Nal-IRI, a liposomal formulation of irinotecan, is designed for extended circulation relative to non-liposomal irinotecan and to exploit leaky 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 (TOP1) by extended SN-38 exposure is hypothesized to enable superior anti-tumor activity compared to traditional TOP1 inhibitors. Topotecan, another TOP1 inhibitor, is an approved second-line treatment option for small cell lung cancer (SCLC). Here, we evaluate the anti-tumor activity of nal-IRI compared to irinotecan and topotecan in preclinical models of SCLC including those that have been pre-treated with therapeutics used clinically to treat SCLC.
Anti-tumor activity of nal-IRI, irinotecan, or topotecan was evaluated based on tumor volume assessments in DMS-53, DMS-114 and NCI-H1048 subcutaneous xenograft models in NOD-SCID mice, as well as in a patient-derived xenograft (PDX) model in nu/nu mice. To approximate clinical dosing: Nal-IRI was dosed at 16 mg/kg (irinotecan HCl basis), q1w, equivalent to a proposed clinical dose of 90 mg/m2 free base, q2w; irinotecan was dosed at 33 mg/kg q1w, equivalent to a clinical dose of 180 mg/m2 q2w; and topotecan was dosed at 0.83 mg/kg/week, day 1-2 every 7 days, which approximates a clinical dose intensity of 1.5 mg/m2 (days 1-5 every 21 days). Additionally, the activity of these agents was evaluated after tumors progressed following prior treatment with either topotecan, irinotecan or the combination of weekly carboplatin (30 mg/kg) plus etoposide (25 mg/kg), a standard first line regimen.
Nal-IRI demonstrated anti-tumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, NCI-H1048 and a PDX model in comparison with irinotecan or topotecan, which each had limited tumor growth control. Furthermore, Nal-IRI demonstrated anti-tumor activity in tumors that progressed following treatment with topotecan, and demonstrated significantly greater anti-tumor activity than both topotecan (p<0.0001) and irinotecan (p<0.0001) in NCI-H1048 tumors (8/8 complete responses) that had progressed on prior carboplatin plus etoposide treatment. These results support the further clinical development of nal-IRI versus IV topotecan in patients with SCLC that progressed on or after prior platinum containing therapy.
Citation Format: Shannon C. Leonard, Daniel Gaddy, Helen Lee, Stephan Klinz, Jonathan Fitzgerald, Bart Hendriks. Nanoliposomal irinotecan (nal-IRI, MM-398) has greater anti-tumor activity than topotecan and irinotecan in mouse models of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5151. doi:10.1158/1538-7445.AM2017-5151