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Combination therapy with everolimus may improve metastatic breast cancer outcomes
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33rd Annual San Antonio Breast Cancer Symposium
SAN ANTONIO — Everolimus plus tamoxifen yielded clinical benefit rates nearly 20% higher than those observed for tamoxifen alone in women with hormone receptor-positive, HER-2–negative metastatic breast cancer, according to findings presented here at the 33rd Annual San Antonio Breast Cancer Symposium.
Thomas Bachelot, MD, of the Centre Léon Bérard in Lyon, France, said everolimus has been shown to reverse resistance to tamoxifen in preclinical studies and may also increase neoadjuvant letrozole efficacy in combination therapy.
The aim of the current study was to estimate the efficacy of everolimus-tamoxifen combination therapy in women with hormone receptor-positive, HER-2–negative metastatic breast cancer who had been pre-treated with an aromatase inhibitor.
Patients were stratified by time to progression after being treated with an aromatase inhibitor. Fifty-seven patients were assigned tamoxifen 20 mg per day alone, and 54 patients were assigned everolimus 10 mg per day plus tamoxifen 20 mg per day.
Results of an intention-to-treat analysis conducted at a median follow-up of 13 months indicated that the clinical benefit rate was 42.1% (95% CI, 29.1-55.9) in the tamoxifen-only arm and 61.1% (95% CI, 46.9-74.1) in the combination arm.
“The clinical benefit remained in selected subgroups,” Bachelot said. “For example, it was observed in patients with or without visceral metastases and with or without previous adjuvant hormone therapy.”
Median time to progression was 4.5 months (95% CI, 3.7-8.7) in the monotherapy group and 8.6 months (95% CI, 6.01-13.9) in the combination group.
“Time to progression may have been observed as a function of intrinsic hormone resistance,” Bachelot said. “The clinical benefit may favor patients with secondary hormone resistance.”
Tamoxifen was decreased to 5 mg per day in 28% of patients. Three patients in the monotherapy arm and two patients in the combination arm ceased treatment because of toxicity. Grade 3 to 4 adverse events were manageable, according to Bachelot.
“As expected, patients in the experimental arm experienced adverse events associated with everolimus,” he said.
There were no toxic deaths, and toxicity was manageable in both groups. There were 17 deaths in the tamoxifen arm and five deaths in the combination arm at the time of analysis.
“Previous exposure to an aromatase inhibitor may increase the proportion of patients whose tumor may be driven by an activation of the PI3K/AKT/mTOR pathway,” Bachelot said.
The researchers defined the primary endpoint of clinical benefit rate as the absence of progression at 6 months in the combination arm. Safety and time to progression were the secondary endpoints.
Bachelot said baseline characteristics were balanced between the two groups.
“Prior aromatase inhibitor treatment had been administered to 31% of patients in the adjuvant setting, 60% in the metastatic setting and 9% in both the adjuvant and metastatic setting,” he said. “Also, it is worth noting that this population was poorly hormone sensitive, as all but 10 patients had progressed either during aromatase inhibitor treatment or within 6 months after that treatment being used as adjuvant therapy.”
Prior chemotherapy had been administered in 51% of patients in the adjuvant setting and 25% of patients in the metastatic setting.
“Based on these promising results, this combination warrants further study in hormone receptor-positive/HER-2–negative metastatic breast cancer after progression on aromatase inhibitors,” Bachelot said.
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