Early clinical trials suggested that shows that the addition of Afinitor to chemotherapy with Herceptin can overcome resistance to Herceptin. Preclinical data have shown that Afinitor, an inhibitor of mTOR, acts on the pathway that mediates Herceptin resistance and has the potential to help restore response in these patients. Afinitor works through direct antitumor activity and through its influence on two of the most important pathways for breast cancer, the erbB receptor and the HER2 pathways.
In 2011, a Phase III clinical trial (BOLERO-2) among 724 women was presented and generated a great deal of interest. All of the women had experienced cancer recurrence or progression in spite of treatment with Femara or Arimidex. Study participants were treated with Aromasin alone or in combination with Afinitor.
■Survival without cancer progression was 6.9 months among women treated with both Afinitor and Aromasin, compared with 2.8 months among women treated with Aromasin alone.
■The most common serious side effects in the Afinitor group were stomatitis (inflammation of the lining of the mouth; 7.7%), anemia (5.8%), shortness of breath (3.9%), hyperglycemia (4.3%), fatigue (3.7%) and pneumonitis (lung inflammation; 3.1%), and elevated liver enzymes (3.1%).
These results suggest that the addition of Afinitor to Aromasin improved outcomes among women with advanced breast cancer that had previously been treated with hormonal therapy.
AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.
For women who failed both anastrozole and examestane, there is the trial: Safety and Efficacy of RAD001 (Everolimus) in Combination With Letrozole in Treatment of Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer NCT01231659. This is a multi-center, Israeli phase II open label study evaluating treatment with RAD001 (10 mg daily) combined with letrozole (2.5 mg daily) in postmenopausal women after recurrence or progression on Tamoxifen, Anastrozole or Examestane.
Some physicians are using Afinitor with tamoxifen. A 2012 open-label, phase II study by Bourgier et al, randomly assigned postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%). Teh authors concluded that this study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.
O’Regan, R., et al. RAD001 (everolimus) in Combinations with Weekly Paclitaxel and Trastuzumab in Patients with HER-2-Overexpressing Metastatic Breast Cancer with Prior Resistance to Trastuzumab: A Multicenter Phase I Clinical Trial. Poster presented at SABCS 2008.
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Fasolo, A., et al. Multicenter Phase I Clinical Trial of Daily and Weekly Everolimus (RAD001) in Combination with Vinorelbine and Trastuzumab in Patients with HER-2-Overexpressing in Metastatic Breast Cancer with Prior Resistance to Trastuzumab. Poster presented at SABCS 2008.
Morrow P.K. et al, “Phase I/II trial of everolimus (RAD001) and trastuzumab in patients with trastuzumab-resistant, HER2-overexpressing breast cancer,”Abstract 1014, Journal of Clinical Oncology. Vol. 28, No. 15s, p. 117s.
Afinitor, Prescribing Information, 2017