Background Neratinib, an oral, irreversible tyrosine kinase inhibitor of multiple HER receptors, was recently approved in combination with capecitabine (neratinib doublet regimen) in the United States (US) for adults with HER2+ metastatic breast cancer (mBC) who have received 2 or more anti-HER2 therapies. Clinical trials showed that neratinib plus capecitabine significantly improved progression-free survival versus lapatinib plus capecitabine. There are several existing and potential treatment options for this population with varying efficacies, side effect profiles, and costs. Objective This analysis estimates the budget impact for US health care payers of adding a neratinib doublet regimen to the currently available third-line HER2+ mBC treatments in the US. Methods A budget-impact model was developed to compare health care payer costs associated with third-line treatment of HER2+ mBC over 5 years between a treatment setting with neratinib and a treatment setting without neratinib for a hypothetical 1-million-person commercial plan of adults over age 18. The treatment options considered in the model include neratinib doublet regimen, oral combination therapy with lapatinib and capecitabine (lapatinib doublet regimen), tucatinib plus capecitabine plus trastuzumab (tucatinib triplet regimen), and intravenous fam-trastuzumab deruxtecan-nxki (DS-8201 single agent). The population eligible for treatment was calculated based on prevalence and incidence of HER2+ mBC and progression to third-line HER2-direct treatment; estimates were obtained from the published literature. The impact of including neratinib doublet regimen was assessed under two market share scenarios: one in which all regimens had equal market share and a second in which a clinical expert provided judgement on projected uptake of the regimens over the five-year period. In the treatment setting without the neratinib regimen, market shares for neratinib were distributed equally to the other treatments. Treatment duration, dosing, adverse event incidence, and monitoring requirements were obtained from key clinical trials and prescribing information. Drug acquisition costs, unit monitoring costs, and adverse event costs were obtained from wholesale acquisition costs, fee schedules, and the Healthcare Cost and Utilization Project, respectively. The total incremental costs and per-member-per-month (PMPM) costs were calculated by comparing total health plan costs in the treatment setting with neratinib with costs in the treatment setting without neratinib over a 5-year period. Costs were presented in 2019 US dollars. Results It was estimated that 47 patients would be eligible for third-line HER2 mBC treatment in the first year, with an additional 17 incident patients becoming eligible each subsequent year. Average monthly costs per treated patient were $15,037, $9,283, $27,759, and $14,826 for neratinib doublet regimen, lapatinib doublet regimen, tucatinib triplet regimen, and DS-8201, respectively. When market shares were assumed to be even across regimens, the treatment setting with neratinib doublet regimen reduced total annual health plan costs by $1.4 million ($0.02 PMPM) over 5 years compared with the treatment setting without neratinib doublet regimen. Cost reductions for the treatment setting with neratinib doublet regimen were $575,738 ($0.01 PMPM) over 5 years when market shares were based on clinical expert estimates. Conclusions The introduction of neratinib over the course of 5 years has the potential to reduce US health plan costs for the treatment of patients with HER2+ mBC by reducing the usage of more expensive treatment regimens. Citation Format: Seri AL Anderson, Justin Carrico, Thor-Henrik Brodtkorb, Deepa Lalla, Adam Brufsky. Budget impact of introducing neratinib for third-line treatment of HER2+ metastatic breast cancer in the United States [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-45.