2017
DOI: 10.1158/1538-7445.am2017-4114
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Abstract 4114: Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in FGFR2 fusion-positive cholangiocarcinoma patients

Abstract: Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in a broad range of cancers and occur in ~20% of ICCs. As seen with other targeted therapies, however, acquired resistance has limited the efficacy of selective FGFR kinase inhibitors such as BGJ398. In a phase II trial of patients with advanced refractory cholangiocarcinoma harboring an FGFR gene alteration, BGJ398 displayed an overall response rate of 22%, but the durability of response was short in … Show more

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Cited by 84 publications
(140 citation statements)
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“…In a recent study, the acquisition of a gatekeeper mutation, p.V564F, in FGFR2 was found to confer resistance in three cholangiocarcinoma patients with acquired clinical resistance to BGJ398 (43). This study highlights the first clinical occurrence of the FGFR2 V564F gatekeeper mutation as a mechanism of acquired resistance, which had been previously investigated in preclinical studies (28,29).…”
Section: Discussionmentioning
confidence: 56%
“…In a recent study, the acquisition of a gatekeeper mutation, p.V564F, in FGFR2 was found to confer resistance in three cholangiocarcinoma patients with acquired clinical resistance to BGJ398 (43). This study highlights the first clinical occurrence of the FGFR2 V564F gatekeeper mutation as a mechanism of acquired resistance, which had been previously investigated in preclinical studies (28,29).…”
Section: Discussionmentioning
confidence: 56%
“…As such, a portion of this database has been included in the Blood Profiling Atlas in Cancer, a National Cancer Moonshot Initiative (34). Improved detection of resistance mutations may facilitate enrollment in clinical trials and enable the development of more accurate biomarkers of response to therapy (21,35,36). Therefore cfDNA, and other minimally invasive techniques, address a real and unmet need, as it is essential to provide realtime tumor genotyping at the time of progression to guide subsequent therapeutic strategies.…”
Section: Discussionmentioning
confidence: 99%
“…Further, 24% of those resistance-harboring samples (91/381) had >1 alteration associated with resistance to the same therapy, suggesting independent evolution in distinct tumor lesions (20) or sequential treatment with distinct therapies targeted to the same gene. For example, one NSCLC patient had an EML4-ALK fusion (VAF of 7.1%) and ALK SNVs reported to confer resistance to crizotinib (L1196M, 2.5%), crizotinib/alectinib (I1171T, 0.1%), and crizotinib/ceritinib/alectinib (G1202R, 5% relative to the original driver alteration and many were missed by single-metastatic-site tissue biopsy but confirmed by repeat biopsy or biopsy of multiple metastases at autopsy (21,22,25).…”
Section: The Landscape Of Actionable Resistance Alterations In Cfdnamentioning
confidence: 99%
“…Some of the challenges facing the clinical development of FGFR inhibitors include selecting the right patient that will benefit from an FGFR inhibitor which may vary with different tumor types, managing the toxicity profile of on-target hyperphosphatemia, predicting the mechanisms of acquired resistance that may emerge and designing a rational combination strategy to abrogate this. The first report of a genetic mechanism driving clinical acquired resistance to FGFR inhibition was recently published (15). In a phase II trial of BGJ398 in cholangiocarcinoma patients exhibiting FGFR2 fusions, the initial efficacy was striking but not durable, as driven by the emergence of FGFR2 resistance mutations, including a gatekeeper mutation, V564I.…”
Section: Discussionmentioning
confidence: 99%