Exploration of Novel Mutation Biomarkers to Repurpose EGFRi for Mutant KRAS Colorectal Cancer

University Of Utah, Salt Lake City UT

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Metastatic colorectal cancer (CRC) has very poor prognosis with median survival of less than 36 months. The epidermal growth factor receptor (EGFR) is a major therapeutic target in metastatic CRC. EGFR inhibitors (EGFRi) such as cetuximab and panitumumab are FDA approved only in patients with WT KRAS/NRAS. MUTANT “RAS” patients have been historically thought to be non-responsive, and more recently, right-sided patients have been considered insensitive as a group, limiting the utility of this drug class. Moreover, while FDA approved for first-line therapy, these agents are seldom used. Using a novel approach fusing gene expression and DNA sequencing, our laboratory recently reported the identification of MUTANT APC + TP53 as a strong predictor of EFGRi sensitivity for WT RAS, but also— surprisingly---for MUTANT KRAS patients. Therefore, we have developed the provocative hypothesis that some MUTANT KRAS CRC patients might benefit from EGFRi. Here we propose an early phase “signal finding” clinical trial to prospectively validate the potential of MUTANT APC + TP53 as biomarkers to predict cetuximab sensitivity, and repurpose/expand the utility of EGFRi to a molecular subset of MUTANT KRAS patients that have been historically overlooked. Moreover, some of these patients may harbor right-sided tumors. For this purpose, two specific aims have been proposed: AIM 1. To perform a “signal-finding”, single agent cetuximab, 3rd-line clinical trial to prospectively assess the potential for APC(A) + TP53(P) mutations to predict EGFRi sensitivity in MUTANT KRAS patients. Based on early historical trials, few if any mutant KRAS patients responded to cetuximab. However, no patients were selected based on mutational profiles. Here we propose, based on intriguing pre-clinical data, that molecular subpopulations harboring APC + TP53 mutations may benefit from EGFRi. A minimally-positive result from a “signal finding” trial, requiring only a few responding/stable patients, would lead to a larger randomized trial. Given the fact that there are really no effective therapies for mutant KRAS patients, particularly in the 3rd line, a cost-effective exponential statistical design has been proposed. AIM 2. Evaluation of an ultrasensitive cfDNA duplex sequencing assay for predicting initial response and monitoring disease progression and minimal residual disease in metastatic CRC. Substantially expanding the utility of an already FDA approved drug—particularly to the “undruggable” MUTANT KRAS genotype---would be considered a breakthrough moment for 40% of metastatic CRC patients, with a major impact on clinical practice. Success in this “signal finding” trial would lead to more definitive trials in the future that would change clinical practice.