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K. Gowen



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    MA 07 - ALK, ROS and HER2 (ID 673)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 07.07 - Clinical Outcomes and ALK Resistance Mutations in ALK+ Non-Small Cell Lung Cancer According to EML4-ALK Variant (ID 8255)

      15:45 - 17:30  |  Author(s): K. Gowen

      • Abstract
      • Presentation
      • Slides

      Background:
      Advanced ALK+ non-small cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes among patients treated with ALK TKIs vary, and the clinical benefit of TKI therapy is limited due to acquired resistance. To date, emerging data suggest that the specific EML4-ALK variant may impact clinical outcome, but whether variant is associated with mechanisms of TKI resistance is unknown.

      Method:
      We identified 108 advanced ALK+ NSCLC cases with known ALK fusion variants. Progression-free survival (PFS) on ALK TKIs and resistance mechanisms were retrospectively evaluated according to ALK variant.

      Result:
      The 108 ALK+ cases consisted of: 42 (39%) EML4-ALK v1 (E13;A20), 8 (7.4%) v2 (E20;A20), 45 (41.7%) v3 (E6;A20), 3 (2.8%) v5 (E2;A20), 4 (3.7%) v5’ (E18;A20), 1 (0.9%) v7 (E14;A20), and 5 (4.6%) non-EML4-ALK variants. Given the small numbers of non-v1/v3 cases, v1 and v3 cases were selected for further analysis. Among the 21 v1 and 25 v3 cases treated with first-line crizotinib, there was no significant difference in PFS (HR = 0.81 [95% CI, 0.42-1.57], p = 0.526). Similarly, there was no difference in PFS on second-generation ALK TKIs among 35 v1 and 35 v3 patients who received ceritinib, alectinib, or brigatinib following first- or later-line crizotinib (HR = 1.32 [95% CI, 0.77-2.26], p = 0.308). Interestingly, among 12 v1 and 17 v3 patients who received the third-generation TKI lorlatinib after failure of a second-generation TKI, v3 was associated with significantly longer PFS than v1 (HR = 0.250 [95% CI, 0.09-0.72], p = 0.006). From our cohort, we identified 11 v3 and 14 v1 post-crizotinib biopsies. No difference was noted in the presence of ALK resistance mutations (27% and 21%, respectively; p = 1.000). In contrast, among 30 v3 and 18 v1 post-second generation TKI biopsies, ALK resistance mutations were more common among v3 vs v1 cases (66% vs 44%, respectively; p = 0.147). Furthermore, the ALK G1202R solvent front mutation occurred more frequently in v3 vs v1 (47% vs 0%, respectively; p = 0.001).

      Conclusion:
      Our findings suggest that EML4-ALK variants 1 and 3 may not be associated with significantly different PFS outcomes on crizotinib or second-generation ALK TKIs. However, ALK resistance mutations, particularly G1202R, occur more frequently in v3 vs v1 post–second generation TKI. Patients with this variant may therefore derive particular benefit from third-generation, pan-inhibitory ALK TKIs. Larger, prospective studies will be needed to confirm these findings.

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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. Gowen

      • 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.