Abstract 4134: MM-302 is more effective than PEGylated liposomal doxorubicin (PLD) at reducing pulmonary metastatic burden in breast cancer models expressing intermediate levels of HER2
Authors: Dumont Nancy , Geretti Elena , Curtis Leonard Shannon , Espelin Christopher , Gaddy Daniel , Hendriks Bart , Nielsen Ulrik , Wickham Thomas 
Published: August 2015

Introduction: Despite improvements in treatment with newly approved HER2-targeted therapies, safe and effective treatments are still needed, not only for HER2-positive metastatic breast cancer (MBC), but also for MBC expressing intermediate levels of HER2 that are still considered HER2-negative (e.g. IHC 2+, FISH-negative). MM-302 is a liposomal antibody drug conjugate (ADC) designed to target doxorubicin to HER2-overexpressing cancer cells. MM-302 is currently being evaluated in HER2-positive locally advanced breast cancer (LABC)/MBC patients in the registration-directed HERMIONE trial. The objective of this study was to compare the relative efficacy of MM-302 and PLD in treating HER2-intermediate MBC (corresponding to 1+/2+ by IHC) using models that closely mimic how HER2-overexpressing metastatic tumors are established in humans.

Methods: To establish metastatic disease, the murine 4T1-HER2 cell line engineered to express intermediate levels of Her2 (median of ∼1×105 HER2 receptors/cell), and the human MDA-MB-453 cells that endogenously express intermediate levels of Her2 (2+ by IHC and median of ∼3×105 HER2 receptors/cell), were inoculated orthotopically into the right and left mammary fat pads of immunocompromised mice. Primary tumors then spontaneously seed cancer cells in distant visceral organs such as the lung. When primary tumor volumes reached ∼150 mm3 (4T1-Her2) or ∼270 mm3 (MDA-MB-453), mice were randomized and treated with vehicle control, PLD or MM-302. At the end of the study, primary tumors and lungs were harvested to assess liposome delivery and quantify pulmonary metastatic burden.

Results: MM-302 was more effective than PLD at reducing total pulmonary metastatic burden in both HER2-intermediate models as evidenced by the lower number of surface metastases in the 4T1-Her2 model and the lower number of human cytokeratin positive cells per lung in the MDA-MB-453 model. MM-302 and PLD were equally effective at slowing (4T1-Her2) and inhibiting (MDA-MB-453) primary tumor growth. Mechanisms responsible for differences in efficacy are being explored. To date, better distribution of liposomes in metastatic lesions than in primary tumors has been observed where liposome delivery appears to be restricted to the tumor periphery in the 4T1-Her2 model.

Conclusion: MM-302 was more effective than PLD at reducing pulmonary metastatic tumor burden in both HER2-expressing models. The superiority of MM-302 over PLD was unique to metastatic lesions where there was better distribution of liposomes than in the primary tumor. These results support the rationale for evaluating MM-302 in patients with HER2-intermediate MBC.

Citation Format: Nancy Dumont, Elena Geretti, Shannon Curtis Leonard, Christopher Espelin, Daniel Gaddy, Bart Hendriks, Ulrik Nielsen, Thomas Wickham. MM-302 is more effective than PEGylated liposomal doxorubicin (PLD) at reducing pulmonary metastatic burden in breast cancer models expressing intermediate levels of HER2. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4134. doi:10.1158/1538-7445.AM2015-4134