)-endoxifen derived from the phase 2 EVANGELINE trial (NCT05607004) of premenopausal patients with metastatic estrogen receptor (ER)–positive, HER2-negative breast cancer.

It is hypothesized that the ability of (Z)-endoxifen to target both ERα and PKCβ1 will reduce the need for ovarian function suppression, and demonstrate noninferiority compared with ovarian function suppression and an aromatase inhibitor in ER-positive, HER2-negative disease. The ongoing, multicenter, neoadjuvant EVANGELINE trial was designed to identify the optimal dose for the potent anti-estrogen agent to demonstrate activity in this patient population without increasing toxicities, Goetz details. A total of 7 women were enrolled onto the pharmacokinetic run-in portion of the study and received 40 mg of the study drug per day, he states.

Results from the pharmacokinetic run-in, which were presented at the 2024 AACR Annual Meeting, demonstrated that concentrations observed with the 40 mg dose ranged between 200 to 400 ng/ml, which was slightly below the target range, Goetz reports. As a result, the study is progressing to evaluate the 80 mg per day dose of (Z)-endoxifen to achieve optimal therapeutic concentrations, he explains. Enrollment to this portion of the study is ongoing.

Thus far, notable anti-tumor activity was observed at the 40 mg dose, with 6 enrolled patients showing a decrease in Ki67 levels of 10% or less at day 28, Goetz states. Moreover, these patients proceeded to undergo surgery after 24 weeks with a surgical Ki-67 level less than 3%, he says, adding that surgical data will be presented at a subsequent meeting. Importantly, no concerning safety signals have emerged thus far from the study.

Based on these findings, it is expected that the 80 mg per day dose level will be identified as the ideal dosage moving forward, Goetz says. Once the optimal dose is established, the study will advance into a larger phase 2 clinical trial to further evaluate the efficacy and safety of this treatment approach in a broader patient population, Goetz concludes.