Abstract 766: Clinical outcomes of patients with PIK3CA mutations in circulating tumor DNA: Update from the MONARCH 2 study of abemaciclib plus fulvestrant
Authors: Tolaney Sara M. , Toi Masakazu , Neven Patrick , Sohn Joohyuk , Grischke Eva-Maria , Soliman Hatem , Litchfield Lacey M. , Wang Hong , Wijayawardana Sameera R. , Jansen Valerie M. , Sledge George W. 
Published: September 2020

Abstract
BACKGROUND: Mutations (mt) in PIK3CA have been implicated in resistance to endocrine therapy (ET) in HR+ advanced breast cancer (ABC). In the MONARCH 2 study the addition of abemaciclib to fulvestrant (fulv) demonstrated a clinically meaningful and statistically significant median overall survival (OS) benefit of 9.4 months (mos) (HR 0.757, p=0.01), in addition to prolonging time to chemotherapy (TTC) (Sledge et al. JAMA Oncology 2019). We previously showed that abemaciclib plus fulv demonstrated improvement in progression-free survival (PFS) regardless of PIK3CA mt status, with a numerically larger magnitude of benefit for patients (pts) with PIK3CA mt in baseline circulating tumor DNA (ctDNA; Tolaney et al. AACR 2019). Here, we assessed the OS, TTC, and chemotherapy-free survival (CFS) in patients with and without PIK3CA mt in MONARCH 2.
METHODS: MONARCH 2 (NCT02107703) was a global, randomized, double-blind phase III trial of abemaciclib plus fulv or placebo plus fulv in pre-/perimenopausal (with ovarian suppression) and postmenopausal women with ET resistant HR+, HER2- ABC. Results of PIK3CA mt status (E542K; E545K; H1047L; H1047R) from baseline ctDNA were available for 238 patients. Exploratory analyses of OS, TTC, and CFS were assessed in pts with and without PIK3CA mt using the Cox Interaction Model including treatment, PIK3CA mt status and treatment by PIK3CA interaction term.
RESULTS: Abemaciclib plus fulv demonstrated a similar OS benefit for pts with PIK3CA mt (HR: 0.57; 95% CI: 0.34, 0.96) and for pts with PIK3CA wild-type (HR: 0.56; 95% CI: 0.34, 0.91) compared with placebo plus fulv. Median TTC and CFS were longer in the abemaciclib plus fulv arm compared with the placebo plus fulv arm both in pts with detectable PIK3CA mt and in pts without PIK3CA mt, as shown in Table 1.
Table 1.PIK3CA mutantPIK3CA wild-typeAbemaciclib +Fulvestrant (n=58)Placebo + Fulvestrant (n=38)Hazard Ratio (95% CI)Abemaciclib + Fulvestrant (n=91)Placebo + Fulvestrant (n=51)Hazard Ratio (95% CI)Interaction p-valueOverall Survival Median (95% CI)44.5 mos (31.0, NR)33.8 mos (24.2, 41.7)0.57 (0.34, 0.96)55.5 mos (47.7, 55.5)41.7 mos (29.4, 49.7)0.56 (0.34, 0.91)0.949Time to Chemotherapy Median (95% CI)39.2 mos (24.6, NR)19.2 mos (6.7, NR)0.65 (0.37, 1.18)NR (34.3, NR)19.2 mos (12.0, 31.1)0.50 (0.31, 0.78)0.463Chemotherapy-Free Survival Median (95% CI)25.8 mos (16.0, 42.1)12.8 mos (5.2, 33.2)0.63 (0.39, 1.03)36.9 mos (20.7, NR)19.2 mos (12.0, 29.4)0.53 (0.35, 0.80)0.588CI = confidence interval; NR = not reached; mos = months
CONCLUSIONS: In this exploratory analysis of MONARCH 2, abemaciclib plus fulv demonstrated benefit in OS, TTC, and CFS in patients with and without PIK3CA mutations.
Citation Format: Sara M. Tolaney, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Eva-Maria Grischke, Hatem Soliman, Lacey M. Litchfield, Hong Wang, Sameera R. Wijayawardana, Valerie M. Jansen, George W. Sledge. Clinical outcomes of patients with PIK3CA mutations in circulating tumor DNA: Update from the MONARCH 2 study of abemaciclib plus fulvestrant [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 766.