Abstract P3-11-06: Pre-clinical assessment of combined ABT-263/Navitoclax and ABT-414 or ABBV-321 treatment for EGFR-expressing TNBC
Authors: Zoeller Jason J , Vagodny Aleksandr , Daniels Veerle W. , Taneja Krishan , Tan Benjamin Y. , DeRose Yoko S. , Fujita Maihi , Welm Alana L. , Letai Anthony , Leverson Joel D. , Blot Vincent , Bronson Roderick T. , Dillon Deborah A. , Brugge Joan S. 
Published: March 2020

Abstract
Despite a notable incidence of EGFR1 copy number alterations and/or enrichment of EGFR protein in a significant fraction of TNBCs, clinical application of classical EGFR-targeted therapeutics has been discouraging. Tumor specific EGFR-targeted antibodies (ABT-806) and their antibody-drug conjugates (ADC:414;321), which eliminate side effects associated with systemic anti-EGFR treatments, represent promising alternative therapeutic approaches. 414, comprised of 806 conjugated to the powerful cytotoxic MMAF, has demonstrated notable effectiveness within EGFR1-amplified/mutated tumors. However, since TNBCs are often enriched for EGFR expression in the absence of EGFR1 amplification or mutation, we explored whether neutralization of BCL-2/XL via ABT-263/Navitoclax would enhance the effectiveness of 414. Here, we evaluated 414+263 in a panel of seven EGFR-expressing patient-derived xenograft (PDX) models of TNBC. Tumor-bearing mice were randomized into one of two groups, either 414+263 or placebos. Tumor volumes were calculated via caliper-based measurements pre- and post-treatment. 14 days post-treatment, tumor growth inhibition was observed in five out of seven combination-treated tumor models; however, consistent tumor regressions were only observed in one of these models (HCI-010). Compared to the other PDX models, HCI-010 tumors were distinguished by EGFR1 low polysomy and the highest EGFR expression levels. To further explore combined treatment within HCI-010, we evaluated single-agents. To determine EGFR relevance, we also included a non-tumor targeted ADC (095-MMAF) as a single agent or in combination with 263. Tumor growth inhibition & regressions were observed in either 263 or 414+263 treated tumors. These responses were most significant under combined treatment conditions (avg. regression=40%). Tumor growth was unaffected by 414 or 095-MMAF single agents. Tumors treated with 095-MMAF+263 were comparable to single agent 263. Based upon these results, we considered an alternative EGFR-targeted ADC (321). 321, comprised of an affinity-matured version of 806 conjugated to the powerful cytotoxic PBD, exhibits enhanced EGFR affinities and has demonstrated notable effectiveness within EGFR-overexpressing tumors. To evaluate 321 combined treatment within HCI-010, tumor-bearing mice were randomized into six groups: placebos; 263; 321; 263+321; 095-PBD; 263+095-PBD. Tumor growth inhibition & tumor regressions were maintained under 263 and, unlike 414, also observed under 321 treatments. 321 resulted in dramatic tumor regressions (avg. regression=66%). Notably, 263 enhanced the effectiveness of 321 as evidenced by even more dramatic and near complete tumor regressions (avg. regression=88%). We extended these studies to include HCI-025, an additional PDX characterized by EGFR1 low polysomy and EGFR expression levels comparable to HCI-010. To evaluate 321 combined treatment within HCI-025; we performed a similar six-group study. HCI-025 tumors were also sensitive to single agent 321 (avg. regression=36%). Similar to HCI-010 and as evidenced by dramatic tumor regressions, 263 also enhanced the effectiveness of 321 within HCI-025 (avg. regression=68%). 095-PBD and 263+095-PBD also resulted in HCI-010 and HCI-025 tumor growth inhibition & regressions; however supportive of EGFR-mediated effects, 321 responses were greater than 095-PBD and 263+321 responses were greater than 263+095-PBD. These results underscore the significant potential of BCL-2/XL-inhibitors to enhance the effectiveness of cytotoxic agents delivered via ADCs. Notably, this strategy avoids the toxicities associated with systemic chemotherapy and BCL-2/XL-inhibitors. These results also highlight the translational relevance of 321+263, within the context of EGFR-expressing TNBC.
Citation Format: Jason J Zoeller, Aleksandr Vagodny, Veerle W. Daniels, Krishan Taneja, Benjamin Y. Tan, Yoko S. DeRose, Maihi Fujita, Alana L. Welm, Anthony Letai, Joel D. Leverson, Vincent Blot, Roderick T. Bronson, Deborah A. Dillon, Joan S. Brugge. Pre-clinical assessment of combined ABT-263/Navitoclax and ABT-414 or ABBV-321 treatment for EGFR-expressing TNBC [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-06.