The tamoxifen metabolite Z-endoxifen has acceptable tolerability and antitumor activity.

  • Major finding: The tamoxifen metabolite Z-endoxifen has acceptable tolerability and antitumor activity.

  • Concept: Unlike tamoxifen, Z-endoxifen activity is not affected by CYP2D6 polymorphisms.

  • Impact: Z-endoxifen may be beneficial after progression on tamoxifen, especially where endoxifen levels were low.

Tamoxifen is a weak antiestrogen used to treat patients with estrogen receptor (ER)–positive breast cancer. Tamoxifen metabolism produces the more potent antiestrogenic metabolites 4-hydroxytamoxifen (4HT) and 4-hydroxy N-desmethyl tamoxifen (Z-endoxifen). Cytochrome P450 2D6 (CYP2D6) is an enzyme required for the conversion of tamoxifen to endoxifen, and CYP2D6 polymorphisms or low CYP2D6 activity can reduce endoxifen concentrations in patients treated with tamoxifen, which may reduce efficacy. Goetz and colleagues hypothesized that direct treatment with Z-endoxifen might achieve higher endoxifen concentrations and antitumor activity than tamoxifen. Based on this hypothesis, 41 patients with endocrine-refractory ER+ metastatic breast cancer were enrolled in a phase I dose-escalation and expansion study to evaluate the toxicity, pharmacokinetics, pharmacogenetics, and clinical activity of Z-endoxifen and determine the maximum tolerated dose. The overall clinical benefit rate was 26.3% including 19% of patients (3 of 16) with prior progression during tamoxifen and 32% (7 of 22) who had either no prior tamoxifen or no progression with adjuvant tamoxifen. In patients with measurable disease, the overall response rate was 12%, with partial responses observed in 3 of 25 patients. The median progression-free survival time was 110 days. CYP2D6 genotype was not associated with differences in clinical benefit. Circulating cell-free DNA was obtained from 36 patients, and mutations were observed in 13 (36.1%) including mutations in ESR1, PIK3CA, TP53, AKT, and KRAS, which were associated with shorter progression-free survival. Z-endoxifen had clinical benefit even in patients with ESR1 amplification or mutation. Z-endoxifen also had acceptable toxicity, and the maximum tolerated dose was not reached. Taken together, the results of this phase I trial suggest that Z-endoxifen provides substantial drug exposure that is not affected by CYP2D6, acceptable toxicity, and antitumor activity in patients with endocrine-refractory ER+ metastatic breast cancer, supporting further investigation in a phase II trial, which is currently under way.

Goetz MP, Suman VJ, Reid JM, Northfelt DW, Mahr MA, Ralya AT, et al. First-in-human phase I study of the tamoxifen metabolite Z-endoxifen in women with endocrine-refractory metastatic breast cancer. J Clin Oncol 2017 Aug 30 [Epub ahead of print].

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