40OBiomarker analyses of Asian women with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC) receiving ribociclib (RIB) + endocrine therapy (ET)

Background: The ongoing Phase Ib MONALEESASIA (NCT02333370) study is a dose-escalation (RIB + letrozole [LET]) and dose-expansion (RIB + LET, fulvestrant [FUL], or tamoxifen [TAM]) study in Asian patients (pts) with HR+, HER2– ABC; here we present biomarker analyses. Methods: In the dose escalation, postmenopausal pts with HR+, HER2– ABC (no prior therapy for ABC) received RIB (300, 400, or 600 mg/day [d]; 3 weeks on/1 week off) + LET (2.5 mg/d). In the dose expansion, pre- and postmenopausal pts (≤1 line of any prior therapy for ABC) received RIB (recommended Phase II dose) + LET (2.5 mg/d), FUL (500 mg, d1 and 15 of Cycle [C] 1, then every 28 d), or TAM (20 mg/d) + goserelin (3.6 mg every 28 d; premenopausal pts only). Baseline (BL) and on-treatment (OT; collected at d15 of C1) samples were assessed for dynamic changes in messenger RNA expression (NanoString 230-gene nCounter® GX Human Cancer Reference panel). Differences in gene expression between pre- and postmenopausal pts were assessed using a Mann-Whitney-Wilcoxon test. Results: As of Mar 2, 2018, BL tumor mRNA expression was evaluated in 68 of 88 pts. Dynamic gene expression changes were assessed in 5 pts with paired BL/OT samples, with an observed decrease in mRNA expression of E2F-responsive (e.g. E2F1, MYC, and TYMS) and cell cycle-related genes (e.g. CDK genes). Super responders (n = 5; no progression ≥24 months post-randomization) and poor responders (n = 6; progressed ≤8 weeks post-randomization) showed differential expression of cell cycle-, proliferation-, and breast cancer-related genes. Genes with different expression levels between pre- (n = 9) and postmenopausal Japanese pts (n = 31) were identified. BL circulating tumor DNA analysis by next-generating sequencing (n = 82) will be presented. Conclusions: In Asian pts with HR+, HER2– ABC, suppression of pharmacodynamic biomarker gene expression, including E2F-responsive genes, indicated that RIB + ET inhibited the intended targets. Differences in BL gene expression patterns were observed between pts with sustained responses vs those who progressed ≤2 treatment cycles. Due to small pt numbers, further investigation is needed. Editorial acknowledgement: Editorial assistance was provided by Claire Wilson, PhD, of ArticulateScience Ltd. Clinical trial identification: NCT02333370. Legal entity responsible for the study: Novartis Pharmaceuticals Corporation. Funding: Novartis Pharmaceuticals Corporation. Disclosure: Y.S. Yap: Personal fees and non-financial support: Novartis, Pfizer, AstraZeneca, Eisai; Personal fees: Eli-Lilly, Roche. N. Masuda: Personal fees: Chugai, AstraZeneca, Pfizer, Kyowa-Kirin, Eisai, Takeda, Eli-Lilly. Y. Ito: Grants: Daiichi Sankyo, Chugai, Novartis, Parexel, EPS, MSD, AstraZeneca, Lilly, Kyowa Hakko Kirin, Covance, Taiho, A2 Healthcare. S.J. Kim: Personal fees: Novartis. T. Toyama: Grants: Novartis Pharma, Eisai, Chugai Pharmaceutical, Nippon Kayaku, Pfizer Japan Inc., Kyowa Hakko Kirin, Taiho Pharma, Daiichi Sankyo, Takeda Pharmaceutical. T. Saeki: AstraZeneca, Eisai, Ono, Kyowa Hakko Kirin, Sanofi, TaishoToyama, Taiho, Takeda, Chugai, Bayer Yakuhin, Fuji, Daiichi Sankyo, Nihon Medi-Physics, Nippon Kayaku, Novartis, Hamamatsu Photonics, Medicon, MSD, Global Software Inc, KyowaHakkoKirin, Taiho. T. Yamanaka: Personal fees: Novartis, Chugai, Pfizer, Taiho, outside the submitted work. J. Watanabe: Personal fees: Novartis Pharma, outside the submitted work. S. Nakamura: AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyou, Eisai, Ltd., Kkyowa Hakko Kirin, Nipponn Kayaku, Novartis Pharma K.K., Pfizer Japan Inc., Taiho Pharmaceutical, Takeda Pharmaceutical. K. Inoue: Institutional grants: Novartis, Pfizer, Chugai, Daiichi Sankyo, Parexel / Puma Biotechnology, MSD, Bayer, Lilly, Esai. J. Suarez-Vizcarra, W. He: Employee: Novartis. N. Solovieff, F. Su: Employee, stock holder: Novartis. All other authors have declared no conflicts of interest.