Abstract CT087: Ribociclib + endocrine therapy (ET) doublet combinations in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): Phase I clinical activity and impact of molecular alterations
Authors: Juric Dejan , Campone Mario , Munster Pamela , Ismail-Khan Roohi , Estévez Laura Garcia , Chavez-MacGregor Mariana , Frassoldati Antonio , Hui Rina , Mayer Ingrid A. , Cortés Javier , Gonçalves Anthony , Boer Richard H. De , Dirix Luc , Tolaney Sara M. , Lee Soo Chin , Maur Michela , Wang Yingbo , Su Faye , Dobson Jason R. , Germa Caroline , Hewes Becker , Bardia Aditya 
Published: July 2017

Abstract
Background: ET is the standard of care for HR+ ABC; however, disease progression eventually occurs. Breast cancer driver mutations can include alterations in the cyclin D–cyclin-dependent kinase (CDK)4/6–inhibitor of CDK4 (INK4; p16)–retinoblastoma pathway and in upstream pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway. Doublet combination strategies with selective CDK4/6 inhibitors such as ribociclib (RIB) have demonstrated increased progression-free survival (PFS) in Phase III studies of HR+ ABC. Here, we evaluate the clinical activity of RIB-based ET combinations in Phase I clinical trials, including in tumors with various molecular alterations.
Methods: Postmenopausal women with HR+, HER2– ABC received RIB with letrozole (LET; 2.5 mg continuous; NCT01872260; previously untreated or first-line patients [pts]), exemestane (EXE; 25 mg continuous; NCT01857193; aromatase inhibitor [AI]-refractory disease), or fulvestrant (FUL; 500 mg; NCT02088684; AI-refractory disease). RIB was administered at 600 mg/day 3 weeks on/1 week off (all combinations) or 400 mg/day continuously (additional subgroup in the RIB + FUL study). Fresh or archival tumor tissue was collected from all pts. Clinical activity and next-generation sequencing (NGS) data from pretreatment tumor samples were assessed.
Results: Preliminary clinical activity was observed with all 3 combinations, with clinical benefit rates (CBR; including stable disease for ≥24 weeks) of: RIB + LET (N=47 pretreated or first-line pts) 60%, RIB + EXE (N=14 pretreated pts) 50%, and RIB + FUL (N=28 pretreated pts; n=13 at 600 mg/day RIB, n=15 at 400 mg/day RIB) 52%. Best overall responses of complete response [CR] or partial response [PR] were observed in 14 pts (RIB + LET), 4 pts (RIB + EXE), and 5 pts (RIB + FUL). In a first-line subset of pts (N=28), RIB + LET had a median PFS of 25.3 months. Most common Grade 3/4 adverse events for all 3 combinations were neutropenia and leukopenia. NGS data were available for 33, 6, and 16 pts treated with RIB + LET, RIB + EXE, and RIB + FUL, respectively. CR and/or PR were observed in pts with PIK3CA and/or CCND1 (cyclin D) alterations treated with RIB + LET (9/19 pts and 4/9 pts, respectively); and RIB + FUL (1/10 pts and 2/5 pts, respectively). Integrated biomarker analyses from all 3 trials will be provided at the time of the meeting.
Conclusions: RIB + ET doublet combinations are well tolerated, with encouraging clinical activity that includes responses and durable PFS in heavily pretreated pts, and are consistent with previously reported first-line data (NCT01958021). Preliminary biomarker analyses suggest pts with PIK3CA and/or CCND1 alterations derive treatment benefit from RIB + ET combinations. Other genetic alterations are being evaluated.
Citation Format: Dejan Juric, Mario Campone, Pamela Munster, Roohi Ismail-Khan, Laura Garcia Estévez, Mariana Chavez-MacGregor, Antonio Frassoldati, Rina Hui, Ingrid A. Mayer, Javier Cortés, Anthony Gonçalves, Richard H. De Boer, Luc Dirix, Sara M. Tolaney, Soo Chin Lee, Michela Maur, Yingbo Wang, Faye Su, Jason R. Dobson, Caroline Germa, Becker Hewes, Aditya Bardia. Ribociclib + endocrine therapy (ET) doublet combinations in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): Phase I clinical activity and impact of molecular alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT087. doi:10.1158/1538-7445.AM2017-CT087