Differentiation of liposomal irinotecan from dose-dense non-liposomal irinotecan in patient-derived pancreatic cancer xenograft tumor models.

Abstract

e16724 Background: Liposomal irinotecan (ONIVYDE) is approved with 5-fluorouracil/leucovorin for metastatic pancreatic ductal adenocarcinoma (PDAC) post progression on gemcitabine-based therapy. The liposomal formulation prolongs payload residence time in the circulation and tumor lesions, where local conversion to the active metabolite SN-38 is thought to occur. The effect of the liposomal formulation on therapeutic index (TI) was assessed in patient-derived xenograft PDAC models (IM-PAN-001 [untreated tumor] and SA-PAN-077) in severe combined immunodeficiency mice. Methods: Liposomal (2.5, 10 or 50 mg/kg, intravenous [IV] 1 x weekly) and non-liposomal irinotecan (2, 5 or 10 mg/kg, IV 5 x weekly) were administered for 3 weeks (n = 8/group). Maximum tolerated dose (MTD) and clinically-relevant weekly doses (10 mg/kg, liposomal; 33 mg/kg, non-liposomal) of irinotecan were evaluated. TI was the ratio of MTD/lowest dose with anti-tumoral activity; time to reach tumor volume of 600 mm3 (TTV600) was a proxy for overall survival. Tumor, plasma, gut and bone marrow were sampled for pharmacokinetics and safety assessment; DNA damage was evaluated via pH2AX and 53BP1 IHC. Results: The Table reports results of the more sensitive IM-PAN-001 model: TI of weekly liposomal irinotecan was 4-fold higher than for 5 x weekly non-liposomal irinotecan (TI was narrower for SA-PAN-077). For liposomal vs non-liposomal irinotecan in IM-PAN-001, TTV600 was longer at both MTD and clinically equivalent doses, and tumoral irinotecan levels were higher at MTD. High levels of DNA damage were present in most cancer cells in IM-PAN-001 compared to SA-PAN-077 one week after the last liposomal treatment cycle. Conclusions: In both PDAC models, TI was higher for weekly liposomal vs 5 x weekly non-liposomal irinotecan, suggesting potential benefits of the liposomal formulation in a clinical setting. [Table: see text]