Combination of Lurbinectedin Plus Irinotecan: Preclinical and Early Clinical Results in Patients With Relapsed SCLC

Introduction Novel treatment approaches are required for relapsed small cell lung cancer (SCLC). Previous studies showed promising activity for lurbinectedin combined with topoisomerase inhibitors in preclinical models of other solid tumors. Methods SCLC cell lines, patient-derived organoids and xenografts were used to evaluate the effects of lurbinectedin plus irinotecan. The underlying mechanism of interaction was elucidated using flow cytometry, immunofluorescence and western blotting. A phase I/II clinical trial assessed the efficacy and safety of the lurbinectedin/irinotecan combination in patients with advanced solid tumors. Results A synergistic antitumor effect was observed for the combination in vitro and in vivo , which resulted from impaired S-phase entry and progression, enhanced DNA damage, and induction of apoptosis. Based on the results of the dose escalation stage of the trial, a recommended dose (RD) of lurbinectedin 2.0 mg/m 2 on Day (D)1 plus irinotecan 75 mg/m 2 on D1,D8 every three weeks with primary growth factor prophylaxis was chosen for further evaluation. Of 47 patients with relapsed SCLC included in the trial, 21 with measurable disease treated at the RD showed overall response rate 61.9%, median progression-free survival 7.2 months, and median overall survival 12.3 months. Most common toxicities at the RD were myelosuppression, fatigue, gastrointestinal disorders and decreased appetite. Conclusions The lurbinectedin/irinotecan combination increased the induction of DNA damage and apoptosis, resulting in increased antitumor efficacy in vitro and in vivo . Early clinical data showed promising antitumor activity and a predictable safety profile for the combination in relapsed SCLC. Further development in this indication is ongoing.