TY - JOUR
T1 - Validation and Characterization of FGFR2 Rearrangements in Cholangiocarcinoma with Comprehensive Genomic Profiling
AU - Silverman, Ian M.
AU - Li, Meijuan
AU - Murugesan, Karthikeyan
AU - Krook, Melanie A.
AU - Javle, Milind M.
AU - Kelley, Robin K.
AU - Borad, Mitesh J.
AU - Roychowdhury, Sameek
AU - Meng, Wei
AU - Yilmazel, Bahar
AU - Milbury, Coren
AU - Shewale, Shantanu
AU - Feliz, Luis
AU - Burn, Timothy C.
AU - Albacker, Lee A.
N1 - Funding Information:
Supported by Incyte Corporation , Wilmington, Delaware.
Funding Information:
Supported by Incyte Corporation, Wilmington, Delaware.Disclosures: I.M.S., L.F., and T.C.B. are employees and stockholders of Incyte Corp.; M.L., K.M., W.M., B.Y., C.M., S.S., and L.A.A. are employees of Foundation Medicine Inc., and stockholders of Roche Holdings AG; M.A.K. has received travel reimbursement from Incyte Corp.; M.M.J. has received research funding from Agios, Aslan, AstraZeneca, Basilea, Eli Lilly, EMD Serono, Incyte Corp., Merck, Novartis, Pieris, QED, and Transthera, has received consulting fees from AstraZeneca, Incyte Corp., Meclun, QED, and Taiho, and has received honoraria from Agios, Merck, and QED; R.K.K. has received research funding (to institution) from Agios, AstraZeneca, Bayer, BMS, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, and Taiho, and has received compensation for advisory board and/or independent data monitoring committee membership from Exact Sciences, Genentech/Roche, Gilead, and Ipsen; M.J.B. has received institutional grants from Adaptimmune, Agios Pharmaceuticals, ARIAD Pharmaceuticals, Basilea, Bioline, Boston Biomed, Celgene Pharmaceuticals, Dicerna, EMD Merck Serono, Halozyme Pharmaceuticals, Incyte Corp., Isis Pharmaceuticals, Mirna Pharmaceuticals, Medimmune, Novartis Pharmaceuticals, Pieris Pharmaceuticals, PUMA Pharmaceuticals, QED Pharmaceuticals, Redhill Pharmaceuticals, Senhwa Pharmaceuticals, Sillajen, Sun Biopharma, Taiho Pharmaceuticals, and Toray, and has received consultancy fees from ADC Therapeutics, Exelixis Pharmaceuticals, G1 Therapeutics, Genentech, Huya, Immunovative Therapie, Inspyr Therapeutics, Lynx Group, Merck, OncBioMune Pharmaceuticals, and Western Oncolytics; S.R. has participated in advisory boards for Abbvie, Inc., Bayer, Incyte Corp., and QED Therapeutics, has received honoraria from Illumina and Integrated DNA Technologies, has received consulting fees from Merck and QED Therapeutics, and has received travel reimbursement from Incyte Corp.
Funding Information:
We thank the investigators and the site personnel who participated in the FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial-202 (FIGHT-202) study; the patients and their families who participated in FIGHT-202 or who underwent testing using FoundationOne College of American Pathologists/Clinical Laboratory Improvement Amendments or FoundationOneCDx. In addition, we would like to acknowledge Avni Patel and Max Wilberding for data generation. Editorial assistance was provided by Roland Tacke, Ph.D., C.M.P.P., and Abigail Marmont, Ph.D., C.M.P.P., of Envision Pharma Group, Inc., and funded by Incyte Corp.
Publisher Copyright:
© 2022 Association for Molecular Pathology and American Society for Investigative Pathology
PY - 2022/4
Y1 - 2022/4
N2 - Cholangiocarcinoma (CCA) is a heterogeneous biliary tract cancer with a poor prognosis. Approximately 30% to 50% of patients harbor actionable alterations, including FGFR2 rearrangements. Pemigatinib, a potent, selective fibroblast growth factor receptor (FGFR) FGFR1–3 inhibitor, is approved for previously treated, unresectable, locally advanced or metastatic CCA harboring FGFR2 fusions/rearrangements, as detected by a US Food and Drug Administration–approved test. The next-generation sequencing (NGS)–based FoundationOneCDx (F1CDx) was US Food and Drug Administration approved for detecting FGFR2 fusions or rearrangements. The precision and reproducibility of F1CDx in detecting FGFR2 rearrangements in CCA were examined. Analytical concordance between F1CDx and an externally validated RNA-based NGS (evNGS) test was performed. Identification of FGFR2 rearrangements in the screening population from the pivotal FIGHT-202 study (NCT02924376) was compared with F1CDx. The reproducibility and repeatability of F1CDx were 90% to 100%. Adjusted positive, negative, and overall percentage agreements were 87.1%, 99.6%, and 98.3%, respectively, between F1CDx and evNGS. Compared with evNGS, F1CDx had a positive predictive value of 96.2% and a negative predictive value of 98.5%. The positive percentage agreement, negative percentage agreement, overall percentage agreement, positive predictive value, and negative predictive value were 100% for F1CDx versus the FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial-202 (FIGHT-202) clinical trial assay. Of 6802 CCA samples interrogated, 9.2% had FGFR2 rearrangements. Cell lines expressing diverse FGFR2 fusions were sensitive to pemigatinib. F1CDx demonstrated sensitivity, reproducibility, and high concordance with clinical utility in identifying patients with FGFR2 rearrangements who may benefit from pemigatinib treatment.
AB - Cholangiocarcinoma (CCA) is a heterogeneous biliary tract cancer with a poor prognosis. Approximately 30% to 50% of patients harbor actionable alterations, including FGFR2 rearrangements. Pemigatinib, a potent, selective fibroblast growth factor receptor (FGFR) FGFR1–3 inhibitor, is approved for previously treated, unresectable, locally advanced or metastatic CCA harboring FGFR2 fusions/rearrangements, as detected by a US Food and Drug Administration–approved test. The next-generation sequencing (NGS)–based FoundationOneCDx (F1CDx) was US Food and Drug Administration approved for detecting FGFR2 fusions or rearrangements. The precision and reproducibility of F1CDx in detecting FGFR2 rearrangements in CCA were examined. Analytical concordance between F1CDx and an externally validated RNA-based NGS (evNGS) test was performed. Identification of FGFR2 rearrangements in the screening population from the pivotal FIGHT-202 study (NCT02924376) was compared with F1CDx. The reproducibility and repeatability of F1CDx were 90% to 100%. Adjusted positive, negative, and overall percentage agreements were 87.1%, 99.6%, and 98.3%, respectively, between F1CDx and evNGS. Compared with evNGS, F1CDx had a positive predictive value of 96.2% and a negative predictive value of 98.5%. The positive percentage agreement, negative percentage agreement, overall percentage agreement, positive predictive value, and negative predictive value were 100% for F1CDx versus the FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial-202 (FIGHT-202) clinical trial assay. Of 6802 CCA samples interrogated, 9.2% had FGFR2 rearrangements. Cell lines expressing diverse FGFR2 fusions were sensitive to pemigatinib. F1CDx demonstrated sensitivity, reproducibility, and high concordance with clinical utility in identifying patients with FGFR2 rearrangements who may benefit from pemigatinib treatment.
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U2 - 10.1016/j.jmoldx.2021.12.012
DO - 10.1016/j.jmoldx.2021.12.012
M3 - Article
C2 - 35176488
AN - SCOPUS:85127215735
VL - 24
SP - 351
EP - 364
JO - Journal of Molecular Diagnostics
JF - Journal of Molecular Diagnostics
SN - 1525-1578
IS - 4
ER -