Abstract A028: Biomarker analysis in a phase 1 study of the antibody-drug conjugate ABBV-221 in patients with solid tumors likely to overexpress the epidermal growth factor receptor (EGFR)
Authors: Calvo Emiliano , Cleary James M. , Moreno Victor , Gifford Maryella , Roberts-Rapp Lisa , Ansell Peter J. , Lee Ho-Jin , Hu Beibei , Barch David , Ocampo Christopher , Tolcher Anthony W. 
Published: August 2018

Abstract
Background: Aberrant EGFR plays a vital role in the oncogenesis of multiple tumor types. ABBV-221 is a 2nd-generation antibody-drug conjugate (ADC) targeting EGFR, based on the 1st-generation ADC depatuxizumab mafodotin (depatux-m, formerly ABT-414). Depatux-m demonstrates efficacy in glioblastoma (GBM) patients (pts) with EGFR amplification in ongoing studies. ABBV-221 is an affinity matured monoclonal antibody against EGFR linked to the microtubule toxin monomethylauristatin E. ABBV-221 has higher affinity for EGFR than depatux-m, potentially allowing it to target a broader range of tumor types. To understand the population most suitable for ABBV-221, molecular assays characterizing EGFR pathway status, including EGFR protein, EGFR mRNA, and EGFR ligand mRNA expression, were evaluated from available tumor tissue of enrolled patients. The results of each assay were correlated with patient outcome to determine which marker may be best associated with prognosis. Methods: In this phase 1, multicenter study of ABBV-221, eligible pts have solid tumors that are likely to overexpress EGFR. EGFR protein expression in tumor tissue samples was analyzed with immunohistochemistry (IHC) using the Dako pharmDx IHC assay. EGFR and mRNA expression from the EGFR ligands epiregulin (EREG) and amphiregulin (AREG) were measured using next-generation RNA sequencing (RNAseq). Results: As of 29 March 2017, 42 pts were treated (13 colon, 5 head & neck [H&N] cancer, 5 non-small cell lung cancer, 5 GBM, 2 breast, 12 other). Ten dose escalation cohorts have been completed with the last cleared dose 4.5 mg/kg per cycle. The most common adverse events were infusion reactions in 19/42 pts (45%) and fatigue in 17/42 pts (41%). Sixteen pts (38%) had stable disease (SD), including 4 pts who remained on study longer than 6 months. All markers are expressed in a wide range across enrolled pts. The pts with response had high EGFR and EGFR ligand. One pt with head and neck cancer who received 5 cycles of ABBV-221 had a partial response and elevated levels of both EGFR (3-fold higher than median for all pts) and EGFR ligand (8-fold higher AREG and 19-fold higher EREG than median for all pts). One colorectal cancer pt with durable SD &gt;6 months had high levels of ligand (EREG) but not receptor, and one H&N pt with SD &gt;6 months had high levels of EGFR receptor but not ligand. Conclusions: Multiple EGFR pathway status biomarkers were evaluated and correlated with clinical outcomes observed in this phase 1 trial of ABBV-221. Patients who observed clinical benefit had high levels of EGFR pathway markers. The duration of SD in pts with refractory solid tumors is encouraging. Clinical trial information: NCT02365662
Citation Format: Emiliano Calvo, James M. Cleary, Victor Moreno, Maryella Gifford, Lisa Roberts-Rapp, Peter J. Ansell, Ho-Jin Lee, Beibei Hu, David Barch, Christopher Ocampo, Anthony W. Tolcher. Biomarker analysis in a phase 1 study of the antibody-drug conjugate ABBV-221 in patients with solid tumors likely to overexpress the epidermal growth factor receptor (EGFR) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A028.