Background: Therapies targeting estrogen receptor (ER) signaling are standard for patients (pts) with hormone receptor positive (HR+) (ER and/or progesterone receptor [PR] positive) metastatic breast cancer (MBC). Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been associated with endocrine therapy (ET) resistance. BOLERO-2 demonstrated that the addition of the mTOR inhibitor, everolimus (EVE), to exemestane doubled the PFS in HR+ HER2- MBC pts who previously progressed on nonsteroidal aromatase inhibitor therapy.The premise of this phase 2 trial in HR+ MBC is that the addition of EVE to the last ET on which the disease progressed may restore sensitivity to ET and extend the benefit of the anti-estrogen therapy.

Methods: Pts ≥18 yrs with HR+, HER2- unresectable, locally recurrent, or MBC refractory to ET in either the adjuvant or advanced/metastatic setting. 0-1 chemotherapy (chemo) regimens for MBC were permitted. Post-/ pre-/peri-menopausal women were eligible with ovarian function suppression permitted. Additional eligibility requirements include: no prior mTOR inhibitor therapy, measurable or evaluable disease, ECOG ≤2, adequate bone marrow and organ function. EVE (10 mg PO daily) was administered on a 4-wk cycle in combination with the same dose and schedule of the last ET to which their disease became resistant. Disease assessments were performed every 2 cycles and treatment continued until disease progression or unacceptable toxicity. Blood samples and archival tumor were collected respectively for the VeriStrat Assay and for the Foundation One molecular profiling platform.

Results: 48 pts were enrolled; data from 26 pts is presented. Median age 63.5 yrs (range, 36-81) with 46% ≥ 65 yrs. 14 (54%) pts had received chemo in the adjuvant setting, 9 pts (35%) received chemo for MBC, and 4 pts (15%) received chemo in both settings. All pts had at least 1 prior hormonal therapy; 9 pts received ≥ 3 hormonal agents. EVE was combined with tamoxifen (27%), AIs (61%), and fulvestrant (12%). Median time on treatment was 18.6 wks (range 1-48.9 weeks). 5 pts (19%) remain on treatment and 21 (81%) have discontinued therapy due to: disease progression - 17, toxicity -2, and other causes - 2. 23 pts were evaluable for response. 1 pt on fulvestrant plus EVE had a PR and 18 pts (78%) had SD as best response, with SD > 6 mos in 7 pts, for a clinical benefit rate (CR+PR+ SD ≥ 6 months) of 35%. With a median follow up of 11 mos (range 2-16 mos), the median PFS was 6.6 months (range 3.6-9.4); the median OS has not been reached. Treatment-related adverse events consisted mostly of stomatitis, rash and fatigue with few G3 events: stomatitis 3 pts, rash 2 pts, and 1 each of fatigue, edema, and neutropenia. G1 pneumonitis was present in 2 pts. There were no G4 events or treatment related deaths.

Conclusions: In HR+ HER2- advanced/MBC patients who progressed on prior ET, the addition of EVE to the ET to which their disease became resistant, resulted in 1 PR and 7 pts with SD > 6 mos. The results of the full study population will be presented. Modulation of the mTOR/AKT/PI3K pathway with EVE may extend the benefit of ET, even after tumor progression on ET alone.

Citation Format: Yardley DA, Blakely L, Hemphill B, Joseph M, Liggett W, Daniel B, Castrellon A, Shastry M, Finney L, DeBusk L, Hainsworth JD, Burris III HA. A phase 2 open label study of everolimus in combination with endocrine therapy in resistant hormone receptor-positive HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-09.