Receptor Tyrosine Kinase Fusions and BRAF Kinase Fusions are Rare but Actionable Resistance Mechanisms to EGFR Tyrosine Kinase Inhibitors

Schrock, Alexa B.; Zhu, Viola W.; Hsieh, Wen-Son; Madison, Russell; Creelan, Benjamin C.; Silberberg, Jeffrey; Costin, Dan; Bharne, Anjali; Bonta, Ioana; Bosemani, Thangavijayan; Nikolinakos, Petros; Ross, Jeffrey S.; Miller, Vincent A.; Ali, Siraj M.; Klempner, Samuel J.; Ou, Sai‐Hong Ignatius

doi:10.1016/j.jtho.2018.05.027

Cited by 107 publications

(110 citation statements)

References 41 publications

(46 reference statements)

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“…However, both of these cases, as well as similar cases in which the FGFR3 fusion was detected in tissue or circulating tumor DNA after administration of an EGFR TKI but was not found in the pretreatment sample, have been described previously. 26 This adds to emerging data that support FGFR alterations not only as a primary driver mutation but also as a potential mechanism of resistance to other targeted agents. Terai et al developed human NSCLC lines resistant to the EGFR TKI gefitinib and showed (after confirming the absence of the T790M mutation) that there was significantly increased expression of FGFR1 compared with that in the parent nonresistant cells.…”

Section: Discussionmentioning

confidence: 80%

Detection of Known and Novel FGFR Fusions in Non–Small Cell Lung Cancer by Comprehensive Genomic Profiling

Qin

Johnson²,

Ross

et al. 2019

Journal of Thoracic Oncology

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Introduction: Activation of the fibroblast growth factor receptor (FGFR) family through fusion with various partners has been described in multiple cancer types, including NSCLC. FGFR inhibitors are currently being evaluated clinically for patients whose tumors harbor these fusions. Methods: Hybrid capture-based comprehensive genomic profiling was performed on 26,054 consecutive formalinfixed, paraffin-embedded specimens of NSCLC. Results: FGFR fusions retaining the kinase domain were identified in 0.2% of NSCLC cases; they included 37 fibroblast growth factor receptor gene 3 (FGFR3)-transforming acidic coiled-coil containing protein 3 gene (TACC3) fusionpositive cases, two fibroblast growth factor receptor 2 (FGFR2)-shootin 1 gene (KIAA1598 [also known as SHTN1]) fusion-positive cases, one BCL2 associated athanogene 4 gene (BAG4)-fibroblast growth factor receptor 1 gene (FGFR1) fusion-positive case, and 12 novel FGFR1, FGFR2, FGFR3, and fibroblast growth factor receptor 4 gene (FGFR4) fusion-positive cases. Co-occurring EGFR or MNNG HOS Transforming gene (MET) alterations were observed in 8% of cases (four of 52), KRAS mutation was observed in three additional cases, and FGFR1 or FGFR3 amplification was observed in 10% of cases. The two patients with cooccurring EGFR mutations were previously treated with EGFR inhibitors. One patient with a novel FGFR2-leucine zipper transcription factor like 1 gene (LZTFL1) fusion had a partial response to the pan-FGFR inhibitor JNJ-42756493 and remained progression-free for 11 months. Conclusion: FGFR fusions were detected by using comprehensive genomic profiling in 0.2% of NSCLCs; they occurred primarily in the absence of other known driver alterations, or in a subset of cases, as likely mechanisms of acquired resistance. One patient with a novel FGFR2 fusion had clinical benefit from an investigational FGFR inhibitor, suggesting that these alterations may predict response to targeted therapies.

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Section: Discussionmentioning

confidence: 80%

Detection of Known and Novel FGFR Fusions in Non–Small Cell Lung Cancer by Comprehensive Genomic Profiling

Qin

Johnson²,

Ross

et al. 2019

Journal of Thoracic Oncology

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“…Rarely, epithelial-to-mesenchymal transition can occur [67]. Other rare mechanisms of resistance to EGFR-TKIs include acquired receptor tyrosine kinase fusions and BRAF kinase fusions [68][69][70].…”

Section: Mechanisms Of Resistance To First-and Second-generation Egfrmentioning

confidence: 99%

Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC)

Gelatti¹,

2019

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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80-85% of cases. Epidermal growth factor receptor (EGFR) mutations are observed in approximately 40% and 20% of patients with NSCLC in Asian and non-Asian populations, respectively. First-generation (gefitinib, erlotinib) and second-generation (afatinib, dacomitinib) EGFR-tyrosine kinase inhibitors (TKIs) have been standard-of-care (SoC) first-line treatment for patients with sensitizing EGFR mutation positive advanced NSCLC following Phase III trials versus platinum-based doublet chemotherapy. However, most patients treated with first-line first-or second-generation EGFR-TKIs develop resistance. Osimertinib, a third-generation, central nervous system active EGFR-TKI which potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and the most common EGFR T790 M resistance mutations, has shown superior efficacy versus first-generation EGFR-TKIs (gefitinib / erlotinib). Osimertinib is now a treatment option for patients with advanced NSCLC harboring EGFRm in the first-line setting, and treatment of choice for patients with T790 M positive NSCLC following disease progression on first-line EGFR-TKIs. The second-generation EGFR-TKI dacomitinib has also recently been approved for the first-line treatment of EGFRm positive metastatic NSCLC. There remains a need to determine appropriate sequencing of EGFR-TKIs in this setting, including EGFR-TKIs as monotherapy or in combination with other TKIs / signaling pathway inhibitors. This review considers the evolving role of sequencing treatments to maximize benefits for patients with EGFRm positive advanced NSCLC.

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“…Use of in situ assays can permit visualization of the compartments containing these alterations and determine if multiple events represent the collision of two independent clones or, in the case of acquired resistance following TKI therapy, induction of an oncogenic bypass pathway. 32 FISH testing can additionally enumerate the number of copies of genetic regions at a cellular level, thus it remains a gold standard for detection of both amplification events and deletion events in several clinical indications. Clinical examples will be provided in the upcoming sections.…”

Section: The Role For In Situ Testsmentioning

confidence: 99%

Molecular Diagnostics in Non-Small Cell Lung Carcinoma

Sholl

2020

Semin Respir Crit Care Med

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Current clinical practice guidelines recognize EGFR, BRAF, ALK, and ROS1 as essential molecular biomarkers, and a host of other genetic alterations as emerging biomarkers for non-small cell lung carcinoma patients. The available approaches to detecting relevant alterations in these genes are diverse and often complementary. Laboratories have increasingly migrated away from a “single-gene test” approach, embracing assays that incorporate panels of genes capable of detecting a diverse set of alterations. The adoption of next generation sequencing (NGS) techniques has driven this shift; however, the approach to incorporation of NGS varies greatly between practices. Choice of molecular diagnostics assay, be it single-gene or NGS-based panel, will be driven by cost, urgency, clinical and laboratory focus, and professional considerations. Preanalytic factors including operator expertise, sample type and choice of fixative, and postanalytic factors including informatics pipeline and approaches to variant reporting have a significant impact on the quality of molecular diagnostics results. There is no real “one-size-fits-all” test for genomic profiling for lung cancer; clinicians and laboratorians must be prepared to offer a diverse set of assays in order to address turnaround time requirements and optimize detection of critical but difficult-to-detect tumor alterations such as gene fusions.

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Receptor Tyrosine Kinase Fusions and BRAF Kinase Fusions are Rare but Actionable Resistance Mechanisms to EGFR Tyrosine Kinase Inhibitors

Abstract: RTK and BRAF fusions are rare but potentially druggable resistance mechanisms to EGFR TKIs. Detection of RTK and BRAF fusions should be part of comprehensive profiling panels to determine resistance to EGFR TKIs and direct appropriate combination therapeutic strategies.

Cited by 107 publications

References 41 publications

Detection of Known and Novel FGFR Fusions in Non–Small Cell Lung Cancer by Comprehensive Genomic Profiling

Detection of Known and Novel FGFR Fusions in Non–Small Cell Lung Cancer by Comprehensive Genomic Profiling

Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC)

Molecular Diagnostics in Non-Small Cell Lung Carcinoma

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