FDA OKs Study Progression of (Z)-Endoxifen in Metastatic Breast Cancer

The FDA issued a “Study May Proceed” letter for a new study investigating oral (Z)-endoxifen in patients with metastatic breast cancer, according to a news release from the developer, Atossa Therapeutics.¹ The subject of a recent investigational new drug (IND) application, the ongoing study aims to provide a new therapeutic strategy for patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer who have limited treatment options.

Previously, investigators evaluated (Z)-endoxifen among premenopausal patients with ER-positive, HER2-negative breast cancer as part of the phase 2 EVANGELINE trial (NCT05607004).² According to the developers, EVANGELINE is the first trial to evaluate the investigational selective estrogen receptor modulator/degrader (SERM/D) among this premenopausal patient group. A pharmacodynamic run-in analysis revealed early biologic activity, including a 4-week KI-67 of no more than 10% rate of 86% in this population, which supported the 40 mg dose with ovarian function suppression (OFS).

"This letter marks an important regulatory milestone for Atossa and to potentially expand the use of (Z)-endoxifen for metastatic [ER-positive, HER2-negative] breast cancer. We believe its activity, even in tumors that have developed resistance to other endocrine therapies and in the oncogenic signaling pathway, protein kinase C beta 1 (PKCβ1), may offer a new tool in treating this disease," Steven Quay, MD, PhD, president and chief executive officer of Atossa Therapeutics, said in the news release.¹ "We appreciate the FDA's review and look forward to advancing this clinical investigation."

The open label phase 2 EVANGELINE trial assigned patients to receive (Z)-endoxifen alone or with OFS against the current standard-of-care treatment, which typically involves a combination of the drug exemestane (Aromasin) and OFS. In the pharmacokinetic arm treatment arm, patients received 40 mg of oral (Z)-endoxifen with an option to evaluate 20 or 80 mg for 4 weeks; if Ki-67 was no higher than 10% at week 4, patients could have continued for a maximum of six 28-day cycles.³ In the treatment cohort, patients received oral (Z)-endoxifen at 40 mg daily for 4 weeks plus goserelin (Zoladex) at 3.6 mg subcutaneously every 4 weeks, with treatment continuing for a maximum of 6 cycles if Ki-67 was no higher than 10%.

The primary end points of the trial included steady-state plasma concentrations in the pharmacokinetic cohort, as well as Ki-67 levels and objective tumor response in the treatment cohorts. Secondary end points included area under the plasma concentration curve, radiographic response rate and pathologic complete response per RECIST v1.1 criteria, safety, and change in menopause quality of life.

(Z)-endoxifen was engineered with additional PKCβ1 inhibition, providing consistent systemic exposure independent of CYP2D6 metabolism.⁴ Additionally, the oral agent has shown a favorable safety profile and pharmacology compared with tamoxifen (Nolvadex), which includes ER targeting and protein kinase C inhibition.

Those eligible for enrollment in the trial were adult patients with ER-positive/HER2-negative disease assigned female at birth; not lactating, pregnant, or planning to become pregnant; and premenopausal, defined as currently menstruating or having a plasma estradiol in the premenopausal range. Additional inclusion criteria included an ECOG performance status of 0 to 2, receipt of an MRI within 35 days of registration, and a willingness to provide blood and breast tissue samples.

Women with bilateral invasive breast cancer, inflammatory breast cancer, and/or documented dermal lymphatic invasion; any diagnosis or treatment for breast cancer or history of other active malignancies within 2 years prior to study entry; and any uncontrolled intercurrent illness were excluded from trial entry. Additionally, those with known metastatic disease, involvement in another investigational clinical trial within 6 months of registration, and allergy to any treatment drugs were precluded from enrollment.

References

1. Atossa Therapeutics receives FDA "Study May Proceed" letter for (Z)-Endoxifen investigational new drug application for metastatic breast cancer. News release. Atossa Therapeutics. January 6, 2026. Accessed January 6, 2026. https://tinyurl.com/429rhu28
2. Atossa Therapeutics presents four clinical trial updates highlighting (Z)-Endoxifen research at the 2025 San Antonio Breast Cancer Symposium. News release. Atossa Therapeutics. December 15, 2025. Accessed January 6, 2026. https://tinyurl.com/44z84z8c
3. (Z)-endoxifen for the treatment of premenopausal women with ER+/​HER2- breast cancer (EVANGELINE). ClinicalTrials.gov. Updated October 30, 2025. Accessed January 6, 2026. https://tinyurl.com/yc6h5pk4
4. Atossa Therapeutics wins 2025 Clinical Trials Arena Research and Development Excellence Award in precision endocrine therapy category. News release. Atossa Therapeutics. December 17, 2025. Accessed January 6, 2026. https://tinyurl.com/yznrh7a7