Liquid Biopsy for Rapid Detection and Real Time Monitoring of FGFR-altered Cancers

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Liquid Biopsy for Rapid Detection and Real Time Monitoring of FGFR-altered Cancers Patients with advanced cancers driven by fibroblast growth factor receptor (FGFR) alterations, including gene fusions and single nucleotide variants (SNVs), are benefiting from several new FGFR kinase inhibitors. Erdafitinib and pemigatinib were recently FDA approved for bladder cancer and cholangiocarcinoma, respectively, and other FGFR inhibitors have received fast-track designation and are being explored in tumor agnostic basket trials. Patients are experiencing improved overall survival and progression free survival, with high overall response rates. Unfortunately, virtually all patients eventually develop resistance to these inhibitors, oftentimes through acquisition of secondary FGFR mutations. FGFR inhibitor development is hindered by the lack of accurate and comprehensive methods to 1) rapidly detect FGFR alterations in order to qualify patients for clinical trials, 2) monitor therapeutic response, and 3) characterize emerging drug resistance. The development of novel testing strategies, such as non-invasive liquid biopsies, can fulfill these unmet needs for diagnosis, prognosis, and therapy selection. Liquid biopsies evaluate a blood sample, from which cell-free DNA (cfDNA) shed by the tumor is sequenced to detect genomic alterations. The technical specifications for existing commercial cfDNA tests show that these assays are not validated for FGFR fusions and have insufficient sensitivities of ~30% for FGFR fusions. Additionally, commercial tests are too large and costly to repeat frequently for therapy and disease monitoring. Thus, we propose to develop and validate an FGFR-focused, accurate, and cost-effective cfDNA sequencing assay (FGFR-Dx) for real-time testing to support rapid detection, response monitoring, and early detection of resistance. Our team at Ohio State University has six active FGFR inhibitor clinical trials, a large cohort of FGFR true positives, and a Clinical Laboratory Improvement Amendments (CLIA)-compliant Cancer Genomics Lab with extensive experience performing clinical-grade tumor sequencing and bioinformatics analysis for detection and interpretation of gene fusions and single nucleotide variants. Further, we have paired this cfDNA development with a rapid research autopsy study that will enable the first systematic evaluation of detection limits for cfDNA by assessing how accurately the heterogeneity observed across tumor samples from multiple sites is represented in cfDNA. We propose the following Aims to address the criteria for PAR-18-317: 1) Analytically validate a targeted liquid biopsy assay (FGFR-Dx) to detect fusions and single nucleotide variants (SNVs) in FGFR1-3; 2) Establish the clinical validity of FGFR-Dx to detect FGFR fusions and SNVs. In summary, coupling the development of an FGFR-focused liquid biopsy with rapid research autopsy can broadly impact the field’s understanding and application of cfDNA approaches in patients with FGFR-altered and other cancers.