First-line ribociclib (RIB) + letrozole (LET) in hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC): MONALEESA-2 biomarker analyses.

1022 Background: In MONALEESA-2, first-line RIB + LET improved investigator-assessed progression-free survival (PFS; primary endpoint) vs placebo (PBO) + LET in postmenopausal pts with HR+, HER2– ABC. Previous MONALEESA-2 biomarker analyses, involving immunohistochemistry, gene expression, and NGS of ctDNA, showed consistent RIB benefit. Here, we present additional MONALEESA-2 gene expression data. Methods: Tumor samples (n/N, 391/668) were evaluated for gene expression using the NanoString 230-gene nCounter® GX Human Cancer Reference panel. To assess correlations between gene expression level and PFS, pts were classified into low (L) and high (H) messenger RNA expression subgroups using a 10% cut-off for RB1 and median expression as the cut-off for other genes. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CI). Results: RIB + LET improved PFS in all pt subgroups (Table). Kaplan–Meier curves will be presented. Clinical trial information: NCT01958021. Conclusions: Benefit of RIB was consistent across gene expression subgroups; H vs L ESR1 and L vs H RTK expression trended towards greater RIB benefit. Genes implicated preclinically in mechanisms of resistance to CDK4/6 inhibitors require further investigation based on metastatic/liquid biopsies, and in larger clinical datasets. Gene(s) Expression level Events, n/N Hazard ratio; 95% CI RIB + LET PBO + LET CDK pathway and breast cancer ESR1 L 51/101 62/95 0.74; 0.51–1.07 H 34/96 58/99 0.39; 0.25–0.60 RB1 L 11/21 14/19 0.52; 0.23–1.16 H 74/176 106/175 0.55; 0.41–0.74 E2F1 L 31/105 45/91 0.56; 0.35–0.89 H 54/92 75/103 0.52; 0.37–0.75 Implicated in CDK4/6 inhibitor resistance CDK2 L 40/103 49/93 0.64; 0.42–0.98 H 45/94 71/101 0.48; 0.33–0.71 CCNE1 L 32/97 51/99 0.53; 0.34–0.83 H 53/100 69/95 0.54; 0.38–0.78 FGFR1 L 32/93 59/103 0.45; 0.29–0.69 H 53/104 61/91 0.63; 0.43–0.91 Involved in alternative pathways Cell cycle control L 32/99 47/97 0.66; 0.42–1.03 H 53/98 73/97 0.45; 0.31–0.64 PI3K pathway L 37/98 54/98 0.57; 0.37–0.86 H 48/99 66/96 0.54; 0.37–0.79 MAPK pathway L 42/99 61/97 0.55; 0.37–0.81 H 43/98 59/97 0.56; 0.37–0.83 RTKs L 39/103 59/93 0.41; 0.27–0.61 H 46/94 61/101 0.74; 0.50–1.08