BACKGROUND: Effective later-line chemotherapy treatment options are scarce for patients with metastatic breast cancer (MBC). Trifluridine-tipiracil has shown survival benefit in heavily pre-treated patients with metastatic colorectal and in gastric cancer refractory to a fluoropyrimidine. This study aimed to investigate the efficacy of trifluridine-tipiracil in a Western population of previously treated patients with oestrogen receptor (ER+), HER2- MBC to facilitate further optimization of this treatment strategy. METHODS: Adult patients at least 18 years old diagnosed with hormone receptor positive, HER2- receptor negative MBC with a performance status of 0 or 1 who have been treated with capecitabine in the metastatic setting and up to two other lines of chemotherapy, including a taxane, were enrolled in this single-arm, multicentre, phase 2 study in the Netherlands. The participants received trifluridine-tipiracil 35 mg/m FINDINGS: Fifty female patients were enrolled from September 2020 to July 2023, with a median of 3 (IQR, 2-3) previous endocrine therapy lines and 2 (IQR, 2-3) chemotherapy lines for MBC. The DCR rate at 8 weeks was 64.0% ( INTERPRETATION: Trifluridine-tipiracil demonstrated promising efficacy in heavily pre-treated patients with MBC, despite prior exposure to a fluoropyrimidine. Clinically, this suggests that trifluridine-tipiracil holds potential as a viable oral later-line treatment option with a manageable toxicity profile while maintaining quality of life. Preparations for a phase 3 trial are underway. FUNDING: Servier, France.