Triple blockade of ER, FGFR and CDK4/6 in endocrine and CDK4/6 inhibitor-resistant hormone-receptor positive breast cancer with FGFR alterations: a co-clinical trial.
Management of advanced hormone receptor-positive, HER2-negative breast cancer after progression on endocrine therapy plus CDK4/6 inhibitors is challenging due to mutational heterogeneity. Current therapies yield limited efficacy, achieving 4-6 months PFS. FGFR signaling is implicated in resistance to endocrine plus CDK4/6 inhibitors, but FGFR inhibitors have shown limited activity in unselected breast cancer populations. Co-clinical trials bridge preclinical and clinical findings, optimize resources, and enable biomarker identification. Using patient-derived organoids (PDOs), we demonstrated that FGFR-amplified PDOs respond to fulvestrant, palbociclib, and rogaratinib only when PIK3CA and ESR1 are wild-type. In a dose-escalation trial of FGFR1/2-amplified (by FISH) and/or overexpressed (by RNAscope) patients, >40% harbored FGFR alterations, and the combination showed activity specifically in PIK3CA- and ESR1-wild type patients (9.1 vs. 1.9 months PFS; P=0.0005). Our findings highlight biomarker-driven approaches as essential for refining FGFR-targeted strategies in this resistant population.