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S. Zupo

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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.02 - Pretreatment evaluation of the T790M mutation and its correlation with the response to tyrosine kinase inhibitors (TKIs) or chemotherapy in advanced non-small cell lung cancer (NSCLC) patients with activated EGFR mutations (ID 2455)

      10:30 - 12:00  |  Author(s): S. Zupo

      • Abstract
      • Presentation
      • Slides

      Preclinical data have shown that the EGFR-T790M mutation confers resistance to reversible EGFR-TKIs (gefitinib, erlotinib) but not to irreversible EGFR-TKIs (afatinib). This study evaluated advanced NSCLC patients (pts) harboring an activated EGFR mutation (exon 18-21) to investigate the incidence of the T790M mutation in pretreatment tumor samples and the correlation between the T790M mutation and the clinical outcome, comparing patients positive for the T790M mutation treated with reversible TKIs, an irreversible TKI or chemotherapy to patients negative for the T790M mutation treated with the same agents.

      We screened 317 advanced NSCLC pts for EGFR mutations using the PCR/Sanger sequencing (PSS) method. Tumor tissues from EGFR-mutated pts were analyzed for the EGFR-T790M mutation using a highly sensitive locked nucleic acid-PSS method (LNA-PSS) capable of detecting EGFR-T790M-mutated alleles at extremely low frequencies. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were evaluated retrospectively in these pts.

      Using PSS, 17.3% (55/317) of pts had an activating mutation in the EGFR-TK domain; 56.3% (31/55) of pts had an in-frame deletion in exon 19, 32.7% (18/55) of pts had point mutation L858R in exon 21, 3.6% (2/55) of pts had an insertion in exon 20, and 7.2% (4/55) of pts had both the T790M mutation and either an exon 19 or 21 mutation. Forty-two pts with EGFR-activating mutations (82.3%) without the T790M mutation (by PSS) were successfully analyzed for the T790M mutation using LNA-PSS. The T790M mutation was detected in 17 (40.5%) pts, with a higher incidence in never smokers (47.7%), adenocarcinoma (76.2%) and females (71.4%). A treatment response evaluation was available in 39 pts, 18 of whom (46.1%) harbored the T790M mutation. Pts with T790M had a lower RR (22.2%) to TKIs than wild-type pts (35.3%); however, mutated pts had better PFS and OS (median PFS 9.2 vs 7 months, respectively; median OS 15.2 vs 11.1 months, respectively). Pts treated with afatinib and positive for T790M obtained longer PFS compared to pts negative for T790M (median PFS 4.7 vs 3.2 months, respectively), but their OS was shorter (median OS, 16.3 vs 18.2 months, respectively). Notably, pts with the T790M mutation had a greater response to chemotherapy (44.4%) compared to pts without the mutation (18.2%) and had a longer PFS (median PFS 8.2 vs 6.1 months, respectively) and OS (median OS 21.8 vs 12.4 months, respectively).

      In this study, the high proportion of pretreatment tumor samples positive for the EGFR-T790M mutation indicates that its identification at diagnosis is more common than expected using a highly sensitive method. Consequently, in NSCLC pts with EGFR-activating mutations, detection of the T790M mutation at diagnosis can help customize therapy and identify a subset of patients with a relatively more favorable prognosis.

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