Abstract OT2-01-02: Phase III study of ribociclib (LEE011) in combination with fulvestrant for the treatment of postmenopausal patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (aBC) who have received no or only one line of prior endocrine treatment: MONALEESA-3
Authors: Fasching PA , Jerusalem G , Pivot X , Martin M , De Laurentiis M , Blackwell K , Esteva FJ , Paquet-Luzy T , Tang Z , Lorenc KR , Slamon DJ 
Published: May 2016

Abstract
Background: Endocrine therapy (ET) is the predominant first-line treatment for HR+, HER2– aBC; however, resistance eventually occurs in a large number of cases. Dysregulation of the cyclin D–cyclin dependent kinase (CDK)4/6–inhibitor of CDK4 (INK4)–retinoblastoma (Rb) pathway has been associated with endocrine resistance. Inhibition of CDK4/6 may overcome such resistance and enhance the efficacy of existing endocrine regimens. Combination of ribociclib (a type of CDK4/6 inhibitor) with fulvestrant (a selective estrogen receptor downregulator) has demonstrated potent tumor regressions in preclinical HR+ breast cancer (BC) models.
Design & Objectives: MONALEESA-3 (NCT02422615) is a randomized, double-blind, placebo-controlled study of oral ribociclib (600 mg QD on Days 1–21 of each 28-day cycle) in combination with fulvestrant (500 mg intramuscularly on Days 1 and 15 of Cycle 1 and Day 1 of each cycle thereafter) in postmenopausal pts with HR+, HER2– aBC. Pts may have newly diagnosed aBC that is treatment-naive, relapsed BC that has progressed at any time during or after (neo)adjuvant ET with no treatment for metastatic disease, relapsed BC that has progressed &gt;12 months after adjuvant ET and then subsequently progressed after one line of ET for metastatic disease (with either an antiestrogen or an aromatase inhibitor), or newly diagnosed aBC that has progressed after one line of ET (with either an antiestrogen or an aromatase inhibitor). Pts must have measurable disease or at least one predominantly lytic bone lesion, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤1. Prior treatment with chemotherapy (except for [neo]adjuvant chemotherapy), fulvestrant, or any CDK4/6 inhibitor is prohibited. Randomization (2:1) to receive ribociclib plus fulvestrant (Arm A) or placebo plus fulvestrant (Arm B) is stratified by visceral disease status and previous ET. Tumor assessments will be performed every 8 weeks for the first 18 months and every 12 weeks thereafter until disease progression, death, withdrawal of consent, loss to follow-up, or patient/guardian decision. The primary endpoint is progression-free survival (PFS; local, RECIST 1.1); secondary endpoints include overall survival, PFS (central, RECIST 1.1), overall response rate, clinical benefit rate, time to response, duration of response, safety and tolerability, ECOG PS, pt-reported outcomes, and pharmacokinetics. Molecular alterations of genes associated with HR+ BC and the cyclin D–CDK4/6–INK4–Rb pathway will also be explored in tumor and blood samples.
Statistical Methods: PFS between Arms A and B will be compared using a stratified log-rank test; 364 PFS events will be required to detect a hazard ratio of 0.67 with 90% power using the log-rank test and a 3-look (interim look futility only, interim look efficacy only, then final analysis) group sequential design at one-sided cumulative 2.5% level of significance.
Target Accrual: Approximately 660 pts at 300 sites worldwide.
Citation Format: Fasching PA, Jerusalem G, Pivot X, Martin M, De Laurentiis M, Blackwell K, Esteva FJ, Paquet-Luzy T, Tang Z, Lorenc KR, Slamon DJ. Phase III study of ribociclib (LEE011) in combination with fulvestrant for the treatment of postmenopausal patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (aBC) who have received no or only one line of prior endocrine treatment: MONALEESA-3. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-02.