Z-endoxifen Demonstrates Encouraging Results in Endocrine Refractory Breast Cancer

Tumor shrinkage was induced in women with ER-positive metastatic breast cancer who had progressed on standard anti-estrogen therapies with treatment with Z-endoxifen, a potent derivative of the drug tamoxifen.

Matthew Goetz, MD

Tumor shrinkage was induced in women with ER-positive metastatic breast cancer who had progressed on standard anti-estrogen therapies with treatment with Z-endoxifen, a potent derivative of the drug tamoxifen.

In results recently published online in theJournal of Clinical Oncology, investigators led by Matthew Goetz, MD, professor of oncology at Mayo Clinic in Rochester, found that Z-endoxifen had acceptable toxicity and “provides substantial drug exposure unaffected by CYP2D6 metabolism.”

“Tamoxifen is converted into endoxifen in the liver by an enzyme called CYP2D6. Our previous research found that tamoxifen may be less effective in women with poor CYP2D6 metabolism,” Goetz said in a press release. “The primary goal of the study was to safely deliver therapeutic levels of endoxifen without the requirement for CYP2D6 liver metabolism. However, one of the most surprising observations was the prolonged anticancer benefit, [which] in some cases lasted more than 2 years in women who had progressed on standard anti-estrogen therapies.”

“We are encouraged by these results and [are] hopeful that, based on these data and ongoing studies, Z-endoxifen could become a new FDA-approved treatment for women with estrogen-positive metastatic breast cancer,” added Goetz.

Forty-one women with ER-positive metastatic or locally recurrent breast cancer enrolled in the dose escalation/expansion study from March 2011 to December 2014. Thirty-eight patients were included in the maximum-tolerated dose analysis.

Of 22 patients in the dose-escalation phase, 54.5% had received 2 to 7 prior treatment regimens, Twenty-one (95.4%) progressed after treatment with aromatase inhibitors (AIs) and 10 (45.5%) progressed after tamoxifen treatment.

Of 16 patients in the expansion phase, 68.8% underwent 2 to 7 prior treatment regimens. Fifteen (93.8%) progressed after treatment with AIs and 6 (37.5%) progressed following treatment with tamoxifen.

Investigators observed tumor responses and prolonged antitumor activity in patients with prior progression during multiple lines of endocrine therapy. Of the 36 patients with prior progression during treatment with AIs, those who experienced additional progression during tamoxifen and fulvestrant treatment derived a clinical benefit. Four patients had received prior treatment with exemestane/everolimus. Of those, 1 maintained stable disease and 2 others had a confirmed partial response (PR; n = 2) lasting more than 6 months.

During the dose-escalation phase, patients were assigned to 1 of 7 daily doses from 20 mg to 160 mg. On the basis of the pattern of toxicities observed, tumor response, and endoxifen steady-state concentrations (Csss), investigators continued the study with 3 daily dose levels: 40 mg (n = 6), 80 mg (n = 5), and 100 mg (n = 5). Patients were randomly assigned to a dose level using a stratified randomization procedure, with the stratification factors of dominant disease, prior everolimus-containing regimen, and hormone resistance.

Investigators observed antitumor activity, defined as confirmed PR or stable disease >6 months, at all dose levels except 20 mg and 120 mg. Among the 25 patients with measurable disease, 14 of whom enrolled during dose escalation, 3 had a PR on 2 consecutive evaluations at least 8 weeks apart. The overall response rate (ORR) was thus 12.0% (95% CI, 2.6-31.2). Five of 25 patients with measurable disease and 2 of 13 patients with unmeasurable disease displayed stable disease for >6 months, for a clinical benefit rate of 26.3% (95% CI, 13.4-43.1).

Three (19%) of 16 patients who experienced progression during tamoxifen treatment derived clinical benefit, defined as stable disease for at least 6 months, as did 7 (32%) of 22 patients who had no prior tamoxifen treatment or did not experience progression with adjuvant tamoxifen.

At the time of data lock, 2 patients were alive without progression, 29 were alive with progression, and 7 had died as a result of disease. The median progression-free survival (PFS) time was 110 days, with a 1-year PFS rate of 15% (95% CI, 6.2-31.4).

Investigators collected CYP2D6 activity score (AS) for 34 patients. PFS among those with AS ≥2.0 was similar to that of patients with AS ≤1.5 (log-rank P = .8604). Within the subset of 24 patients with prior tamoxifen exposure, the median PFS time was 60 days (IQR, 31-132) among those with AS ≥2.0 (n = 11) and 157 days (IQR, 72-296) among those with AS ≤1.5 (n = 12).

Goetz et al did not observe the eye toxicity typically associated with tamoxifen, even in patients who remained on study for as long as 6 months. Previous studies have shown that high doses of tamoxifen (Csss of 4 to 8 µmol/L) are associated with renal toxicity, and substantial neurotoxicity, including tremor, hyperreflexia, dysmetria, unsteady gait, and dizziness when administered in combination with vinblastine. Z-endoxifen was not associated with neurotoxicity, despite concentrations greater than 5 µmol/L at the 160-mg dose.

Goetz and investigators with the Alliance for Clinical Trials in Oncology and the National Cancer Institute recently completed the randomized A011203 trial comparing 20 mg of daily tamoxifen with 80 mg of daily Z-endoxifen in women who progressed during prior aromatase inhibitor therapy. Results are expected in 2018.


Goetz MP, Suman VJ, Reid JM, et al. First-in-human phase I study of the tamoxifen metabolite Z-endoxifen in women with endocrine-refractory metastatic breast cancer [published online August 30, 2017].J Clin Oncol.doi: 10.1200/JCO.2017.73.3246.