Virtual Library

Start Your Search

W. Zhai

Author of

  • +

    OA 09 - EGFR TKI Resistance (ID 663)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
    • +

      OA 09.07 - Clonality of c-MET Copy Number Gain as a Determinant of Primary TKI Resistance in EGFR-Mutant NSCLC (ID 8887)

      11:00 - 12:30  |  Author(s): W. Zhai

      • Abstract
      • Presentation
      • Slides

      cMET activation is a valid mechanism of secondary TKI resistance in EGFR mutation-positive (EGFR-M+) NSCLC. However, its role in the treatment-naïve setting remains unclear. We sought to ascertain the prevalence and clinical impact of co-existing cMET copy number gain(CNG) in TKI-naïve early-stage and metastatic EGFR-M+ NSCLC.

      Multi-region SNP array analysis (n=59 sectors) was performed on 13 early-stage resected EGFR-M+ NSCLC. cMET FISH was performed in a separate cohort of 206 metastatic treatment-naïve EGFR-M+ patients, all of whom were treated with first-line EGFR TKIs. We defined cMET-high as CNG≥5 copies, with an additional criteria of MET:CEP7 ratio >2.0 for amplification. Time-to-treatment failure(TTF) in patients cMET-high/low was estimated by Kaplan-Meier method and compared using log-rank test. A cell line from a cMET-high patient exhibiting primary TKI resistance was established.

      Relative to median ploidy across sectors, 7/13(53.8%) early-stage EGFR-M+ tumors showed cMET CNG in at least one sector, with majority displaying(n=6/7) copy number intra-tumor heterogeneity. In the metastatic cohort, 55/206 patients (26.7%) were found to be cMET-high at diagnosis: 6(10.9%) had MET amplification, 49(89.1%) MET polysomy, with the following distribution: 5-6 copies(n=11), 6-8 copies(n=32), and >8 copies(n=12). We next evaluated clinical outcomes stratified by MET-high v low: median TTF was 14.7m(12.2–NE) vs 14.6m(12.7–16.5), p=0.985 respectively, with no significant difference in response rates(RR) to EGFR TKI (66.7%v73.7%; p=0.940). Further stratification by level of CNG did not reveal any differences in RR (5-6 copies:75.0%, 6-8 copies:63.0%, >8 copies:71.4%; p=0.868). In MET-high amplified group, only 2/6 (33.3%) had a partial response to EGFR TKI. In the cohort with suboptimal TKI response (PFS<6m, n=22), we did not observe significant enrichment for MET-high, relative to rest of the cohort (36.4%v25.5%, p=0.278). Finally, in 6 patients with progressive disease within 4 weeks of initiating EGFR TKI, 2/6(33.3%) were MET-high. In a cell line model derived from a MET-high patient (L858R, cMET:7.3 copies) genomic profiling of cell colonies revealed clonal cMET CNG and subclonal EGFR, with the patient demonstrating clinical response to crizotinib.

      Although up to 26% of TKI-naïve EGFR-M+ NSCLC harbor high cMET CNG by FISH, this occurs on the background of a highly variegated copy number landscape. cMET CNG alone does not significantly impact clinical outcomes to EGFR TKI, with the exception of one patient with a clonal cMET-driven tumor. Our data challenges the utility of arbitrary copy number thresholds to define clinically relevant MET pathway dysregulation and underscores the importance of targeting dominant truncal drivers.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.