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

Abstract

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.

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis

“…In our analysis, KRAS G12C mutations were not considered a targetable alteration, although there is emerging efficacy data in early phase trials for novel compounds [24]. Other novel biomarkers with targeted treatments in early phase clinical trials include FGFR fusions [25], MET exon 14 skipping mutations [26] and NRG1 fusions [27]. With the rapid pace of drug development, the proportion of patients eligible for targeted therapy will undoubtedly rise.…”

Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers

“…There are a number of other rare fusions that have been detected in NSCLC for which there are targeted therapies in development or approved for other indications. FGFR fusions were identified in approximately 0.2% of NSCLC cases from a large series of 26,054 patients and included one patient that had clinical benefit to an investigational FGFR inhibitor [90]. Similarly, low frequencies have been identified for BRAF fusions (0.2-2.8%) [91,92], MET fusions (0.04%) [93], and EGFR fusions (0.08%) [94].…”

FGFR Fusions in Cancer: From Diagnostic Approaches to Therapeutic Intervention

“…The FGFR1-NTM fusion, whose functional effect is unknown, was detected in bladder urothelial carcinoma [17,29]. BAG4-FGFR1 was identified in non-small cell lung cancer (NSCLC) [30,31].…”

“…FGFR2-BICC1 has been also identified in colorectal cancer and hepatocarcinoma, although with low frequency [32]. Two FGFR2-KIAA1598 fusions and other FGFR2 fusions with novel partners (CIT, ERC1, LZTFL1, POC1B, SORBS1, TP73, TXLNA) have been recently identified in a large cohort (n = 26054) of lung cancer patients [31].…”

“…TACC3 protein has a coiled-coil domain at the C terminus and is involved in mitotic spindle assembly and stability [41]. FGFR3-TACC3 fusions have been described in different tumor types, including glioma, lung cancer, bladder cancer, head and neck squamous cancer, lung squamous cell carcinoma, and cervical cancer [26,27,30,31,38,42,43]. The FGFR3-TACC3 fusion protein induces a constitutive activation of the tyrosine kinase domain with the consequent activation of MEK/ERK and STAT1 signaling, but not PLCγ1, as the tyrosine residue in exon 19, responsible for the interaction with PLCγ1, is lost [38,42].…”