Abemaciclib: OS benefit in HR-positive / HER2-negative ABC still statistically insignificant

Overall survival seems numerically longer with abemaciclib + NSAI in post-menopausal patients with HR-positive / HER2-negative advanced breast cancer.

OS benefit of abemaciclib/NSAI was requested by the EMA

Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that -in the MONARCH 2 trial (NCT02107703), in combination with fulvestrant- demonstrated significant OS benefit in pre- and post-menopausal patients with HR-positive/HER2-negative advanced breast cancer who had disease progression on prior endocrine therapy1. The phase 3 MONARCH 3 trial (NCT02246621) investigates the efficacy and safety of abemaciclib plus a NSAI in the first-line setting in post-menopausal patients with HR-positive/HER2-negative advanced breast cancer. 

Previously, results from MONARCH 3 demonstrated a robust progression-free survival (PFS) benefit (HR 0.540; P<0.0001) of treatment with abemaciclib/NSAI versus placebo/NSAI, leading to global regulatory approval2,3. Being a gold standard for efficacy, demonstration of an OS benefit of abemaciclib/NSAI was requested by the EMA. 

In MONARCH 3, 493 postmenopausal women with HR-positive/HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting were randomised 2:1 to receive abemaciclib/NSAI or placebo/NSAI. Dr Mathew Goetz (Mayo Clinic Rochester, MN, USA) presented the results of the pre-specified second interim OS analysis (data cut-off 2 July 2021), which was scheduled after ∼252 events in the intention-to-treat population (80% of planned events for final OS analysis)4.

No new safety concerns with prolonged exposure

With 70.2 months median follow-up, the median OS was 67.1 months for abemaciclib/NSAI versus 54.5 months for placebo/NSAI (HR 0.754; P=0.0301). This P-value is not statistically significant due to the pre-defined statistical analysis plan. In the subgroup of patients with visceral disease (sVD; n=263) the median OS was 65.1 months versus 48.8 months in the abemaciclib/NSAI and placebo/NSAI arm respectively (HR 0.708; P=0.0392). This is again not statistically significant due to the statistical analysis plan. 

Median chemotherapy-free survival in the intention-to-treat population favoured abemaciclib/NSAI over placebo/NSAI (46.7 vs 30.6 months; HR 0.636). No new safety concerns were observed with prolonged exposure to abemaciclib. 

“In the second interim OS analysis from MONARCH 3, a numerically longer OS was observed in both the intention-to-treat and sVD population with the addition of abemaciclib to NSAI,” summarised Dr Goetz. “Neither met the threshold for formal statistical significance, but data are maturing favourably.” Follow-up is ongoing for the final OS analysis, which is expected in 2023.

  1. Sledge GW, et al. JAMA Oncol. 2020;6:116–124.
  2. Goetz MP, et al. J Clin Oncol. 2017;35:3638–3646.
  3. Johnston S, et al. NPJ Breast Cancer 2019;5:5.
  4. Goetz M, et al. MONARCH 3: Interim overall survival (OS) results of abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+, HER2- advanced breast cancer (ABC). Abstract LBA15, ESMO Congress 2022, Paris, France, 09–13 September.