Abstract 5986: Lurbinectedin/Irinotecan as a new therapeutic combination for small cell lung cancer

Abstract Small Cell Lung Cancer (SCLC) is one of the most frequent and deadliest types of Cancer, with an overal survival (OS) of less than 14 months and a 2- year survival rate not exceeding 7%. Potentially targetable molecular alterations in kinase genes are uncommon in SCLC, and consequently, treatment has barely changed in the last fifty years. Irinotecan, a Topoisomerase II inhibitor, and Lurbinectedin, an inhibitor of transcription, are the two only recently approved chemotherapy agents employed as monotherapy in second line of treatment. Our group has led a Clinical Trial to test the efficacy of the combination of these two drugs in SCLC in patients previously treated with the standard of care. The Clinical trial shows a consistent reduction in tumor size and a significant improvement in the Progression-free survival (PFS) of patients. To determine the mechanisms behind this promising effect, we have conducted a series of experiments using our platform of Patient-Derived models (Patient Derived Xenografts (PDX), Circulating tumor Cell-Derived Xenografts (CDX) and PDX/CDX-derived organoids/spheroids). Treating our PDX/CDX models faithfully recapitulates the results observed in patients, with a clear increase in survival in mice treated with the combination. Short term treatment of PDX models, as well as 3D cultures of organoids (PDXDO) and spheroids (CDXDS) and 2D cultures of SCLC cell lines, helped us determine that the treatment causes elevated levels of DNA Damage, a blockade in DNA Replication, and finally apoptosis. The results from this study highlight the relevance of the combination of these two already approved drugs in the treatment of SCLC. Citation Format: Miguel Ruiz Torres, Santiago Ponce, Juan Manuel Coya, Reyes Bernabe, Jon Zugazagoitia, Alvaro Ucero, Javier Baena, Luis Paz-Ares, Irene Ferrer. Lurbinectedin/Irinotecan as a new therapeutic combination for small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5986.