Extended topoisomerase 1 inhibition through liposomal irinotecan results in improved efficacy over topotecan and irinotecan in models of small-cell lung cancer

Abstract

Liposomal irinotecan (irinotecan liposome injection, nal-IRI), a liposomal formulation of irinotecan, is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior antitumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan. We evaluated the antitumor activity of nal-IRI compared with irinotecan and topotecan in preclinical models of small-cell lung cancer (SCLC) including in a model pretreated with carboplatin and etoposide, a first-line regimen used in SCLC. Nal-IRI demonstrated antitumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, and NCI-H1048 cell line-derived models as well as in three patient-derived xenograft models. The antitumor activity of nal-IRI was superior to that of topotecan in all models tested, which generally exhibited limited control of tumor growth and was superior to irinotecan in four out of five models. Further, nal-IRI demonstrated antitumor activity in tumors that progressed following treatment with topotecan or irinotecan, and demonstrated significantly greater antitumor activity than both topotecan and irinotecan in NCI-H1048 tumors that had progressed on previous carboplatin plus etoposide treatment. These results support the clinical development of nal-IRI in patients with SCLC.

Nanoliposomal irinotecan in combination with leucovorin and 5‑fluorouracil in advanced biliary tract cancers

“…In these studies, PFS and OS ranged from 2.4 to 3.5 months and from 5.5 to 6.6 months, respectively ( 11 , 29 , 30 ). Superiority of liposomal irinotecan over standard irinotecan in other malignancies has also been described in previous preclinical and clinical studies ( 17 , 18 , 31 ).…”

Liposomal Irinotecan + 5-FU/LV in Metastatic Pancreatic Cancer

“…23 nal-IRI therapy has been shown to overcome irinotecan resistance in models of small cell lung cancer. 24 We therefore investigated whether patients who had received nonliposomal irinotecan before entry into the NAPOLI-1 trial benefited from treatment with nal-IRI+5-FU/LV. A similar proportion of patients were irinotecan-naive in the nal-IRI+5-FU/LV arm (90%, n = 105/117) and the 5-FU/LV arm (86%, n = 102/119).…”

“…Liposomal irinotecan shows sustained efficacy in tumors resistant to nonliposomal irinotecan and topotecan in preclinical models of small cell lung cancer. 24 A recent retrospective observational study of patients with mPAC receiving nal-IRI+5-FU/LV indicated that of patients who received nonliposomal irinotecan, those whose disease did not progress on prior irinotecan-containing therapy had similar OS to those who had not received prior irinotecan, whereas those who had progressed had worse survival outcomes. 28 Thus, a better understanding of the interplay between nal-IRI and irinotecan resistance in mPAC is needed.…”

Nanoparticles from Gantrez-based conjugates for the oral delivery of camptothecin

“…This approach would be in line with an improved efficacy of this anticancer drug. In fact, it has been described that a prolonged and sustained Topo 1 inhibition (including with daily low-dose dosing regimens) can mediate a hypoxia-inducible factor 1 alpha (HIF-1) inhibition mechanism, augmenting the efficacy of the anticancer drug ( Rapisarda et al, 2004 ; Leonard et al, 2017 ).…”