Ribociclib (RIB) + fulvestrant (FUL) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC): MONALEESA-3 biomarker analyses
2018-10-01

Background: In the Phase III MONALEESA-3 study (NCT02422615), RIB + FUL significantly improved progression-free survival (PFS) vs placebo (PBO) + FUL in patients with HR+, HER2– ABC who received no or up to 1 line of prior endocrine therapy for ABC (hazard ratio 0.593; 95% confidence interval 0.480–0.732). Here we present PFS data by baseline tumor Ki67, total Rb, and p16 protein expression, and CCND1, CDKN2A, and ESR1 messenger RNA (mRNA) levels. Methods: Postmenopausal women (N = 726) with HR+, HER2– ABC were randomized 2:1 to RIB (600 mg/day; 3 weeks on/1 week off) + FUL (500 mg) or PBO + FUL. The primary endpoint was PFS. PFS by biomarker expression was an exploratory endpoint. Baseline tumor tissue was evaluated for protein expression (immunohistochemistry) and gene expression (NanoString® nCounter Customized Panel). To assess correlations between protein/gene expression and PFS, patients were classified into prespecified low vs high expression subgroups; 14% of positively stained cells was used as a cutoff for Ki67, 10th percentile was used as a cutoff for total Rb, and median expression was used as a cutoff for all other proteins/genes. Results: PFS hazard ratios for all biomarker subgroups favored RIB + FUL vs PBO + FUL (Table). Consistent RIB + FUL treatment benefit was seen regardless of Ki67 protein expression or CCND1 gene expression. A numerically greater PFS benefit was observed with RIB + FUL in patients with low vs high p16 protein expression and low vs high CDKN2A mRNA expression; a similar trend was observed in patients with low vs high ESR1 mRNA expression. Conclusions: RIB + FUL significantly prolonged PFS vs PBO + FUL, with consistent treatment effects observed regardless of biomarker expression. There was a trend towards greater PFS benefit with RIB + FUL in patients with low vs high expression of p16 protein, and low vs high CDKN2A and ESR1 mRNA levels. Clinical trial identification: NCT02422615 April 21, 2015. Editorial acknowledgement: Editorial assistance was provided by Kate Gaffey PhD of ArticulateScience Ltd. Legal entity responsible for the study: Novartis Pharmaceuticals Corporation. Funding: Novartis Pharmaceuticals Corporation. Disclosure: K. Petrakova: Consulting/advisory role, speaker's bureau, travel/accommodation and expenses: Roche, Pfizer and Novartis during the conduct of the study. G. Jerusalem: Grants and personal fees from Novartis during the conduct of the study; Grants, personal fees and non-financial support: Novartis, Roche, BMS; Personal fees and non-financial support: Lilly; Personal fees: Celgene, Pfizer, Puma, Daiichi-Sankyo; Grants and personal fees: Amgen; Grants: MSD; Personal fees and non-financial support from AstraZeneca outside the submitted work. G.S. Sonke: Institutional reimbursement for patient accrual: Novartis during the conduct of the study; Institutional reimbursement for education and steering committee activities: Novartis; Institutional research support: Merck, AstraZeneca, and Roche, outside the submitted work. S. Chia: Honoraria and research funding: Novartis and Roche; Research funding: BMS and Genetech. W. He: Employment: Novartis. K. Rodriguez Lorenc, F. Su: Novartis Employee and owns stock: Novartis. S-A. Im: Advisory role: Novartis, during the conduct of the study; Grants: AstraZeneca; Advisory role: Hanmi, Roche and Pfizer, outside the submitted work. All other authors have declared no conflicts of interest.Table: 346PRIB + FULPBO + FULHazard ratio (95% confidence interval)Events, n/nMedian PFS, monthsEvents, n/nMedian PFS, monthsKi67Low55/11819.443/6814.50.612 (0.408–0.919)High95/20819.156/9312.30.637 (0.456–0.891)Total RbLow8/32Not reached10/1612.80.359 (0.130–0.988)High138/29519.187/14312.80.648 (0.495–0.850)p16Low66/16122.157/8311.90.449 (0.312–0.645)High76/15116.641/6712.80.719 (0.486–1.064)CCND1Low83/17518.662/9111.20.631 (0.453–0.880)High81/18419.445/8114.90.713 (0.494–1.028)CDKN2ALow73/17720.656/8911.00.527 (0.370–0.751)High91/18216.451/8314.50.802 (0.567–1.136)ESR1Low85/18019.158/8610.80.544 (0.386–0.765)High79/17919.449/8614.90.802 (0.560–1.149) Open table in a new tab