Abstract 4527: Patient-derived organoids and xenografts identify neratinib plus HER2 antibody drug conjugate as a synergistic drug combination for HER2 mutated, nonamplified metastatic breast cancer
Authors: Li Shunqiang , Maureen Highkin , Primeau Tina M. , Pratt Stephanie L. , Diala Irmina , Cutler Richard E. , Mann Grace , Lalani Alshad S. , Ma Cynthia X. , Bose Ron 
Published: August 2019

Abstract
HER2 activating mutations are a novel, druggable genomic alteration in metastatic breast cancer (MBC). These HER2 mutations are predominantly found in HER2 gene amplification negative, hormone receptor positive breast cancers. We have previously demonstrated that HER2 mutations can be potently inhibited by the second generation, irreversible pan-HER tyrosine kinase inhibitor, neratinib (Bose et al., Cancer Discovery 2013). Further, we performed a phase II clinical trial to treat HER2 mutated MBC and we found that neratinib monotherapy produced a clinical benefit rate of 31% and progression free survival (PFS) of 16 weeks in a heavily pre-treated patient population (Ma et al., Clin. Can. Res. 2017). A second clinical trial, the SUMMIT trial (Hyman et al., Nature 2018), similarly showed a response rate of 32% and median PFS of 3.5 months for neratinib monotherapy for HER2 mutated, metastatic breast cancer. The objective of the current study is to explore novel combination strategies to improve the efficacy of neratinib in HER2 mutated breast cancer. In order to accelerate progress on testing multiple drug combinations, we developed organoids from two patient-derived xenografts (PDX’s) of HER2 mutated, ER positive metastatic breast cancer from our institution. We found that the ex vivoculture of these patient-derived organoids provides a platform to rapidly perform drug screens and drug combination testing on a scale that cannot be matched by other existing experimental platforms for patient-derived samples. The drug sensitivity of these organoids cultured ex vivo recapitulates the data previously obtained with transfected cell lines and in vivo experiments using PDX’s. Further, multiple drug combinations can be tested on these organoids in just two weeks, which is much shorter than the four to six months required for the corresponding slow-growing ER positive, breast cancer PDX’s that they are derived from. Strong, single agent activity was seen with neratinib, the HER2 antibody drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1), and the chemotherapy drug vinorelbine. Therefore, we tested combinations of neratinib plus the HER2 ADC and neratinib plus vinorelbine on these patient derived organoids. Neratinib plus HER2 ADC showed a strong drug synergy in both HER2 mutated organoids, as judged by the Loewe model of drug synergy. Prior publications suggest that the mechanism of action of neratinib in this combination is by increasing HER2 ubiquitylation and endocytic degradation, which will increase the uptake of the ADC that binds to HER2. We are now performing 384 well drug screens with these HER2 mutated, ER positive metastatic breast cancer organoids, and the results of the screens will be shown in our presentation.
Citation Format: Shunqiang Li, Highkin Maureen, Tina M. Primeau, Stephanie L. Pratt, Irmina Diala, Richard E. Cutler, Grace Mann, Alshad S. Lalani, Cynthia X. Ma, Ron Bose. Patient-derived organoids and xenografts identify neratinib plus HER2 antibody drug conjugate as a synergistic drug combination for HER2 mutated, nonamplified metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4527.