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K.S. Thress



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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): K.S. Thress

      • 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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    OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 10.01 - Detection of EGFR mutations from plasma ctDNA in the osimertinib Phase III trial (AURA3): comparison of three plasma assays (ID 8984)

      11:00 - 12:30  |  Author(s): K.S. Thress

      • Abstract
      • Presentation
      • Slides

      Background:
      AURA3 (NCT02151981) showed osimertinib, a third-generation EGFR-TKI, significantly prolongs progression‑free survival and improves response rate vs platinum‑pemetrexed in patients with T790M-positive advanced NSCLC, whose tumors had progressed on first-line EGFR-TKI therapy. Using patient baseline samples, we report concordance between plasma circulating tumor DNA (ctDNA) and tissue for the detection of EGFR mutations (T790M, exon 19 deletions [Ex19Del], L858R) using three distinct plasma detection technologies.

      Method:
      Tumor tissue biopsy samples were taken following progression on first-line EGFR‑TKI treatment. Baseline central confirmation of EGFR mutation status was by cobas[®] EGFR Mutation Test (Roche Molecular Systems). Where possible, baseline blood samples for plasma ctDNA screening were collected from patients in the osimertinib treatment group and analyzed using allele specific (AS)‑PCR (cobas[®] EGFR Mutation Test v2), ddPCR (Biodesix) and next generation sequencing (NGS, Guardant Health).

      Result:
      Figure 1 ctDNA was undetectable (negative for all three EGFR mutations [T790M, Ex19Del, L858R]) in 51/228 (22%) patients by AS-PCR, 58/211 (27%) by ddPCR, and 54/230 (23%) by NGS. Robust correlations (Spearman’s Rank) were observed for EGFR mutant allelic fractions (AFs) between ddPCR and NGS assays: T790M R[2] 0.9129 (n=201), Ex19Del R[2] 0.9384 (n=201), L858R R[2] 0.8090 (n=200). Discordant results between ddPCR and NGS were observed in 24/201 (12%) samples for T790M, 17/201 (8%) Ex19Del and 11/200 (6%) L858R. All discordant samples had AFs ≤1% by both assays.



      Conclusion:
      Using cobas tissue test as a reference, sensitivity for the detection of plasma T790M appeared higher for ddPCR and NGS assays compared with AS-PCR. Robust correlations were observed between quantitative ddPCR and NGS assays for determination of AFs across all three mutations. About 25% of AURA3 patients did not appear to shed ctDNA, as evidenced by absence of all three EGFR mutations across the three platforms.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

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    P2.02 - Biology/Pathology (ID 616)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.02-052 - A Clinically-Validated Universal Companion Diagnostic Platform for Cancer Patient Care (ID 8212)

      09:30 - 16:00  |  Author(s): K.S. Thress

      • Abstract

      Background:
      The increase in targeted therapies and associated companion diagnostics (CDx) has led to the need for efficient determination of therapeutic eligibility from a single assay. Comprehensive genomic profiling (CGP) provides a solution, but due to the complexity and number of assays available today, standardization of validation has become critically important. We present here the first NGS-based universal CDx platform developed and performed in compliance with FDA 21 CFR part 820. The assay interrogates 324 genes, and is anticipated initially to have eight CDx indications (Table 1). The versatile assay design will facilitate streamlined development of future CDx indications.

      Method:
      DNA extracted from FFPE tumor tissue underwent whole-genome shotgun library construction and hybridization-based capture, followed by sequencing using Illumina HiSeq 4000. Sequence data were processed using a proprietary analysis pipeline designed to detect base substitutions, indels, copy number alterations, genomic rearrangements, microsatellite instability (MSI), and tumor mutational burden (TMB).

      Result:
      Concordance with FDA-approved CDx are shown in Table 1. Clinical validity was established such that the concordance between CGP and approved CDx were statistically non-inferior to that of two runs of approved CDx. For analytical validity, limit of detection (LoD) was at allele frequency 4% for known substitutions and indels. LoD was 16% tumor content for copy number amplifications, 30% for homozygous deletions, 11% for genomic rearrangements, 12% for MSI, and estimated 20% for TMB. Positive percent agreement (PPA) with an orthogonal NGS platform was 95.8% in substitutions and indels. PPA with FoundationOne was 98.3% across all variant types. Within-assay reproducibility was measured with PPA 99.4%.

      Companion diagnostic Indicated use PPA Comparator CDx assay
      EGFR exon 19 deletions and L858R erlotinib, afatinib or gefitinib in NSCLC 98.1% (106/108) cobas® EGFR Mutation Test v2
      EGFR T790M osimertinib in NSCLC 98.9% (87/88) cobas® EGFR Mutation Test v2
      ALK rearrangements crizotinib in NSCLC 92.9% (78/84) Ventana ALK (D5F3) CDx Assay Vysis ALK Break-Apart FISH
      KRAS cetuximab or panitumumab in CRC 100% (173/173) therascreen® KRAS PCR
      ERBB2 (HER2) Amplifications trastuzumab, pertuzumab and ado-trastuzumab-emtansine in breast and gastric cancer 89.4% (101/113) Dako HER2 FISH PharmDx®
      BRAF V600E/K vemurafenib, dabrafenib, trametinib in melanoma 99.4% (166/167) cobas® BRAF V600 PCR
      BRCA1/2 rucaparib in ovarian cancer N/A N/A: Novel CDx that was previously validated in PMA P160018


      Conclusion:
      Rapid expansion of targeted therapies and CDx has necessitated a new approach and urgency to defining performance standards. We developed a universal CDx assay and established a robust approach for demonstrating clinical and analytical validity to support and accelerate the use of CGP for routine clinical care.

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.01-074 - Genomic Analysis of Tumor and Plasma in T790M Mutant Positive EGFR Lung Cancer Patients before and after Osimertinib Treatment (ID 9224)

      09:30 - 16:00  |  Author(s): K.S. Thress

      • Abstract

      Background:
      Osimertinib is a third-generation, central nervous system active epidermal growth factor receptor (EGFR) – tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-sensitising and EGFR T790M resistance mutations. Osimertinib is approved for EGFR mutation positive non small cell lung cancer (NSCLC) patients who develop EGFR T790M resistant mutation and resistant to prior EGFR TKI. Osimertinib resistance pattern and clinical outcome after osimertinib treatment are undergoing intensive investigation.

      Method:
      Seventy-one EGFR-TKI resistant patients received osimertinib in the AURA study in one medical center. We excluded patients treated as first-line or who do not have detectable T790M mutation. We collect available data of pre-osimertinib treatment plasma and tissue and post-osimertinib plasma, tissue samples and tested for EGFR, HER2, K-ras, B-raf, mutations, ALK fusion and cMET or HER2 gene amplification. Clinical and pathological characteristics before and after osimertinib treatment were collected.

      Result:
      Of the 53 T790M-positive patients, 6 did not progress. Three and 18 patients discontinued osimertinib due to side effect or progression, respectively; 26 received osimertinib beyond progression (1.1 to 20.5 months); 7 patients received osimertinib combination after progression. Fourteen patients are still alive. Median progression-free survival(PFS), overall survival(OS) and post-progression survival (PPS) were 11.1 months, 16.9 months and 5.0 months, respectively (only progression patients). In 47 progressive patients, post progression EGFR plasma tests were available in 40 patients. T790M was detected by BEAMing in 12 patients (4 patients combined with C797S) and not detected in 28 patients (70%). OS and PPS was longest for patients with no detectable EGFR activating mutation and T790M in the plasma before and/or after osimertinib treatment. Patients who lost detectable T790M but maintained activating EGFR mutation in the plasma had shortest osimertinib PFS. Post progression tissue sample or pleural effusion tumor cells were available in 22 patients. Two patients developed small cell transformation, one patient developed squamous cell carcinoma. Post progression tissue or effusion genomic tests were performed (N= tested patient number) and showed T790M+ in 9 patients(N=18), C797S in 2 (N=12), cMET amplification in 5 (N=10), B-Raf V600 mutation in 1 (N=13), K-ras mutation in 1 (N=13) and no ALK, ROS1 and RET fusions.

      Conclusion:
      Heterogeneous resistance mechanisms develop after osimertinib treatment, in tumors retain T790M or losing T790M. Patients who have no detectable activating EGFR mutations in the plasma had best survival outcomes. Loss of T790M but maintainance activating EGFR mutations in the plasma correlated with short osimertinib PFS.

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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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      P3.02-062 - An EGFR Follow-On Companion Diagnostic for Clinical Care of Patients with NSCLC (ID 10414)

      09:30 - 16:00  |  Author(s): K.S. Thress

      • Abstract

      Background:
      Late-stage NSCLC patients may benefit from treatment with EGFR tyrosine kinase inhibitors if they harbor certain activating mutations in EGFR. While the FDA has approved companion diagnostics (CDx) using PCR to detect EGFR mutations, molecular diagnostic testing is evolving towards comprehensive genomic profiling (CGP). However, clinical validity of EGFR testing using CGP has not yet been demonstrated in an FDA-approved manner. We present here the first follow-on CDx EGFR test using CGP as part of our universal CDx platform.

      Method:
      Clinical validity was established against FDA-approved PCR-based cobas® EGFR Mutation Test v2, using 406 procured samples containing EGFR L858R mutations and exon 19 deletions, and 354 samples from the AURA clinical trials for T790M mutations. For each sample, two tests of cobas were run, and clinical validity was established such the concordance between CGP and cobas were statistically non-inferior to the performance between two runs of cobas. Concordance (PPA and NPA) reported on Table 1 was calculated on samples that were in agreement between the two cobas runs.

      Result:
      Concordance is shown in Table 1. For L858R and exon 19 deletions, statistical non-inferiority demonstrated a non-inferiority margin of 1.9%. For T790M, our assay has higher sensitivity: of the 61 samples that were below 10% mutant allele fraction (MAF) as detected by NGS, 30 were missed by cobas. Table 1.

      Companion diagnostic EGFR exon 19 deletions and L858R EGFR T790M
      Indicated use erlotinib, afatinib, or gefitinib in NSCLC osimertinib in NSCLC
      Approved CDx comparator cobas® EGFR Mutation Test v2 cobas® EGFR Mutation Test v2
      Positive Percent Agreement (PPA) 98.1% (106/108) 98.9% (87/88)
      Negative Percent Agreement (NPA) 99.4% (153/154) 86.1% (93/108)
      Median unique sequence coverage L858R: 1165X Exon 19: 1028X 1126X
      Precision 100% 100%
      Limit of Detection L858R: 1.9% MAF Exon 19 deletions: 3.4% MAF 1.8% MAF


      Conclusion:
      We present a follow-on CDx for EGFR as part of the universal CDx platform. The platform provides a single assay with well-defined performance characteristics, identifies patients with cancer who may be eligible to receive FDA-approved targeted therapeutics, conserves tissue by avoiding serial testing and can serve as clinical trial assay for studies requiring a molecular biomarker for eligibility. The data demonstrating clinical and analytical validity of EGFR may accelerate the use of CGP for routine clinical care.