First-line ribociclib + letrozole in HR+, HER2– ABC: Efficacy by baseline tumor markers

Abstract

Background: CyclinD-cyclin-dependent kinase (CDK) 4/6 complexes promote cell proliferation through retinoblastoma protein (Rb) phosphorylation. CyclinDgene (CCND1) amplification or loss of p16 (CDK4/6 negative regulator) can increase cyclin D-CDK4/6 activity. In the Phase IIIMONALEESA-2 study, ribociclib (RIB; CDK4/6 inhibitor)+ letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO)+ LET in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Here we assess RIB+LET efficacy by baseline tumor levels of Rb, p16, and Ki67 (cell proliferationmarker), and gene expression levels ofCDKN2A (p16), CCND1, andESR1 (estrogen receptor). Methods: Postmenopausal women (N=668) withHR+,HER2-ABCwere randomized 1:1 to RIB (600 mg/day; 3weeks on/1 week off)+ LET (2.5mg/day; continuous) or PBO+ LET. Primary endpoint was PFS. Provision of archival tissue or a fresh tumor biopsy at screening was mandatory. Samples were evaluated for protein levels (immunohistochemistry) and gene expression (NanoString nCounterVR Human Cancer Reference panel). Results: 479 pts were evaluable for total Rb; 416 (87%) had high levels (H-score 100). p16 protein levels were evaluable in 405 pts; 165 (41%) had low (H-score <50), 182 (45%) medium (H-score 50-149), and 58 (14%) high (H-score 150) levels. Ki67 was detected in-14% and>14% of tumor cells in 216 (47%) pts and 247 (53%) pts, respectively. Median mRNA expression was used as a cut-off to define low or high baseline CDKN2A, CCND1, and ESR1 gene expression. RIB+ LET improved PFS vs PBO + LET in all the above pt subgroups; hazard ratios ranged from 0.40 (high p16; 95% confidence interval [CI] 0.16-1.04; p=0.06) to 0.68 (low ESR1; 95% CI 0.43-1.05; p=0.08). Treatment benefit was consistent in pts with high or low Ki67, p16, or Rb levels, or CDKN2A, CCND1, or ESR1 gene expression. Conclusions: Consistently improved benefit from RIB +LET over PBO +LET was observed irrespective of baseline Rb, p16, or Ki67 level, or CDKN2A, CCND1, or ESR1 gene expression level. Hormone receptor expression remains the only established biomarker of response to CDK4/6 inhibitors.