A Phase Ii Study Of Combined Fulvestrant And Everolimus In Metastatic Estrogen Receptor (Er) Plus Breast Cancer After Aromatase Inhibitor (Ai) Failure

541 Background: Fulvestrant, an ER downregulator, can be effective in metastatic ER+ breast cancer but resistance is a problem. Everolimus inhibits mTOR; a key pathway in endocrine resistance. We hypothesized that everolimus may delay resistance to fulvestrant and thus improve its efficacy. Methods: We enrolled postmenopausal women with ER+ breast cancer who experienced disease relapse or progression within 6 months of AI use and had measurable/evaluable disease. Fulvestrant was given at 500 mg IM on day1, 250 mg d14, d28, and monthly thereafter. Everolimus was given at 10 mg po daily. Primary endpoint was time to progression (TTP) and secondary endpoints included safety, response, and biomarker analysis. A sample size of 40 patients was calculated to meet a median TTP of 7 vs. 3.7 months for fulvestrant alone as reported in the EFECT trial. Tumor blocks were collected and biopsies done for accessible disease. Results: 33 patients were enrolled. 2 were ineligible and are excluded from analysis. Median age was 54 years (range 40-85). Most common disease sites were bone 84%, liver 62%, and lung 55%. 81% of patients received prior tamoxifen, 71% had prior chemotherapy and 23% had multiple AIs. Median TTP is currently 7.4 months with 4 patients remaining on therapy. Responses include complete response 3%, partial response 10%, and stable disease 42%. 32% of patients had primary refractory disease and 13% discontinued therapy before disease assessment. Most common adverse events were elevated AST 81% or ALT 68%, hyperglycemia 61%, anemia 61%, elevated cholesterol 60%, hypokalemia 52%, mucositis 48%, and weight loss 48%. The majority of adverse events were grade I/II. Fasting lipid profile data is summarized. Conclusions: These results suggest that adding everolimus to fulvestrant improves its efficacy in heavily pretreated ER+ metastatic breast cancer. Toxicity was manageable but needs close monitoring. Biomarker analysis is ongoing in order to identify patients not likely to benefit from this treatment strategy. Clinical trial information: NCT00570921. [Table: see text]