Abstract P2-14-05: A phase II study of combined fulvestrant and RAD001 (everolimus) in metastatic estrogen receptor (ER) positive breast cancer after aromatase inhibitor (AI) failure.

Background: Fulvestrant is used to treat women with metastatic ER-positive breast cancer after AI failure, but has a short duration of benefit. Pi3K/mTOR signaling has been implicated in preclinical models of fulvestrant resistance and recent trials suggest that everolimus, an oral inhibitor of mTOR, can overcome resistance to other forms of endocrine therapy. We hypothesized that everolimus may delay resistance to fulvestrant and prolong time to progression (TTP). Methods: We designed a phase II clinical trial of combined fulvestrant and everolimus in postmenopausal women with ER-positive breast cancer who relapsed or experienced metastatic disease progression within 6 months of AI use. Fulvestrant was given at 500 mg IM on day1, 250 mg d14, 250 mg d28, and monthly thereafter. Everolimus was given at 10 mg po daily. Patients were required to have measurable or evaluable disease with preserved performance status and adequate organ function. Primary endpoint is TTP, and secondary endpoints are safety, response rate, clinical benefit rate, and biomarker analysis. A sample size of 40 patients was calculated to meet a median TTP of 7.0 vs. 3.7 months for fulvestrant alone as reported in the EFECT trial. Patients were followed monthly for clinical and toxicity assessment and imaging was obtained every 2 months. Tumor blocks were collected when available and biopsies were offered if disease was accessible. Results: To date, 30 patients enrolled on study with a median age of 56 years (range 39–85). Most common metastatic disease sites were bone in 26 patients (87%), liver in 19 (63%), and lung in 16 (53%). Prior therapy included tamoxifen in 21 patients (70%), and chemotherapy in 20 (67%), of those 17 were in the adjuvant/neoadjuvant setting. 6 patients (20%) received more than one AI. 2 patients were ruled ineligible immediately after enrollment and starting study treatment, one because of a creatinine level outside the reference range and one because of the need for palliative radiation. Of the remaining 28 patients, 18 discontinued therapy because of disease progression, 3 because of toxicity, 2 upon patient request, and 1 because of unrelated intercurrent illness, with 4 patients currently on therapy. Most common adverse events reported were mucositis in 13 patients (43%) and rash in 11 (36%). Most common laboratory abnormalities were elevated ALT/AST in 18 patients (60%), elevated cholesterol in 13 (43%), and hypokalemia in 13 (43%). The majority of toxicities were grade I/II. Most common grade III toxicities, regardless of attribution, were infection requiring hospitalization in 3 patients (10%), hypokalemia in 3 (10%) and mucositis in 2 (7.4%). There was one grade 4 toxicity reported-hypokalemia. Overall, treatment was reasonably tolerated and toxicities manageable. Efficacy findings, including the primary endpoint of TTP, will be analyzed and presented at the meeting. Conclusions: Combined everolimus with fulvestrant is feasible and has manageable toxicities in this cohort of women with metastatic ER-positive breast cancer. Detailed efficacy analysis along with updated toxicity data will be presented at the meeting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-05.