Neoadjuvant (Z)-endoxifen demonstrated promising antitumor activity for premenopausal patients with ER-positive, HER2-negative breast cancer, according to phase 2 data presented at the 2024 American Association for Cancer Research Annual Meeting.

However, results also showed the steady-state concentrations of (Z)-endoxifen remained below the target for the pharmacokinetic run-in cohort of the study. “While neoadjuvant therapy is effective and widely used across many cancer types, the current treatment options for premenopausal women diagnosed with ER+ breast cancer are sub-optimal,” Steven Quay, MD, PhD, president and CEO of Atossa Pharmaceuticals, said in a press release. “An effective and tolerable neoadjuvant therapy would transform the treatment approach in this setting, making surgery more effective and reducing the likelihood that the cancer will recur.”

In xenograft models, (Z)-endoxifen showed superiority to tamoxifen and aromatase inhibitors in promoting antitumor activity in premenopausal patients with endocrine-resistant disease. In a pharmacokinetic run-in cohort of the ongoing EVANGELINE study, researchers conjectured that (Z)-endoxifen would be non-inferior to the combination of aromatase inhibitors and ovarian function suppression for premenopausal patients, thus removing the need for neoadjuvant ovarian function suppression.

The pharmacokinetic run-in cohort included data from 7 patients (median age, 46 years; range, 28-51), who received (Z)-endoxifen at a daily dose of 40 mg. The researchers’ steady-state concentration target was between 500 ng/mL and 1000 ng/mL to target both estrogen receptor alpha and protein kinase C beta 1.

In this cohort, the median Ki67 level was 13 (range, 4-33), and the majority of patients had T2 tumors (n = 6) and grade 2 tumors (n = 6). At day 28, the median steady-state concentration was 263.6 (range, 180.3-376.6). Treatment was discontinued for 1 patient at week 4, with Ki67 levels remaining above 10%. For the remaining 6 patients, endocrine-sensitive disease was achieved by week 4, with 3 patients maintaining Ki67 levels at or below 10% and 3 patients achieving those levels.

The remaining 6 patients underwent surgery at week 24, all with Ki67 levels at or below 3% (range, 0-3). Target lesion decreases were observed by MRI central review in all patients at weeks 12 and 24. One complete response and one partial response were seen, along with four cases of stable disease. (Z)-endoxifen treatment was well tolerated. Adverse events included grade 3 headache (n = 1), grade 2 amenorrhea (n = 1), and grade 2 hot flashes (n = 1).

“The median baseline estrone (n = 5) was 54 pg/mL (range, 19‑114) with median fold increase from baseline of 9 (range, 1.3-23.2) at week 4 and 4.7 (range, 0.4-25.9) at week 24,” the researchers wrote. “The median baseline estradiol level (n = 5) was 29 pg/mL (range, 19-209) with median fold increases from baseline of 17.9 (range, 0.4-57) at week 4 and 8.1 (range, 0.04-56.6) at week 24.”

In the EVANGELINE study, enrollment remains ongoing for a pharmacokinetic run-in cohort to be treated at a daily dose of 80 mg.

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Disclosures: Some authors declared financial ties to drugmakers. See full study for details. Quay is an employee of Atossa Therapeutics. EVANGELINE is being supported by Atossa Therapeutics.

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