The postMONARCH trial demonstrated a progression-free survival (PFS) of 6.0 months for abemaciclib (ABE) combined with fulvestrant (FUL) in patients with hormone receptor (HR)-positive/HER2-negative metastatic breast cancer who experienced disease progression on cyclin-dependent kinase (CDK)4/6 inhibitors plus endocrine therapy (ET). However, only 8% of patients in that trial received prior ABE, leaving unanswered questions about the ABE rechallenge in this population.
This phase 2, multicenter, single-arm study evaluated the efficacy and safety of the ABE rechallenge in HR-positive/HER2-negative metastatic breast cancer patients whose disease progressed following ABE plus ET. Patients switched ET regimens, either from aromatase inhibitor (AI)/tamoxifen to FUL or from FUL to AI, while continuing ABE treatment. The primary endpoint was PFS, and secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), chemotherapy-free interval (CFI), overall survival (OS), safety, and biomarker analysis. Liquid biopsies were obtained before the ABE rechallenge, 2 months post-rechallenge, and at disease progression.
Between June 2021 and November 2023, 65 patients were enrolled, with 64 patients receiving intervention. The median number of prior treatment lines was 1 (range, 1-4). Patients received ABE plus FUL (n=28) or ABE plus AI (n=36). Median PFS was 4.2 months (90% confidence interval [CI], 2.8-4.4), with an ORR of 8.7% (95% CI, 2.4-20.8) and a CBR of 23.9% (95% CI, 12.6-38.8). Median CFI was 6.7 months (95% CI, 4.9-11.0), and OS was 28.7 months (95% CI, 25.4-not evaluable). Subgroup analysis showed a median PFS of 7.1 months (95% CI, 3.9-11.3) for ABE plus FUL and 2.8 months (95% CI, 1.9-4.2) for ABE plus AI. Upon the ABE rechallenge, the most common grade >3 adverse event was neutropenia (17 patients, 26.6%) and febrile neutropenia occurred in 2 patients (3.1%). Biomarker analysis revealed FGFR1 amplification was associated with shorter PFS (P=.003) and OS (P=.01) before the rechallenge. At 2 months post-rechallenge, CCND1 amplification (P=.03) and FGFR1 amplification (P=.03) correlated with shorter PFS.
This phase 2 study demonstrates that the abemaciclib rechallenge may offer clinical benefit for select patients with HR-positive/HER2-negative metastatic breast cancer, particularly when combined with FUL after progression on ABE plus AI or tamoxifen. Although the sample size was small, the results suggest that ABE plus FUL could serve as a viable treatment option in this setting. Biomarker analysis highlights the potential role of FGFR1 and CCND1 amplifications in guiding treatment decisions and predicting outcomes.
Source: Nishimura N, Kogawa T, Sugiyama KI, et al. Abemaciclib rechallenge after progression on abemaciclib plus endocrine therapy in patients with hormone receptor-positive and HER2-negative metastatic breast cancer: results from the phase Ⅱ AGAIN study (WJOG14220B). Presented at: ESMO Congress 2025. October 2025; Berlin, Germany. Abstract 499P.