In an exploratory analysis of patients with available post-baseline scans, 26 patients with high levels DL元 expression had an ORR of 31% by independent review (eight patients with ≥50% DL元 expression by mouse antibody immunohistochemistry assay). In a first-in-human phase I study, Rova-T showed encouraging results with objective response rates (ORR) per independent review in nine (16%) of 56 assessable patients with 2L or 3L SCLC and any level of DL元 expression ( 18). PBD dimers then bind to the DNA minor groove where they form covalent adducts causing stalling of the replication forks, cell-cycle arrest at the G 2–M boundary, and apoptosis. Rova-T selectively binds to DL元 on target-expressing cells, is internalized, and upon proteolytic cleavage releases the toxin. Rovalpituzumab tesirine (Rova-T) is an antibody–drug conjugate (ADC) composed of SC16, a humanized IgG1 antibody against DL元, conjugated to the cytotoxic pyrrolobenzodiazepine (PBD) dimer D6.5 (SC-DR002) via a protease-cleavable linker ( 15). Although DL元 is mostly found within the Golgi apparatus under physiological conditions, it may reach the cell surface in case of overexpression and lead to Notch inhibition in cis ( 13, 17).
Furthermore, DL元 expression appears to be stable over time in SCLC tumors pre- and post-chemotherapy ( 16). DL元 is highly expressed in SCLC and other neuroendocrine tumors, but has little to no expression in normal tissues or non-neuroendocrine tumor types ( 15). There is no globally approved agent for patients with SCLC who recur following 2L treatment, although nivolumab is FDA-approved in this patient population and is associated with benefit in a small percentage of patients ( 12).ĭelta-like 3 protein (DL元) is an atypical Notch ligand that has been implicated in regulation of cell development and cell fate decisions ( 13), and is a downstream target of achaetescute homolog-1 (ASCL1), suggesting its role in neuroendocrine tumorigenesis ( 14). Outcomes are particularly poor among patients with chemotherapy-resistant disease, generally defined by a period from the completion of 1L therapy to the development of tumor progression of less than 90 days, with overall response rates usually below 10% ( 10, 11). The topoisomerase I inhibitor topotecan, the only drug currently approved by the FDA and European Medicines Agency in the second-line (2L) setting, has been associated with overall response rates of 16.9% to 21.9%, median progression-free survival (PFS) of 3.4 to 3.5 months, and median overall survival (OS) of 7.8 to 8.7 months in randomized clinical trials ( 9, 10). Despite high initial responses to first-line (1L) platinum- and immunotherapy-based treatment regimens ( 5), which are associated with rapid responses and symptomatic improvement, virtually all patients with extensive-stage SCLC develop tumor progression, mostly within 6 months, with rare survivors at 5 years ( 6– 8). This high-grade neuroendocrine tumor is characterized by rapid growth and early development of metastases to both regional lymph nodes and distant sites ( 4). Small-cell lung cancer (SCLC) accounts for approximately 13% to 15% of all lung cancers with an estimate of more than 180,000 new cases diagnosed annually worldwide ( 1– 3). CarboneĪdministrative, technical, or material support (i.e., reporting or organizing data, constructing databases): A. Writing, review, and/or revision of the manuscript: D. CarboneĪnalysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): D.
CarboneĪcquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): D.
Authors’ Contributions Conception and design: D.
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