Studies in preclinical models have suggested that combining lurbinectedin with 5-fluorouracil enhances antitumor effects against solid tumors. This phase I clinical trial aimed to assess the safety, efficacy, and pharmacokinetics of combining capecitabine and lurbinectedin in patients with advanced solid tumors, with a particular focus on those with relapsed metastatic breast cancer (MBC). Patients in the trial were given capecitabine orally from day (D)1 to D14, alongside lurbinectedin administered intravenously either on D1 and D8, or every 3 weeks on D1 alone, following a traditional 3 + 3 dose escalation approach. Once the recommended dose (RD) was identified, the study continued to explore its efficacy and safety. Among the 81 patients enrolled, 28 had relapsed MBC, including 20 with hormone receptor (HR)-positive and 8 with triple-negative breast cancer. Three patients followed the D1, D8 schedule, and 25 followed the D1-only regimen. The recommended dose for this combination was capecitabine 1650 mg/m² daily from D1 to D14, with lurbinectedin 2.2 mg/m² administered on D1 every three weeks. At all dose levels, 16 patients achieved confirmed responses and 2 showed prolonged disease stabilization lasting more than 6 months, leading to an overall response rate (ORR) of 57% and a clinical benefit rate (CBR) of 64%. At the RD, ORR and CBR were 47% and 60%, respectively. Notably, patients with HR-positive tumors demonstrated a higher response rate (ORR of 60%, CBR of 70% across all doses; ORR of 56%, CBR of 78% at the RD). Among the triple-negative cohort, 4 patients showed responses (ORR and CBR of 50% at all doses, dropping to 33% at the RD). The treatment was generally well tolerated, with reversible myelotoxicity at the RD and mostly mild-to-moderate non-hematologic side effects. No serious cases of febrile neutropenia or severe palmar-plantar erythrodysesthesia syndrome were reported, and there were no major pharmacokinetic interactions between capecitabine, its metabolites, and lurbinectedin. The combination of capecitabine and lurbinectedin exhibited promising antitumor activity in relapsed MBC, particularly in HR-positive cases. The toxicity profile was manageable, and further investigation into this combination therapy for relapsed MBC is warranted.
