A phase II randomized study to compare abemaciclib plus trastuzumab with or without fulvestrant to standard of care chemotherapy plus trastuzumab in hormone receptor positive, HER2-positive advanced breast cancer (monarcHER).

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TPS1109 Background: Inhibition of CDK4 in preclinical models, demonstrated efficacy in HER2+ breast cancer and enhanced activity of HER2-targeted therapy suggesting a crosstalk between HER2 signaling and the cyclin D/CDK4 signaling pathway in which CDK4 & CDK6 inhibitors may re-sensitize resistant tumors to HER2 blockade.Abemaciclib is a selective inhibitor of CDK4 & CDK6 inhibitor that demonstrates single-agent anti-tumor activity on a continuous dosing schedule in women with hormone receptor positive (HR+) advanced breast cancer. Triple regimens with abemaciclib have been tolerable. Methods: monarcHER is an ongoing Phase 2, open-label, study in postmenopausal women with HR+, HER2+ locally advanced or metastatic breast cancer. Eligible patients (pts) are those previously treated with ≥2 HER2-directed therapies in advanced disease setting; T-DM1 and a taxane in any disease setting; no prior treatment with fulvestrant or any CDK4 & CDK6 inhibitor or with ECOG PS ≤1; LVEF ≥50%; no visceral crisis and no CNS metastases that are untreated, symptomatic or requiring steroids. Pts are randomized 1:1:1 to Arm A (abemaciclib [150mg PO Q12H] plus trastuzumab [IV infusion Q3 weeks] plus fulvestrant [IM injection on D1, 15, 29 then Q4 weeks]), Arm B (abemaciclib plus trastuzumab), or Arm C (trastuzumab plus SOC single-agent chemotherapy of physician’s choice); stratified based on number of prior systemic regimens (excluding single agent endocrine therapy) and disease status (measurable vs nonmeasurable). The primary objective evaluates investigator-assessed progression-free survival (PFS). Secondary objectives include overall survival, objective response rate, duration of response, disease control rate, clinical benefit rate, safety and tolerability, efficacy, health outcomes and pharmacokinetics. Analysis is planned at 165 PFS events, providing ≥80% power to detect superiority of Arm A and Arm B over Arm C, assuming a hazard ratio of 0.67 at a one-sided alpha of 0.10. First pt visit occurred in May 2016; with a target enrollment of 225 pts. Contact information: 1-877-CTLILLY (1-877-285-4559) Clinical trial information: NCT02675231.