Clinical validation of FGFR-Dx in plasma cell-free DNA from patients with FGFR-altered advanced pancreatic cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Commercial cell-free DNA (cfDNA) assays are not sufficient for fibroblast growth factor receptor (FGFR) fusion detection with sensitivities ranging from 20-50%. Due to the large genomic content in these cfDNA panels (>100 genes) and depth of coverage required for cfDNA variant calling, these assays are limited in their ability to target repetitive intronic regions that would increase off-target sequencing. As a result, gene fusions occurring in these regions are missed. Motivated by the need for a highly sensitive test to monitor FGFR-positive cholangiocarcinoma patients receiving FGFR targeted therapy, we developed and analytically validated FGFR- Dx. FGFR-Dx comprehensively targets introns in FGFR1-3 previously shown to be involved in gene fusions as well as all coding exons. Analytic validation of FGFR-Dx revealed a sensitivity of 92.9% for fusion detection, which is a considerable improvement over commercial assays. Through basket trials for FGFR kinase inhibitors, we have observed exceptional clinical outcomes in four patients with FGFR2 fusion-positive pancreatic cancer. We estimate FGFR alterations are present in 1.5% of pancreatic cancers (~900 patients per year). Strengthened by telemedicine experiences during the COVID19 pandemic, we have launched a nationwide telemedicine prospective phase 2 therapeutic trial of pemigatinib for FGFR-altered pancreatic cancer. This is accompanied by a nationwide patient registry for FGFR-positive pancreatic cancer. Telemedicine has the potential to radically accelerate drug development for such rare precision oncology targets. Our telemedicine study includes remote collection of serial blood for correlative cfDNA analysis. cfDNA has emerged as a new tool for precision oncology, but the dynamics have not been adequately studied, and how test results should be utilized is not certain. To date, most studies have evaluated just two blood timepoints: before starting treatment and at first radiologic imaging. There is a knowledge gap to understand the early temporal kinetics of cfDNA for both initial response and development of resistance. Additionally, no studies have evaluated cfDNA when patients have breaks or dose reductions from therapy that are either planned or due to toxicities. We hypothesize that cfDNA dynamics of FGFR will inform therapy and clinical decision-making in pancreatic cancer and more broadly serve as a blueprint for other targeted therapies. We propose the following Aims : 1) Clinical validation of FGFR-Dx in cfDNA from pancreatic cancer patients, including accuracy, precision and reportable range; 2) Establish the dynamics of serial FGFR-Dx in response to treatment, including the ideal time frame to measure the impact of therapy, lead time between increasing cfDNA alterations and disease progression, acquired resistance in response to FGFR targeted therapy in pancreatic cancer, and dynamics related to chemotherapy treatment (naïve or resistant to FGFR inhibitors).

Public health relevance public domain (NIH RePORTER)

Title: Clinical validation of FGFR-Dx in plasma cell-free DNA from patients with FGFR-altered advanced pancreatic cancer Project Relevance Patients with advanced pancreas cancer have poor outcomes and most do not live more than one year. The use of gene sequencing technologies to detect genetic changes in cancer has improved patient care by offering novel therapies that specifically target these genes. New approaches to detect genetic changes from blood samples offer a non-invasive approach to test patients. In this proposal, we will study how a blood test for FGFR genes can help patient with advanced pancreas cancer.