Phase 2 neratinib pan-HER (EGFR/HER2/HER4) TKI added to endocrine therapy in ER+/HER2- breast cancer.

This single-center, randomized Phase 2 UC San Diego study tests whether adding neratinib (an oral, irreversible pan-HER tyrosine kinase inhibitor targeting EGFR/HER2/HER4) can improve disease control when layered onto a physician-chosen, standard endocrine regimen (fulvestrant or aromatase inhibitor options, with tamoxifen allowed) with or without a CDK4/6 inhibitor for metastatic, endocrine-resistant ER+/HER2-negative breast cancer enriched for MLH1-low biology. The experimental arm is “standard systemic therapy + neratinib,” and the control arm is the same endocrine approach without neratinib, aiming to quantify incremental benefit and characterize added toxicities (notably diarrhea risk typical of this class). This is commercially interesting because it repurposes Puma Biotechnology’s approved neratinib into a biomarker-selected, HER2-negative population where HER-family signaling may act as a resistance bypass rather than a primary driver. For these patients today, common care is sequential endocrine-based combinations (often endocrine therapy + CDK4/6 inhibitor when appropriate), then other targeted options guided by tumor mutations (e.g., PI3K/AKT pathway) or chemotherapy as resistance accumulates; this trial tests a targeted “add-on” aimed at prolonging endocrine sensitivity rather than switching immediately to chemo.