Abstract
Rovalpituzumab tesirine is well tolerated and has single-agent antitumor activity.
Major finding: Rovalpituzumab tesirine is well tolerated and has single-agent antitumor activity.
Concept: Rovalpituzumab tesirine has activity in small-cell lung cancer and large-cell neuroendocrine tumors.
Impact: Targeting DLL3 with rovalpituzumab tesirine may be effective in patients with DLL3-positive tumors.
Delta-like protein 3 (DLL3) is an inhibitory Notch receptor ligand that is frequently expressed in large-cell neuroendocrine tumors and small-cell lung carcinomas, but not in normal adult tissue or non-neuroendocrine tumors, suggesting it may be a potential therapeutic target in these cancers. Rudin and colleagues performed an open-label, phase I, dose-escalation study to evaluate the safety and efficacy of rovalpituzumab tesirine, a DLL3-targeted antibody–drug conjugate, in patients with small-cell lung cancer or other high-grade neuroendocrine tumors. In total, 82 patients enrolled in the study, 74 with small-cell lung cancer and 8 with large-cell neuroendocrine carcinoma. The primary objectives were to assess the safety of rovalpituzumab tesirine and determine the maximum tolerated dose. Secondary objectives included evaluation of antitumor activity and determination of the recommended phase II dose and schedule. Rovalpituzumab tesirine was generally well tolerated, although adverse events grade 3 or greater occurred in 38% of patients. Of the 60 assessable patients who received an active dose, 11 (18%) achieved an objective response and 30 (50%) achieved stable disease. Notably, 10 of 26 patients (38%) with high expression of DLL3 achieved an objective response, whereas no objective responses occurred in patients with low expression of DLL3. In 68 patients receiving an active dose of rovalpituzumab tesirine, the median overall survival was 4.6 months. In 29 assessable DLL3-high patients the median overall survival was 5.8 months compared with 2.7 months in 10 DLL3-low patients. In addition to validating DLL3 as a therapeutic target in small-cell lung cancer and large-cell neuroendocrine tumors, the results of this phase I trial indicate that rovalpituzumab tesirine is well tolerated and active as a single-agent therapy and warrants further clinical investigation in patients with tumors exhibiting high DLL3 expression.