Abstract: Lung cancer is the leading cause of death of all cancer entities and small-cell lung cancer (SCLC) is the most malignant subtype. Despite good initial response to chemotherapy, many patients relapse early and success of second line treatment remains poor. For years, no relevant improvement of second line treatment has been achieved in the field of SCLC. Lurbinectedin, a novel RNA-polymerase II inhibitor has shown promising results in pretreated SCLC patients as single agent and in combination with other chemotherapeutic drugs leading to an orphan drug designation from the FDA. This article reviews the current data on this emerging substance and its impact on the treatment of SCLC.
Keywords: SCLC, chemotherapy, lurbinectedin, orphan drug
Small-cell lung cancer (SCLC) accounts for about 15% to 17% of all diagnosed lung cancers. Nevertheless, due to its aggressive and rapid behavior, SCLC is the leading cause of death among all malignancies.1 Promising progress in the field of non-small cell cancer (NSCLC) regarding targeted therapy and immunotherapy has been achieved in the last few years. However, the prognosis and therapeutic options of SCLC are still limited with a median survival of patients with extensive disease between 7 to 10 months and a 1-year survival of 20% to 40%.2
Despite the slight improvement of overall survival by adding checkpoint inhibitors to first line treatment,3 and the development of other various treatment options, eg, PARP inhibitors, or cell cycle modulating agents, chemotherapy remains the backbone of SCLC therapy.4
Despite the good response of first line chemotherapy in SCLC, patients generally relapse early and therapeutic options in second line treatment are limited. In sensitive disease, topotecan, which is the current standard second line treatment in Europe, irinotecan and amrubicin have shown modest activity as monotherapy,5–7 while doxorubicin and ifosfamide were revealed not to be effective in refractory relapse.8,9 Given the disappointing results in second line therapy, new therapeutic approaches are desperately needed in the field of SCLC.
Lurbinectedin is a novel RNA-polymerase-II inhibitor showing promising results in several cancer entities. Also in SCLC, lurbinectedin has proven relevant activity leading to an orphan drug designation from the FDA in August 2018.
In this article, we review the current literature of preclinical and clinical data on lurbinectedin in SCLC treatment.
MECHANISM OF ACTION AND PRECLINICAL DATA OF LURBINECTEDIN
Lurbinectedin (PM01183) is a derivative of ecteinascidin, a marine-derived agent that covalently binds to the DNA minor groove and thus leads to double-strand DNA breaks. Furthermore, it inhibits RNA-polymerase-II activity and promotes its specific degradation by the ubiquitin/proteasome machinery.10,11 Lurbinectedin is a second-generation trabectedin analog with similar structure except for the C subunit, where tetrahydroisoquinoline was replaced by a tetrahydro β-carboline in lurbinectedin.10,12 This difference may have an impact on pharmacokinetics and pharmacodynamics. It has been proposed that modification of the C-ring could enhance the direct interactions with specific factors of DNA repair.10,13,14 It has been shown to have potent cytotoxic activity in several cell lines and murine xenograft human cancer models.10 Furthermore, by attenuating the activity of the nucleotide excision repair (NER) mechanism, lurbinectedin was able to overcome cisplatin resistance in NER hyperactive cell lines.12 Single lurbinectedin as well as in combination with cisplatin was effective in cisplatin-resistant ovarian tumor models.15,16 Also, cervical cell lines and cervical cancers in xenograft mouse models were highly affected by single agent lurbinectedin.17 Lurbinectedin was also shown to inactivate Ewing Sarcoma Oncoprotein (EWS-FLI1) by nuclear redistribution leading to promotor inactivity and decreased mRNA and protein levels.18
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