Lasofoxifene combined with CDK4/6 inhibitor demonstrated clinical benefit in HR+/HER2- mBC patients harboring ESR1 mutation and other co-alterations
Medical News
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2024-02-23
Abstract: Acquired ESR1 co-alterations, such as RB1, FGFR1, CCND1, ERBB2, TP53, and CCNE1, often occurred in HR+/HER2- breast cancer after endocrine therapy (ET). According to an analysis of the phase 2 ELAINE 2 study, these ESR1 co-alterations didn’t impact the combination of lasofoxifene and abemaciclib efficacy in ESR1+ metastatic breast cancer (mBC). These results were published in 2023 San Antonio Breast Cancer Symposium.
Mutations in TP53 and PIK3CA, as well as amplification of FGFR1 and CCND1, have frequently been correlated with poor prognosis in HR+/HER2- breast cancer. These associations suggest potential resistance mechanisms to endocrine therapy (ET) or cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Lasofoxifene, a next-generation selective estrogen receptor modulator (SERM) and potent antagonist of breast estrogen receptors (ER), has demonstrated a progression-free survival (PFS) benefit compared to fulvestrant in the phase 2 ELAINE 1 study for women with ESR1-mutated, ER+/HER2- metastatic breast cancer (mBC) (median PFS 5.6 vs. 3.7 months; P=0.138).
The objective of the single-arm, phase 2 ELAINE 2 study is to investigate whether baseline genomic alterations co-occurring with ESR1 mutations impact the efficacy of lasofoxifene combined with abemaciclib in HR+/HER2- mBC patients previously treated with ET and CDK4/6 inhibitors. In ELAINE 2, baseline circulating tumor (ct)DNA genomic alterations were assessed using liquid-based next-generation sequencing (NGS). Among 26 patients with ESR1 mutations, 12 had ≥2 co-alterations in other genes of interest. TP53 mutations were identified in 11 patients (42.3%), PIK3CA mutations in 8 (30.8%), CCND1 amplifications in 6 (23.1%), and FGFR1 amplifications in 5 (19.2%). The median PFS and clinical benefit rate (CBR) for all patients were 12.9 months and 73.1%, respectively. In patients with TP53 mutations, the median PFS and CBR were 8.3 months and 64%, respectively; with PIK3CA mutations, they were 7.8 months and 63.6%. For patients with co-occurring CCND1 or FGFR1 amplifications, the median PFS was 16.6 months, and the CBR was 100%.
Based on these data, it is suggested that the combination of lasofoxifene and abemaciclib may offer potential clinical benefits in ESR1-mutated, ER+/HER2- mBC in the post-ET and CDK4/6i setting, irrespective of prior treatment-related resistance alterations.
Reference:
1. Damodaran S, Cristofanilli MA, Goetz MP, et al. Presented at: 2023 San Antonio Breast Cancer Symposium; Abstract PO2-14-09.
2. Goetz MP, Plourde P, Stover DG, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089.
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