Author of

• 18502

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  P3.02c - Poster Session with Presenters Present (ID 472)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 18526

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    P3.02c-024 - Detection of Novel Activating FGFR Rearrangements, Truncations, and Splice Site Alterations in NSCLC by Comprehensive Genomic Profiling (ID 4905)

    14:30 - 14:30  |  Author(s): A. Johnson
    • Abstract

    Background:
    Activation of the fibroblast growth factor receptor (FGFR) family through mutation, amplification , C-terminal truncation, and 3’ fusion has been described in multiple cancer types, and FGFR inhibitors are currently being evaluated in the clinic. Though FGFR1 amplification has been defined in several datasets, other FGFR alterations in NSCLC are not well defined.
    
    Methods:
    Hybrid-capture based comprehensive genomic profiling (CGP) was performed on 13,898 consecutive FFPE lung cancer specimens (adeno 71%; squamous 12%) to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer.
    
    Results:
    CGP of 13,898 NSCLCs led to the identification of 53 cases (0.4%) with FGFR1-4 rearrangements, truncations or splice site mutations resulting in an intact kinase domain (KD). The median age was 63 years old (range 36-83 years). Patients with these alterations were 60% (26/53) male, and 72% (31/43) with available data were stage IV. 26 patients (49%) had adenocarcinomas and 18 patients (34%) had squamous histology. FGFR alterations identified included 19 FGFR3-TACC3 fusions, one FGFR2-KIAA1598 fusion, and 7 novel fusions involving FGFR2, FGFR3 or FGFR4. We also identified 16 cases with C-terminal truncations resulting in loss of exon 18, but retention of the KD, 9 cases with mutations predicted to result in alternative splicing in the FGFR extracellular domain (exons 3 or 4), and one case with deletion of exons 3-6. Genomic analysis revealed concurrent FGFR amplification in 13% (7/53) of cases. Co-occurring alterations were observed in known drivers including EGFR, ERBB2, MET, and BRAF in 15% of (8/53) cases, and KRAS mutation in an additional 15% (8/53) of cases. The average tumor mutation burden in cases with these FGFR alterations was relatively high (mean 16.9 mutations/Mb, median 10.1 mutations/Mb, range 0.9-86.5 mutations/Mb) as compared to a mean of 9.2 mutations/Mb in NSCLCs. One patient with a novel FGFR2-LZTFL1 fusion had a partial response to the pan-FGFR inhibitor JNJ-42756493 and remained progression free for 11 months.
    
    Conclusion:
    Diverse FGFR alterations were detected using CGP in 0.4% of NSCLCs. Of the 53 cases identified, 37 (70%) were negative for other known driver alterations. In cases with co-occurring drivers, including two with EGFR exon 19 deletion, the possibility of an FGFR fusion arising in the setting of acquired resistance will be evaluated. 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.