作者
F. Blackhall,Kevin Jao,L. Greillier,Byoung Chul Cho,Konstantin Penkov,Noemi Reguart,Margarita Majem,Kristiaan Nackaerts,Konstantinos Syrigos,Karin Holmskov Hansen,Wolfgang Schuette,Jeremy Cetnar,Federico Cappuzzo,Isamu Okamoto,Mustafa Erman,Seppo W. Langer,Terufumi Kato,Harry J.M. Groen,Zhaowen Sun,Yan Luo,Poonam Tanwani,L. Caffrey,Philip Komarnitsky,Niels Reinmuth
摘要
IntroductionDLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated.MethodsThe TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m2) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS).ResultsPatients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6–7.3) in the Rova-T arm and 8.6 months (7.7–10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17–1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports.ConclusionsCompared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.