INTRODUCTION: SCLC has limited second-line treatment options after chemotherapy. We assessed the efficacy and safety of lurbinectedin combined with pembrolizumab in relapsed SCLC patients who had not received prior immunotherapy, aiming to prevent early progression and achieve sustained responses. METHODS: The LUPER trial (NCT04358237) is a phase I/II, single-arm, open-label, multicenter study. Phase I established the recommended phase II dose. The primary endpoint of phase II was the investigator-confirmed objective response rate. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Patients were categorized as platinum-sensitive (chemotherapy-free interval ≥ 90 d) or platinum-resistant (<
90 d). RESULTS: The recommended phase II dose was 3.2 mg/m CONCLUSIONS: Lurbinectedin plus pembrolizumab reported promising efficacy in relapsed SCLC, particularly for platinum-sensitive patients, with a known and manageable safety profile. These results support further exploration of this combination in SCLC treatment.