A randomized trial of abemaciclib in combination with fulvestrant compared to chemotherapy in women with HR+, HER2-advanced breast cancer with visceral metastases

Background: Abemaciclib is a potent oral cyclin-dependent kinase (CDK) 4 and 6 inhibitor that demonstrated statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR) in combination with endocrine therapy (ET) in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced and metastatic breast cancer patients in Phase 3 studies. In contrast to NCCN guidelines, cytotoxic chemotherapy is still often initiated early in the course of HR+, HER2- advanced breast cancer despite absence of visceral crises, potentially denying patients effective and tolerable standard-of-care regimens containing ET. The current study aims to compare the efficacy and safety of abemaciclib in combination with ET to chemotherapy in patients with HR+, HER2- advanced breast cancer with ≥1 site of visceral metastases. Trial design: I3Y-MC-JPCU is a multicenter, open-label, randomized, controlled study of abemaciclib in combination with fulvestrant compared to physician’s choice of chemotherapy in women with HR+, HER2- locally advanced or metastatic breast cancer who have poor prognosis due to visceral metastases. Approximately 300 patients will be randomized 1:1 to Arm A (abemaciclib, 150 mg BID, in combination with fulvestrant, n=150) or Arm B (physician’s choice of chemotherapy [capecitabine, docetaxel, nab-paclitaxel, or paclitaxel], n=150). Stratification factors will include liver metastasis, sensitivity to endocrine therapy (sensitive vs primary resistance vs secondary resistance, and postmenopausal status (natural/surgical/therapeutic radiation vs GnRH use). It will be conducted in the USA. Accrual is planned to start in 2019. Eligibility: Key inclusion criteria are postmenopausal HR+, HER2- patients with locally advanced recurrent and unresectable or metastatic HR+, HER2- breast cancer and ≥1 site of visceral metastasis as well as disease progression after ≥1 line of ET in (neo)adjuvant or metastatic setting. Individuals will be excluded if they have visceral crisis, have received prior systemic therapy other than ET for metastatic disease, have received \u003e1 prior ET for metastatic disease, and/or have been treated with fulvestrant or any CDK 4 and F6 inhibitor for any duration. Objectives: The primary objective is ORR. Secondary objectives include PFS, time to response, duration of response, time to second disease progression (PFS2), and safety. Exploratory objectives include healthcare resource utilization, patient reported outcomes, and relationship of pharmacogenomics/biomarkers to clinical outcomes. Statistical Methods: Comparability of abemaciclib in combination with fulvestrant to chemotherapy will be evaluated with respect to ORR and PFS. The study is designed to demonstrate comparability using a 10% ORR margin and a 20% PFS margin. Comparability will declared if the posterior probability the true difference is less than the comparability margin is at least 80%. PFS comparability will be assessed only if ORR comparability is declared after a gatekeeping testing strategy. The tested hypotheses will be 1) ORR comparability: ≥80% posterior probability that true ORRArm B - true ORRArm A Citation Format: Peter Kaufman, John Glaspy, Wei Zhang, Andrew Koustenis, Yanyun Chen, Adam Brufsky. A randomized trial of abemaciclib in combination with fulvestrant compared to chemotherapy in women with HR+, HER2- advanced breast cancer with visceral metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-05.