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M. Lanuti

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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)

      15:45 - 17:30  |  Author(s): M. Lanuti

      • Abstract
      • Presentation
      • Slides

      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.

      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.

      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.

      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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