Lurbinectedin, a DNA minor groove inhibitor for neuroendocrine neoplasms beyond small cell lung cancer.

Abstract

Neuroendocrine tumors (NETs) encompass a variety of neoplasms which display a wide spectrum of biologic behavior, ranging from the aggressive neuroendocrine carcinoma (NEC) to often indolent well-differentiated NETs. For well-differentiated NETs, somatostatin analogs (SSAs) are widely accepted as an effective frontline therapy for progressive or symptomatic disease; however, subsequent therapy options such as capecitabine/ temozolomide, sunitinib, everolimus, and radionuclide therapy in selected cases are associated with variable response rates (typically less than 20%) and limited progression-free survival. NECs can respond to platinum-based chemotherapy, but responses are typically short lived. There is evidence to suggest that neuroendocrine neoplasms such as small-cell lung cancer (SCLC) and pancreatic NETs are responsive to DNA alkylators such as temozolomide [1, 2]. Recently, lurbinectedin a DNA minor groove inhibitor and marine derivative was shown to inhibit oncogenic transcription through binding to CG-rich sequences near the promoters of protein-coding genes to promote apoptosis and cell-death [3]. Encouraging results from a phase II basket study of lurbinectedin as a second-line treatment for patients with SCLC, which demonstrated a 35% response rate, resulted in the FDA-approval of lurbinectedin in pre-treated patients with SCLC [4]. Moreover, in a subset analysis lurbinectedin was shown to effective treatment for platinum-sensitive relapsed SCLC, especially in patients with chemotherapy-free interval (CTFI) ≥180 days with an objective response rate of over 60% [5]. It was shown to be active in BRCA1/2 germline mutated breast cancer [6]. In addition