First-in-Human Study of Tamoxifen Metabolite Z-Endoxifen in Endocrine-Refractory Metastatic Breast Cancer


Key Points

  • Antitumor activity was observed with Z-endoxifen in patients with endocrine-refractory estrogen receptor–positive metastatic breast cancer.
  • Drug exposure was unaffected by CYP2D6 metabolism.

A first-in-human phase I study of the oral tamoxifen metabolite Z-endoxifen showed high drug exposure, acceptable toxicity, and antitumor activity in endocrine-refractory estrogen receptor–positive metastatic breast cancer. The findings were reported in the Journal of Clinical Oncology by Goetz et al.

Study Details

In the study, 38 evaluable patients received endoxifen at 7 dose levels from 20 to 160 mg/d. Disease progression had occurred with prior aromatase inhibitor treatment in 36 patients, with fulvestrant (Faslodex) in 21 patients, and with tamoxifen in 15 patients. Circulating tumor cell–free DNA was obtained from all patents, and simultaneous fresh tumor biopsies were obtained from 14 patients.

Drug Exposure

Dose escalation was stopped at 160 mg/d given a lack of maximum tolerated dose and achieved endoxifen concentrations of > 1,900 ng/mL. Low CYP2D6 activity resulted in reduced conversion of tamoxifen to the endoxifen metabolite; no effect of endoxifen clearance was observed according to CYP2D6 genotype. One patient had cycle 1 dose-limiting toxicity (pulmonary embolus) at 60 mg/d.

Antitumor Activity

Overall, partial response was observed in 3 patients and stable disease > 6 months was seen in 7 patients, yielding a clinical benefit rate of 26.3%. The clinical benefit was observed in 3 patients with disease progression on prior tamoxifen.

Circulating Tumor Cell–Free DNA and Tumor Mutations

Circulating tumor cell–free DNA mutations were observed in 13 patients, including alterations in PIK3CA in 8, ESR1 in 5, TP53 in 4, and AKT in 1; these patients had reduced progression-free survival vs those without circulating tumor cell–free DNA mutations (median = 61 vs 132 days, P = .046). Clinical benefit was observed in patients with ESR1 amplification (in tumor, at 80 mg/d) and ESR1 mutation (in circulating tumor cell–free DNA, at 160 mg/d). Tumor mutations in PIK3CA, TP53, and AKT were undetected by circulating tumor cell–free DNA, whereas circulating tumor cell–free DNA mutations in ESR1, TP53, and AKT were undetected by biopsy.


The investigators concluded: “In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.”

The study was supported by National Cancer Institute grants, Regis Foundation, Prospect Creek Foundation and George M. Eisenberg Foundation for Charities.

Matthew P. Goetz, MD, of Mayo Clinic, Rochester, is the corresponding author of the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.




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