Background: Lurbinectedin is a novel synthetic chemical entity that acts as an inhibitor of oncogenic transcription and is active in tumors addicted to transcription. A phase II Basket trial (NCT02454972) in patients with small cell lung cancer (SCLC) treated with lurbinectedin in the second-line setting showed overall response rate (ORR) of 35.2% and median duration of response (DoR) of 5.3 months, with durable responses (43.0% ≥ 6 months). Based on these results, lurbinectedin was granted accelerated approval by the US FDA. An ongoing phase I/II trial (NCT02611024) is evaluating the lurbinectedin/irinotecan combination. Preliminary results showed ORR of 62% and median DoR of 5.7 months (2020 World Conference on Lung Cancer) warranting expansion to 100 patients. These results have supported the conduction of a phase III trial (LAGOON - NCT05153239). Methods: LAGOON is a randomized phase III clinical trial evaluating two experimental arms (lurbinectedin alone, 3.2 mg/m² D1 q3wk, or lurbinectedin 2 mg/m² D1 plus irinotecan D1, D8 q3wk) versus Investigator’s Choice (topotecan D1-5 q3wk or irinotecan D1 q3wk according to label) as control arm in relapsed SCLC patients. Approximately 705 patients will be enrolled. Central randomization will be implemented (1:1:1 ratio). Stratification will be done according to chemotherapy-free interval (CTFI) after first line (sensitive vs. resistant); prior anti-PD-(L)1; baseline central nervous system (CNS) involvement; lactate dehydrogenase value, and Investigator’s preference for the Control Arm. Main inclusion criteria include age ≥ 18 years, confirmed SCLC diagnosis, one prior line of platinum-containing chemotherapy with/without anti-PD-(L)1, and CTFI ≥ 30 days. Patients with CNS metastases can participate if pretreated and radiologically stable for at least 4 weeks. Main exclusion criteria include platinum-naïve patients, patients pretreated with more than one prior chemotherapy regimen (including platinum re-challenge), and prior treatment with lurbinectedin, trabectedin, PM14, or topoisomerase I inhibitors. An Independent Data Monitoring Committee will oversee the conduct of the study. An Independent Review Committee will provide the patient’s response at each tumor assessment endpoint to determine the best patient’s response and the date of objective response or progression/censoring according to RECIST v.1.1. Clinical trial information: NCT05153239.