Steven J Gibson1,2, Krishnansu S Tewari3, Bradley J Monk1,2 and Dana M Chase1,2* .
...
Lurbinectedin is a synthetic analogue of trabectedin (previously discussed) [1]. Positive phase III results were reported for the combination of trabectedin with pegylated liposomal doxorubicin, increasing PFS and overall response rate in women with relapsed ovarian cancer [45]. Trabectedin became the first marine-derived cancer drug, derived from the colonial tunicate, Ecteinascidia turbinate, and marketed in Europe as Yondelis® [46].
Lurbinectedin has the same structure as trabectedin, differing only in the C subunit. Soares et al. found that the modified C subunit did not significantly alter lurbinectedin activity or cytotoxicity, and suggested the new analogue may be useful for altering dosages to increase antitumor activity [47]. Lurbinectedin works by covalently binding the minor groove in DNA.
This binding causes the DNA strand to bend, increasing the incidence of double-strand breaks while also interfering with cell cycle processes and the nucleotide excision repair pathway [48].
Early in vivo mouse models demonstrated that singleagent lurbinectedin was effective in treating cisplatinsensitive and cisplatin-resistant ovarian tumor models.
Preclinical data also suggested that the combination of lurbinectedin with cisplatin-combined therapy was especially effective in the cisplatin resistant tumors [49].
A randomized, phase II study of 81 platinum-resistant/refractory ovarian cancer patients compared lurbinectedin to topotecan and found that lurbinectedin had significantly improved OS (10.6 vs 5.7 months), PFS (3.9 vs 2.0 months), and the overall response rate (22%). In the lurbinectedin treatment arm, 85% of patients experienced grade 3/4 neutropenia, which was found to be preventable by using a G-CSF blood stimulating factor [50]. With this encouraging data and the success of trabectedin, lurbinectedin has received Orphan Drug status from the FDA and phase III trials in platinum-resistant patients have been planned .
...