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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
MA 12.03 - Kinase Fusions as Recurrent Mechanisms of Acquired Resistance in EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC) (ID 10309)
11:00 - 12:30 | Author(s): B. Creelan
Resistance invariably develops in EGFR-mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKI). In approximately 50% of cases, resistance is mediated by the EGFR T790M mutation; however, multiple other mechanisms of resistance have also been described, including case reports of acquired kinase fusions (PMIDs: 26187428, 28089157).
Hybrid-capture based genomic profiling (FoundationOne® or FoundationACT™) was performed prospectively on DNA isolated from tissue-based FFPE samples or blood-based circulating tumor (ctDNA) samples from NSCLC patients.
From a dataset of 3,014 unique EGFR-mutated (exon 19 deletion, L858R, G719X, L861Q, or S768I) TKI naïve or relapsed NSCLCs we identified 28 (0.9%) cases with co-occurring likely activating kinase rearrangements (BRAF , FGFR3 , RET , ALK , NTRK1 , EGFR ), including 24 confirmed fusions. Treatment histories were available for 21/28 cases, and prior evidence of EGFR mutation and treatment with an EGFR TKI was evident in 21/21 (100%) cases. In 25/28 cases no other known mechanisms of acquired resistance co-occurred with the primary EGFR mutation and the kinase fusion. The 3 cases with co-occurring known resistance mechanisms (T790M or MET amplification) were those with BRAF rearrangements for which no fusion partner was identified. Additionally, our dataset included 10 paired pre- and post-EGFR TKI treatment samples where the latter sample showed an acquired kinase fusion (4 FGFR3-TACC3, 2 EML4-ALK, 2 CCDC6-RET, 1 AGK-BRAF, 1 TPM3-NTRK1) in addition to the primary EGFR alteration. Notably, in 3/10 paired cases (2 FGFR3 and 1 BRAF) the fusion was acquired in the setting of dropout of an existing T790M mutation.
Acquired kinase fusions are rare yet recurrent mechanisms of acquired resistance in EGFR-driven NSCLCs, and may be enriched in the setting of resistance to T790M-specific inhibitors. Genomic profiling capable of detecting all classes of genomic alterations, including base substitutions, indels, copy number alterations, and fusions, is warranted at the time of progression on EGFR TKIs, and often provides rationale for treatment in such cases.
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