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J. Temel



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    OA 07 - Biomarker for Lung Cancer (ID 659)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      OA 07.05 - Serial Biopsies in Patients with EGFR-Mutant NSCLC Highlight the Spatial and Temporal Heterogeneity of Resistance Mechanisms (ID 10181)

      16:40 - 16:50  |  Author(s): J. Temel

      • Abstract
      • Presentation
      • Slides

      Background:
      Resistance to EGFR tyrosine kinase inhibitors (TKIs) limits treatment outcomes among patients with EGFR-mutant NSCLC. Resistance mechanisms have previously been conceptualized as binary “positive/negative” variables, but emerging evidence suggests resistant cancers are heterogeneous, and subclones may be appreciated through multiple biopsies.

      Method:
      We retrospectively analyzed 221 EGFR mutant pts at MGH who had >1 biopsy after progression on their initial EGFR inhibitor. Data on acquired resistance (AR) mechanisms observed at each biopsy, adverse events, and treatment were collected.

      Result:
      Among 221 pts with a total of 355 post-AR tissue biopsies, median age was 59 (range, 28-88), 69% were female, 64% had EGFR del19, 33% L858R and 3% other activating mutations. Median number of biopsies per patient was 1 (range, 1-4). Biopsies at first resistance to EGFR TKI showed 61% T790M, 5% MET amplification (amp), 3% SCLC transformation, 2% acquired PIK3CA and 1% acquired BRAF mutations. 83 pts had two biopsies during their post-resistance course; 43/83 (52%) had heterogeneity between biopsy 1 and 2. In particular, 20% “lost” T790M, while 11% “gained” T790M. Among 17 pts who lost T790M, 3 gained a separate resistance mechanism, including MET amp and BRAF V600E. In some cases, synchronous biopsies identified spatial heterogeneity. For example, an osimertinib-resistant patient had a T790M/C797S lung nodule, while a concurrent mediastinal lymph node was wild-type at both loci (both sites retained the activating EGFR mutation). Similarly, another osimertinib-resistant patient with MET amp in a pleural effusion cell block had a lung nodule biopsy which lacked MET amp; the patient was treated with combination EGFR and MET inhibitors with a partial response. Additional details regarding concurrent liquid biopsies, treatment histories and clinical outcomes will be presented.

      Conclusion:
      In this large cohort of EGFR mutant NSCLC patients, we frequently observed variations in resistance mechanisms in patients with > 1 post-AR biopsy. Our data highlights the heterogeneity of resistant cancers and the limitations of a single biopsy in fully capturing the spectrum of resistance mechanisms in each patient. Serial biopsies or non-invasive methods may be required to characterize resistance and identify potential therapeutic targets.

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