Lasofoxifene combined with CDK4/6 inhibitor demonstrated clinical benefit in HR+/HER2- mBC patients harboring ESR1 mutation and other co-alterations

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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