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Background: Currently, no therapies are approved specifically for EGFR-overexpressing tumors. AVID100 is a novel anti-EGFR antibody drug conjugate (ADC, DM1 payload) that was rationally designed for anti-tumor efficacy without accompanying on-target, off-tumor toxicity by employing an EGFR function-blocking antibody moiety. Although EGFR is overexpressed in a multitude of malignancies including squamous non-small cell lung cancer (sqNSCLC), head and neck carcinoma (HNSCC) and triple-negative breast cancer (TNBC), historically limited activity has been reported for EGFR monoclonal antibodies or EGFR TKIs in unselected patients. This emphasizes the need to develop novel and more efficacious agents targeting EGFR, and for biomarker- directed approaches to enrich for patients likely to respond. In pre-clinical models, AVID100 showed potent anti-tumour efficacy and a Phase 1 dose-escalation study in patients with advanced solid malignancies concluded that AVID100 was well tolerated at doses expected to be therapeutically active. An RP2D of 220 mg/m2 (~6 mg/kg) was established. Methods: This open-label, multicenter, multicohort, prospective Phase 2a study (NCT03094169) is designed to further evaluate the safety, tolerability, and preliminary efficacy of AVID100 when administered at 6 mg/kg Q3W per iv infusion in patients with locally advanced/unresectable or metastatic solid tumor malignancies of epithelial origin, and with documented EGFR over-expression. Additional endpoints include PK profiling and exploratory biomarkers. sqNSCLC and HNSCC patients with EGFR IHC of 3+ as well as mTNBC patients whose EGFR IHC shows 3+ intensity in ≥ 50% of tumor cells, or ≥ 2+ intensity in ≥ 75% of tumor cells, are eligible to enroll. Patients must have measurable disease according to RECIST v1.1 at enrolment and disease status is assessed radiographically every 6 weeks. EGFR over-expression positivity is established by a validated IHC assay (DAKO EGFRpharmDX) conducted by a central laboratory. Initial validation of the EGFR IHC was carried out retrospectively on archival tissue microarrays (US Biomax, Derwood, MD) from advanced sqNSCLC, HNSCC and TNBC patients. Results Initial validation of the EGFR IHC assay conducted with archival tissue samples yielded EGFR 3+ positivity in ≥ 50% of tumor cells for 30% (32 out of 105 samples tested) of sqNSCLC and 22% (31 out of 140) of HNSCC samples. Among TNBC samples tested, 6% were EGFR 3+ in ≥ 50% of tumor cells and 25% EGFR 2 or 3+ in ≥ 50% of tumor cells (16 and 62 out of 249, respectively). The prospective Phase 2a trial assessing AVID100 in patients selected for EGFR overexpression was is actively accruing and one sqNSCLC, four SCCHN and three TNBC patients had been enrolled at time of writing. Conclusions A significant proportion of retrospectively assessed sqNSCLC, HNSCC and TNBC patient samples were found to overexpress the EGFR. The prospective Phase 2a trial assessing AVID100, a novel growth factor receptor function-blocking anti-EGFR ADC, remains ongoing and updated results will be presented at the meeting. Citation Format: Jason Melear, Nehal Lakhani, Joyce A O'Shaughnessy, Sharon T Wilks, Saad Khan, Sree R Chandana, Anthony W Tolcher, Kyri P Papadopoulos, Yvette Cole, Karla Rivas, Ria Ghosh, Sandra Sinclair, Robert Lutz, Paul I Nadler, Debra L Wood, Barbara Burtness. Novel anti-EGFR antibody-drug conjugate AVID100: A phase 2a trial in patients with EGFR-overexpressing advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A088. doi:10.1158/1535-7163.TARG-19-A088