ENDOXIFEN INSTEAD OF TAMOXIFEN?

SAN ANTONIO – In the first human experience with a drug that is the main metabolite of tamoxifen, promising responses were observed in woman diagnosed with aromatase inhibitor resistant, metastatic breast cancer, researchers said here.

In a dose-ranging Phase 1 trial that included 22 women, two partial responses were observed and nine women achieved disease stabilization on seven different doses of endoxifen, said Matthew Goetz, MD, deputy director of the Mayo Clinic Breast Cancer Specialized Program of Research Excellence (SPORE), Rochester, Minn.

Ten women progressed while on endoxifen; one woman was not evaluable, Goetz said in his poster discussion sessions at the annual San Antonio Breast Cancer Symposium.

He said that low concentrations of endoxifen were associated with poorer outcomes in both breast cancer patients and in animal models.

He noted that in an animal model of a letrozole resistant xenograft, endoxifen appeared superior to tamoxifen, exemestane and exemestane plus everolimus (RAD001). "The reasons for the superior antitumor activity of endoxifen appears to be complex, and related to the fact that endoxifen is a more potent anti-estrogen, does not activate critical oncogenes involved in nongenomic signaling and may inhibit other kinases."

The women in the trial were treated at doses from 20 mg to 160 mg. One dose limiting toxicity – a pulmonary embolus – was observed in one patient at the 60 mg dose. The most common grade 2 side effect seen was hot flashes. There was no evidence of eye toxicity on serial dilated eye exams.

Although the maximum tolerated dose of endoxifen was not established in the Phase 1 trial because Goetz and colleagues plan to take the 40 mg a day dose and the 160 mg a day dose further in clinical studies.

Two patients were treated at the 20 mg level; two women received 40 mg; six women received 60 mg, and three women were dosed at 80 mg, 100 mg, 120 mg and 160 mg.

Steven Vogl, MD, a private practice oncologist in The Bronx, told MedPage Today, "There is a subset of women with breast cancer who die because we don't have any more hormone therapy to give them. We need more of these drugs. Endoxifen is an interesting drug. It looks promising.

"There are all sorts of problems with tamoxifen. Some people can't convert tamoxifen to the active agent endoxifen; some people take antidepressants that interfere with tamoxifen. Maybe if you gave the real drug, you wouldn't have to worry about that."

The median age of the women in the study was 58 years and all were in performance status 0-1. Nine of the women in the study had been on at least three previous treatment regimens and seven women had been on two previous regimens. The remaining women had been on a single previous regimen. In all cases disease had progressed despite treatment.