Targeting the Epidermal Growth Factor Receptor (EGFR) to Revert Trastuzumab Deruxtecan Resistance in HER2-low Colorectal Cancer.

Sloan-Kettering Inst Can Research, New York NY

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Therapeutic exploitation of the HER2 (human epidermal growth factor receptor 2) receptor tyrosine kinase (RTK) has led to remarkable improvements in clinical outcomes for many cancer types. HER2 amplification occurs in ~4% of metastatic colorectal cancers (mCRCs), in which it acts as an oncogenic driver and can be targeted with the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd). However, in the larger group of patients (~10–50%) with HER2 expression but lacking frank amplification (i.e., HER2-low), targeting HER2 with T-DXd has been ineffective, with a response rate of 0% in mCRC. This is in contrast with breast and gastric cancers, in which T-DXd is active against HER2-low tumors. We have investigated this insensitivity of CRC and have published preliminary evidence that the antitumor activity of T-DXd is attenuated by the frequent overexpression of epidermal growth factor receptor (EGFR) in the large bowel. In the presence of high levels of EGFR, we find that instead of forming HER2-HER2 homodimers, HER2 abundantly heterodimerizes with EGFR and is thereby less effective at internalizing T-DXd. We further demonstrated that combined treatment of the anti-EGFR antibody cetuximab with T-DXd restores the ability of HER2 to form homodimers and internalize drug in several HER2-expressing CRC patient-derived xenograft (PDX) models. This drug combination leads to durable and more profound tumor growth inhibition than T-DXd alone in multiple PDX models of HER2-expressing CRC. However, some of the molecular details on which cancers have the best response to this combination need to be elucidated. In this proposal, we will conduct a biomarker-intensive, investigator-initiated phase 2 trial of T-DXd + cetuximab in patients with chemorefractory HER2-low mCRC to determine both the safety of this drug combination, as well as the molecular context in which it proves most efficacious. The trial will begin with a safety lead-in of 6–18 patients followed by an expansion phase to enroll a total of 27 patients to a single cohort following a Simon minimax two-stage design. Our central hypothesis is that the addition of cetuximab will enhance the efficacy of T-DXd in patients with HER2-low mCRC. To facilitate a mechanistic understanding of therapeutic response, we propose a co-clinical trial to generate novel PDX models of HER2-low CRC to study in vivo mechanisms of response and resistance to T-DXd + cetuximab. We hypothesize that expression of other RTKs, receptor dimerization dynamics, and downstream RAS/MAPK signaling will affect internalization of T-DXd and tumor response to T-DXd + cetuximab. We will evaluate these factors at baseline and at resistance in patient samples and throughout treatment in PDX models to define mediators of response and resistance. Resistance alterations identified in clinical samples will be functionally validated in cell lines and PDXs. We believe that T-DXd + cetuximab has the potential to become the first targeted therapy for patients with HER2-low mCRC, improving outcomes for a large portion of patients with CRC and refining our understanding and application of HER2-targeted ADCs in CRC.