Atossa Therapeutics, Inc. (Nasdaq: ATOS) announced new data from its Phase 2 EVANGELINE trial at the 2024 San Antonio Breast Cancer Symposium (SABCS), highlighting the potential of (Z)-endoxifen as a neoadjuvant treatment for premenopausal women with estrogen receptor-positive (ER+), HER2-negative breast cancer. The study aimed to evaluate the pharmacokinetic profile and tolerability of (Z)-endoxifen, a selective estrogen receptor modulator (SERM).
The EVANGELINE trial is a randomized, Phase 2 non-inferiority study. The initial pharmacokinetic (PK) run-in phase evaluated (Z)-endoxifen monotherapy at 40 mg (previously reported) and 80 mg (new data) doses, both with and without goserelin for ovarian function suppression (OFS).
Key Findings from the EVANGELINE Trial
The trial's primary endpoint was met, with 50% of patients (3 out of 6) in the group receiving 80 mg of (Z)-endoxifen with goserelin achieving the target steady-state plasma concentrations (Css) of 500–1000 ng/mL. Approximately 38% of patients (3 out of 8) in the 80 mg/day (Z)-endoxifen-only group reached target Css levels. The average plasma Css level for all patients receiving 80 mg/day of (Z)-endoxifen was 484 ng/mL. Notably, prior data showed that no patients in the 40 mg/day (Z)-endoxifen arm reached the target plasma Css level of 500 ng/mL.
Tissue penetration was also evaluated, revealing that the 80 mg/day dose, in both treatment arms, achieved tissue Css levels more than double that of plasma levels, surpassing the 500 ng/g target in 90% of patients. This level is considered adequate for targeting PKCβ, a known oncogenic protein.
Across all dosing levels, substantial tumor suppression was observed, irrespective of ovarian function suppression (OFS). The 4-week Ki-67 ≤10% response rate was generally above 85% across dose levels, with or without OFS.
Safety and Tolerability
Overall, (Z)-endoxifen was well-tolerated, and target tissue Css levels were achieved without significant Grade 3–4 toxicities. However, four gynecologic events were reported in the 80 mg groups, including one Grade 3 hemorrhagic cyst. These findings led to protocol amendments to optimize dosing and tolerability.
Quality of life (QOL) data indicated that (Z)-endoxifen was generally well-tolerated, with most patient-reported side effects being low grade. Symptoms such as hot flashes and reduced libido were reported as mildly to moderately bothersome, while amenorrhea and menstrual suppression were common but generally manageable.
Next Steps for EVANGELINE
Based on these findings, the EVANGELINE trial is expected to proceed with an amended protocol. The randomized trial will compare (Z)-endoxifen 40 mg/day plus OFS to exemestane plus OFS, using the 4-week Ki-67 reduction as the primary endpoint. While tumor tissue (Z)-endoxifen levels were not tested at the 40 mg/day dose level, based on the plasma/tumor Css ratio, (Z)-endoxifen tumor concentrations are expected to be >500 ng/g, meeting the required levels for PKCβ targeting.
Recruitment for this cohort is expected to begin in 2025, following the conclusion of the PK run-in phase.
Implications for Breast Cancer Treatment
These results suggest that (Z)-endoxifen could offer a better-tolerated alternative for premenopausal women with ER+/HER2- breast cancer. The high tissue penetration and significant tumor suppression observed in the EVANGELINE trial support its potential as an effective neoadjuvant treatment. The decision to proceed with a lower 40 mg/day dose in the randomized trial reflects a careful risk-benefit assessment, aiming to optimize tolerability while maintaining efficacy.
According to Steven Quay, M.D., Ph.D., Atossa’s President and Chief Executive Officer, the company is encouraged by the breadth of data being presented at SABCS, which collectively advances the understanding of (Z)-endoxifen’s safety, efficacy, and impact on patient quality of life. Atossa plans to advance this arm of the study in 2025 to demonstrate the potential of (Z)-endoxifen to improve outcomes and provide a better-tolerated option for premenopausal women with ER+/HER2- breast cancer.
