Abstract A111: Effects of unconjugated antibody pretreatment to reduce ADC-related toxicity: Preclinical effects of trastuzumab on T-DM1 activity in low passage breast PDX models.

Abstract

Abstract Background: Antibody-drug conjugates (ADC) are comprised of a cytotoxic agent linked to an antibody that targets surface proteins of tumors. Once bound, the cytotoxin enters and destroys the tumor cell while sparing surrounding healthy tissue. Recent approval of the ADC molecules brentuximab (mAb(CD30)-auristatin) for Hodgkin's lymphoma and T-DM1 (mAb(trastuzumab)-emtansine) for HER2-positive breast cancer has renewed interest in this agent class leading to development of a number of new molecules. While several of these agents have shown promising activity, low level expression of target proteins on healthy tissue has led to clinical dose-limiting toxicities. Pretreatment with the unconjugated antibody prior to ADC therapy may bind to target proteins on healthy tissue and reduce or prevent ADC-related toxicities. To test this possibility we identified three START-PDX breast models with high HER2 expression: ST225, ST340 (clinically trastuzumab-resistant) and ST910 (T-DM1 sensitive), and tested trastuzumab and T-DM1, alone and in combination, to compare model growth and drug effects. Methods: START-PDX breast models were established in immune-deficient mice from primary or metastatic patient tissue. Once established, models were confirmed by histologic comparative analysis and linked with patient treatment and outcome data. For each study, trastuzumab and T-DM1 were administered alone or in combination at 1:10 or 1:1 trastuzumab: T-DM1 ratios; trastuzumab was administered 24h prior to T-DM1 and all groups were dosed weekly. Study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition, delay and regression reported at study completion. Results: Trastuzumab alone was inactive in all models, while single agent T-DM1 induced tumor regressions including partial and complete responses. Co-administration of trastuzumab at 1:10 or 1:1 had slight to no effect on T-DM1 activity in ST225 or ST340, most likely due to the high inherent activity of T-DM1 towards these models. However, in the ST910 model, trastuzumab: T-DM1 at the 1:1 but not 1:10 combination group showed reduced activity compared with T-DM1 alone, suggesting competitive binding between the naked antibody and ADC at the higher trastuzumab concentration. Conclusion: We have identified trastuzumab refractory, T-DM1-sensitive breast START-PDX models and demonstrated that low level pretreatment with unconjugated trastuzumab prior to T-DM1 therapy did not inhibit its activity, suggesting that sequenced administration of the unconjugated antibody followed by the linked ADC may bind to target proteins on healthy tissue and reduce or prevent ADC-related toxicities without impacting efficacy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A111. Citation Format: Roger Chavez, Michael J. Wick, Teresa L. Vaught, Anthony W. Tolcher, Meredith P. Tolcher, Armando Diaz, Drew Rasco, Amita Patnaik, Gladys Rodriguez, Lon Smith, Kyriakos P. Papadopoulos. Effects of unconjugated antibody pretreatment to reduce ADC-related toxicity: Preclinical effects of trastuzumab on T-DM1 activity in low passage breast PDX models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A111.