Liposomal Irinotecan Achieves Significant Survival and Tumor Burden Control in a Triple Negative Breast Cancer Model of Spontaneous Metastasis

Abstract

Triple negative breast cancer (TNBC) represents a significant therapeutic challenge due to its highly aggressive nature and lack of effective treatment options. Liposomal irinotecan (nal-IRI, ONIVYDE) was approved in 2015 (by the Food and Drug Administration, European Medicines Agency, and Therapeutic Goods Administration) and is a topoisomerase inhibitor indicated, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. This study investigates the potential therapeutic benefit of nal-IRI for the treatment of advanced TNBC in a clinically relevant mouse model of spontaneous metastasis (LM2-4). Female SCID mice were orthotopically inoculated with TNBC LM2-4-luc cells in the lower mammary fat pad. Following primary tumor resection, bioluminescence imaging (BLI) was used to monitor both metastasis formation and spread as well as response to treatment with nal-IRI. Weekly treatment with 10 mg/kg of nal-IRI provided a 4.9-times longer median survival compared to both 50 mg/kg irinotecan treated and untreated animals. The survival benefit was supported by a significant delay in the regrowth of the primary tumor, effective control, and eventual regression of metastases assessed using longitudinal BLI, which was confirmed at the study end point with magnetic resonance (MR) imaging and post-mortem observation. This preclinical investigation demonstrates that, at a five-times lower dose compared to the free drug, liposomal irinotecan provides significant survival benefit and effective management of metastatic disease burden in a clinically relevant model of spontaneous TNBC metastases. These findings support the evaluation of nal-IRI in patients with advanced and metastatic TNBC.

Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

“…Liposomal irinotecan (nal-IRI, ONIVYDE) was approved in 2015 [ 105 ]. Since then, new liposomal irinotecan formulations have been developed and used as second-line treatments of metastatic pancreatic cancer [ 106 , 107 ].…”

“…PEGylated liposomal formulation of irinotecan (MM-398) improved the cytotoxic effects of irinotecan in a mouse model of brain metastasis compared to irinotecan monotherapy [ 111 ]. Liposomal formulations of irinotecan are promising new cytotoxic agents that can be utilized to treat other malignancies such as metastatic breast cancer [ 105 ]. Zhang et al [ 112 ] conjugated irinotecan with a series of fatty acids to increase its lipophilicity and allow particles to self-assemble in an aqueous environment in order to protect estrified irinotecan from bond hydrolysis by carboxylesterases.…”

Spatiotemporal assessment of spontaneous metastasis formation using multimodal in vivo imaging in HER2+ and triple negative metastatic breast cancer xenograft models in mice

“…A similar increased incidence of brain metastasis following chemotherapy was also described in the preclinical setting in long-term surviving animals in a mouse model of melanoma metastatic disease [ 28 ] and following trastuzumab treatment in the LM2-4H2N model [ 19 ]. In a separate study performed by our group, a brain metastatic lesion was indeed observed in the LM2-4 model on day 77 post primary tumor removal (56 days later than the study endpoint for this investigation), after the animal received weekly chemotherapy for 9 weeks [ 29 ].…”

Sacituzumab Govitecan-hziy: An Antibody-Drug Conjugate for the Treatment of Refractory, Metastatic, Triple-Negative Breast Cancer

“…Topoisomerase-I inhibitors have demonstrated activity in mTNBC, but their use has been limited because of poor intratumor exposure and dose-limiting toxicities. 7,8 Incorporating a topoisomerase-I inhibitor with a targeted delivery method, therefore, presents an opportunity to maximize therapeutic potential. On April 22, 2020, the Food and Drug Administration (FDA) granted accelerated approval for the use of sacituzumab govitecan in mTNBC after granting orphan drug, fast track, and breakthrough therapy designations.…”