Abstract P3-08-01: MONARCH 2: Interim analysis of overall survival in patients with poor prognostic factors
Authors: Neven Patrick , Johnston Stephen , Toi Masakazu , Sohn Joohyuk , Inoue Kenichi , Pivot Xavier , Burdaeva Olga , Okera Meena , Masuda Norikazu , Kaufman Peter A , Koh Han , Grischke Eva-Maria , Conte PierFranco , Lu Yi , Haddad Nadine , Hurt Karla , Llombart-Cussac Antonio , Sledge George W 
Published: March 2020

Abstract
Background: In MONARCH 2 (M2), abemaciclib, an oral selective cyclin dependent kinase 4 & 6 inhibitor, demonstrated significant progression-free survival (PFS) improvement in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer when added to fulvestrant. Treatment with abemaciclib plus fulvestrant provided a statistically significant and clinically meaningful median overall survival (OS) benefit of 9.4 months (hazard ratio 0.757; 95% confidence interval, 0.606, 0.945; p=0.0137).1 High grade tumors, progesterone receptor (PgR) negativity, liver metastases, and absence of bone-only disease were identified as independent poor prognostic disease characteristics.2 In a retrospective analysis of M2, among subgroups analyzed, patients within those poor prognostic subgroups numerically received the largest improvement from the addition of abemaciclib to endocrine therapy (ET) with PFS hazard ratios in the range of 0.4 to 0.5.2 Methods: M2 (NCT02107703) was a global, randomized, double-blind Phase 3 trial of abemaciclib + fulvestrant (N=446) or placebo + fulvestrant (N=223) in women with ET resistant HR+, HER2- advanced breast cancer. Investigator-assessed PFS was the primary objective and OS was a key secondary endpoint. Here, we present exploratory OS results conducted within the previously described prognostic subgroups.2 Hazard ratios were estimated using Cox models with a test of interactions of subgroups with treatment performed. Results: As of the data cut-off (20 June 2019), OS prolongation was consistent across all subgroups; a numerically greater OS effect was observed in patients with previously identified negative prognostic factors including patients with high tumor grade, PgR negativity, baseline liver metastases, and absence of bone-only metastases, relative to their complementary subgroups (Table). However, no statistically significant interaction between these prognostic factors and treatment effect were observed. Similar to OS, a more pronounced effect for abemaciclib plus fulvestrant for patients with high tumor grade, PgR negativity, baseline liver metastases, and absence of bone-only metastases was also observed when examining the time to chemotherapy or death, whichever is earlier (chemotherapy free survival [CFS]). Conclusions: Consistent with the statistically significant and clinically meaningful benefit observed in the overall study population, abemaciclib plus fulvestrant improved OS across all exploratory subgroups, with the largest OS effects observed in patients with poor prognostic factors, consistent with previously reported PFS data. Refernces: 1. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: Overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer. Abstract to be presented at: European Society for Medical Oncology 2019; Barcelona, Spain. 2. Di Leo A, O’Shaughnessy J, Sledge GW Jr, et al. Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy. NPJ Breast Cancer. 2018;4:41. Abbreviations: CFS, chemotherapy free survival; HR, hazards ratio; N, number in overall study population; n, number in specified subgroup; OS, overall survival; PgR, progesterone receptor.
n (%) N=669Overall Survival Hazard Ratio (95% CI)Chemotherapy Free Survival Hazard Ratio (95% CI)Tumor gradeHigh169 (25.26)0.66 (0.44, 1.01)0.52 (0.36, 0.75)Low/intermediate345 (51.57)0.79 (0.58, 1.08)0.78 (0.60, 1.02)Unknown155 (23.17)0.83 (0.52, 1.31)0.50 (0.34, 0.76)PgR statusNegative141 (21.08)0.66 (0.41, 1.05)0.59 (0.39, 0.89)Positive509 (76.08)0.79 (0.61, 1.01)0.68 (0.55, 0.85)Baseline liver metastasesYes174 (26.01)0.73 (0.49, 1.08)0.60 (0.42, 0.85)No495 (73.99)0.76 (0.58, 0.99)0.64 (0.51, 0.81)Bone-only metastasesYes180 (26.91)0.91 (0.56, 1.46)0.69 (0.46, 1.01)No486 (72.65)0.72 (0.57, 0.93)0.64 (0.52, 0.80)
Citation Format: Patrick Neven, Stephen Johnston, Masakazu Toi, Joohyuk Sohn, Kenichi Inoue, Xavier Pivot, Olga Burdaeva, Meena Okera, Norikazu Masuda, Peter A Kaufman, Han Koh, Eva-Maria Grischke, PierFranco Conte, Yi Lu, Nadine Haddad, Karla Hurt, Antonio Llombart-Cussac, George W Sledge. MONARCH 2: Interim analysis of overall survival in patients with poor prognostic factors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-01.