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R.J. Nagy



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    OA06 - Prognostic & Predictive Biomarkers (ID 452)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      OA06.01 - Clinical Utility of Circulating Tumor DNA (ctDNA) Analysis by Digital next Generation Sequencing of over 5,000 Advanced NSCLC Patients (ID 6096)

      14:20 - 14:30  |  Author(s): R.J. Nagy

      • Abstract
      • Presentation
      • Slides

      Background:
      Detection of actionable genomic alterations is now required for NCCN guideline-compliant work-up of NSCLC adenocarcinoma. Next-generation sequencing (NGS) of ctDNA, if sufficiently sensitive and specific, could provide a non-invasive, comprehensive genotyping platform relevant to clinical decision-making when tissue is insufficient or at time of progression on targeted therapies.

      Methods:
      A highly accurate, deep-coverage (15,000x) ctDNA plasma NGS test targeting 54-70 genes (Guardant360) was used to genotype 5,206 advanced-stage NSCLC patients accrued between 6/2014 – 4/2016. The frequency and distribution of somatic alterations in key genes were compared to those described in TCGA (Pearson and Spearman correlations). The clinical impact of ctDNA testing was evaluated by identification of resistance mechanisms emergent at progression on targeted therapies, and through analysis of additional driver mutations detected by ctDNA at baseline in 362 consecutive NSCLC patients with tissue mutation data available. The positive predictive value (PPV) of ctDNA sequencing was assessed in 229 patients with known tumor driver alterations.

      Results:
      ctDNA alterations were detected in 86% of cases; EGFR mutations in 25%, KRAS mutations in 17%, MET amplification in 4%, BRAF mutations in 3% and other rare but potentially actionable alterations in 9%. Mutation patterns among driver oncogenes were highly consistent with those from TCGA (Pearson r=0.92, 0.99, 0.99 for EGFR, KRAS, and fusion breakpoint location). PPV of ctDNA-detected variants was 100% for EGFR[L858R], 98% for EGFR[E19del], 96% for ALK, RET, or ROS1 fusions, and 100% for KRAS[G12/G13/Q61] mutations. In 362 cases with tissue information available, 63% (229/362) were tissue quantity-insufficient or undergenotyped (QNS/UG). ctDNA analysis identified driver mutations in 51 of the 229 QNS/UG cases, a 38% increase in detection rate over tissue alone. Among 1,111 EGFR-mutant cases, resistance mutations were identified at progression at frequencies consistent with published literature: EGFR[T790M] 47%, MET amp 5%, ERBB2 amp 5%, FGFR3 fusions 0.4%, ALK/other fusions 1%, BRAF mutations 1.8%, PTEN inactivation 2.5%, NF1 inactivation 3%, RB1 inactivation 3%, KRAS mutations 1.9%. In 143 consecutive NSCLC patients with detailed follow-up and serial analysis seen at the UC Davis Cancer Center, informative driver mutations were observed in 48 (34%).

      Conclusion:
      This series represents the largest NSCLC ctDNA study to date. Genotypic patterns of truncal mutations were highly consistent with TCGA in terms of frequency and distribution. At baseline, ctDNA augmented tissue analysis by identifying additional, actionable mutations when tissue was QNS/UG. ctDNA NGS conducted at progression identified emergent resistance mutations that could inform subsequent courses of therapy.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-103 - Identification of On-Target Mechanisms of Resistance to EGFR Inhibitors Using ctDNA Next-Generation Sequencing (ID 5645)

      14:30 - 14:30  |  Author(s): R.J. Nagy

      • Abstract
      • Slides

      Background:
      Osimertinib (OSM) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) recently approved for use in EGFR T790M-positive non-small cell lung cancer (NSCLC) with a 65-70% response rate. However, patients invariably develop resistance to OSM, in ~30% of cases due to an acquired EGFR C797S mutation. Understanding additional, non-C797S resistance mechanisms will be critical to developing new therapeutic approaches. Here, we describe a case of T790M-positive NSCLC with progression on OSM, genotyped using cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS).

      Methods:
      A 68-year-old male with EGFR L858R-mutant metastatic NSCLC whose disease progressed despite multiple lines of EGFR inhibitors (erlotinib, afatinib, cetuximab/afatinib) and chemotherapy was found to be T790M-positive, and initiated on OSM. Initial restaging scans demonstrated response. On disease progression 7 months later, ctDNA testing was performed with a highly sensitive and ultra-specific 70-gene NGS panel (Guardant360™) that includes all EGFR exons and reports on all EGFR single nucleotide variants, indels, and amplification.

      Results:
      Twelve somatic alterations were identified, including 7 mutations in EGFR. The original L858R driver mutation was present at a mutant allele fraction (MAF) of 16.9%, and T790M at MAF of 8.4%. C797S was detected at MAF of 4.6%. Four additional subclonal TK domain mutations were identified: L792H (1.4%), L718Q (0.7%), F795C (0.4%) and L792F (0.1%). Mutations within sufficient genomic proximity were phased to determine allelic origin, and a presumptive evolutionary history was constructed. T790M and C797S were in cis, and the F795C mutation arose on that allele. L792H and L792F were in cis to T790M, but arose independently from each other and from C797S. Review of the Guardant Health database, which includes 5,609 NSCLC samples, identified 1,228 samples with EGFR activating mutations L858R and exon 19 deletion. Of these, 341 (28%) had T790M, of which 17 (5%) carried C797S. Sixteen of 17 C797S mutations were in cis with T790M, and 1 in trans. There were 3 additional cases with L718 mutation and 1 with L792.

      Conclusion:
      Deep sequencing of ctDNA can reveal the global landscape and evolution of resistance mutations within a patient’s tumor. The T790M and C797S mutations were predominantly in cis configuration, underscoring the importance of developing new EGFR TKIs. The role of mutations L792H, L792F, and F795C is currently unknown. These mutations impinge on the ATP-binding pocket, which could be a potential structural resistance mechanism. Further studies are needed to validate and functionally characterize these candidate resistance mutations.

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