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Y. Hu



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    OA 09 - EGFR TKI Resistance (ID 663)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 09.02 - Osimertinib Resistance Mediated by Loss of EGFR T790M Is Associated with Early Resistance and Competing Resistance Mechanisms (ID 9000)

      11:00 - 12:30  |  Author(s): Y. Hu

      • Abstract
      • Presentation
      • Slides

      Background:
      Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in EGFR-mutant NSCLC with resistance to prior TKI. Improved understanding of the clinical and molecular characteristics of acquired resistance to osimertinib is needed.

      Method:
      We initially studied resistance biopsies and plasma specimens from an institutional cohort of 119 patients treated with osimertinib for T790M-positive NSCLC with resistance to prior TKI. For validation, we studied plasma from 157 patients treated with osimertinib on the AURA trial (NCT01802632).

      Result:
      45 of 119 patients underwent a resistance biopsy and 33 had resistance tumor genotyping available. 11 patients maintained T790M at resistance: 7 acquired EGFR C797S, 1 had a PIK3CA mutation. 22 patients had loss of T790M at resistance: 14 harbored a competing resistance mechanism, including histologic transformation to SCLC, MET amplification, mutations in BRAF, PIK3CA, or KRAS, or fusions in RET or FGFR. Median time to treatment failure (TTF) on osimertinib was 3 months in patients with loss of T790M and 15 months in patients with maintained T790M. In the validation cohort, 110 of 157 patients had detectable tumor DNA in plasma and were eligible for analysis. 58 patients (53%) maintained T790M at resistance; 24 (22%) also acquired a C797S mutation. 52 patients (47%) had loss of T790M at resistance and no C797S. Median TTF was shorter in patients with loss of T790M than in those with maintained T790M at resistance (5.7 vs 12.5 months). 50 patients had both pre- and post-osimertinib plasma genotyping. Studying the relative allelic fraction (AF) of T790M compared to driver EGFR mutation, patients with T790M loss had only slightly lower relative T790M AF pretreatment (29% vs. 38% median, p = 0.06). The ability of plasma response to predict subsequent resistance was studied in 19 patients from the initial cohort with baseline and follow-up plasma genotyping after 1-3 weeks on osimertinib. Studying the difference between the relative change in plasma levels of T790M and the EGFR driver, patients with T790M loss at time of resistance consistently had a greater T790M response than driver response (median difference 16%), suggesting incomplete suppression of the driver due to competing resistance mechanisms.

      Conclusion:
      In patients with acquired resistance to osimertinib, repeat testing for T790M could offer key insights into disease biology. Patients with early resistance on osimertinib are at risk of T790M loss with emergence of a complex variety of competing resistance mechanisms, and represent intuitive candidates for combination approaches such as combined EGFR & MET inhibition.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.02-014 - Amplicon-Based Next-Generation Sequencing (NGS) of Plasma Cell-Free DNA (cfDNA) for Detection of Driver and Resistance Mutations in NSCLC (ID 10551)

      09:30 - 16:00  |  Author(s): Y. Hu

      • Abstract
      • Slides

      Background:
      While several studies have evaluated hybrid-capture NGS for cfDNA genotyping, amplicon-based NGS is an attractive alternative with the potential to be faster and less expensive. We performed a blinded evaluation of this approach for the characterization and monitoring of the molecular profile of advanced NSCLC during genotype-directed therapy.

      Method:
      Plasma samples from patients with advanced NSCLC and a known targetable genotype (EGFR, BRAF, MET, HER2 mutations; ALK, ROS1 rearrangements) were collected and analyzed, blinded to tumor genotype, with IRB approval. Up to 4 specimens were collected for each patient: baseline, initial 2 follow-ups, and progression. Plasma NGS was performed using enhanced tagged amplicon sequencing of hotspots and coding regions from 36 genes. A novel approach was used to detect ALK/ROS1 fusions using amplicon sequencing in cfDNA. Diagnostic accuracy was compared to plasma ddPCR and tumor genotype (including NGS when available).

      Result:
      A total of 146 specimens from 49 patients were studied. Testing was completed for 115 specimens at the time of analysis. Matched plasma NGS and ddPCR were available across 95 samples and revealed high concordance of allelic fraction (AF). At baseline, sensitivity of plasma NGS for the detection of the driver was 100% (26/26) for EGFR (88.5% ddPCR sensitivity). Sensitivity for the detection of ALK/ROS1 fusions was 89% (6/7 ALK, 2/2 ROS1). Rare instances of plasma NGS-positive/tissue NGS-negative discordance were seen across 13 cases with match tumor NGS (3/442 genes sequenced) and appear related to resistance heterogeneity, clonal hematopoiesis, and low tumor content of biopsy. Among patients with acquired T790M and available specimens at osimertinib resistance (n=21), 11 resistance mechanisms could be detected including tertiary EGFR mutations (e.g. C797S), mutations in BRAF, PIK3CA, or KRAS, and amplification of MET, HER2, or FGFR1. 4 were detected pre-osimertinib.

      Conclusion:
      This blinded analysis demonstrates for the first time the ability of amplicon-based plasma NGS to detect a full range of targetable genotypes in NSCLC. This approach has attractive sensitivity and specificity and deserves further study as an alternative to better-established hybrid capture approaches. Serial plasma NGS can detect competing resistance mutations in patients with TKIs resistance, highlighting the pitfalls of PCR-based plasma assays in patients with heterogeneous resistance and paving the way towards combination therapies.

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