16O - First-line ribociclib + letrozole in HR+, HER2– ABC: Efficacy by baseline tumor markers

Date 04 May 2017
Event IMPAKT 2017
Session Best abstracts session – Oral abstracts
Topics Breast Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Fabrice André
Citation Annals of Oncology (2017) 28 (suppl_1): i7-i8. 10.1093/annonc/mdx137
Authors M. Campone1, N. Marschner2, C. Villanueva3, G.S. Sonke4, E. Alba5, E. Jakobsen6, F. Su7, W. He8, C. Germa7, F. André9
  • 1-, Institut de Cancérologie de l’Ouest/Centre René Gauducheau, 48805 - Saint-Herblain/FR
  • 2-, Joint Practice for Interdisciplinary Oncology and Hematology, Freiburg/DE
  • 3-, University Hospital of Besançon, 25030 - Besançon/FR
  • 4Department Of Medical Oncology, Netherlands Cancer Institute and BOOG Study Center, 1066 CX - Amsterdam/NL
  • 5Ibima, Hospital Universitario Virgen de la Victoria, 29010 - Málaga/ES
  • 6Department Of Oncology, Vejle Hospital, 7100 - Vejle/DK
  • 7-, Novartis Pharmaceuticals Corporation, NJ 07936 - East Hanover/US
  • 8-, Novartis Institutes for BioMedical Research, MA 02139 - Cambridge/US
  • 9Institut Gustave Roussy, Université Paris-Sud, 94800 - Villejuif/FR



Background: Cyclin D–cyclin-dependent kinase (CDK) 4/6 complexes promote cell proliferation through retinoblastoma protein (Rb) phosphorylation. Cyclin D gene (CCND1) amplification or loss of p16 (CDK4/6 negative regulator) can increase cyclin D–CDK4/6 activity. In the Phase III MONALEESA-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 proliferation marker), and gene expression levels of CDKN2A (p16), CCND1, and ESR1 (estrogen receptor).

Methods: Postmenopausal women (N=668) with HR+, HER2– ABC were randomized 1:1 to RIB (600 mg/day; 3 weeks on/1 week off) + LET (2.5 mg/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 nCounter® 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.

Clinical trial identification


Legal entity responsible for the study

Novartis Pharmaceuticals Corporation


Novartis Pharmaceuticals Corporation


M. Campone: Grant: Novartis Advisory board: Novartis, AstraZeneca, Pfizer, Roche Speaker bureau: Novartis. G.S. Sonke: Institutional research funding: AstraZeneca, Merck, Novartis, Roche Travel support: Roche. E. Alba: Advisory board membership: Roche, Novartis, Pfizer Research grants: Roche F. Su: Full time employee of Novartis Pharmaceuticals. Ownership of Novartis Pharmaceuticals stock options. W. He: Novartis Pharmaceuticals employee. C. Germa: Employee of Novartis Pharmaceuticals Ownership of Novartis stock. F. André: Research grant: Novartis, AstraZeneca, Pfizer, Lily. All other authors have declared no conflicts of interest.