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Nitzan Rosenfeld



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    MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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      MA16.02 - Prospective Clinical Validation of the InVisionFirst™ ctDNA Assay for Molecular Profiling of Patients with Advanced NSCLC (ID 13885)

      13:35 - 13:40  |  Author(s): Nitzan Rosenfeld

      • Abstract
      • Presentation
      • Slides

      Background

      Clinical practice guidelines advocate molecular profiling as a part of the evaluation of advanced NSCLC, with ctDNA based profiling being an option for those with insufficient tissue. Thorough prospective clinical validation studies of NGS based ctDNA assays are lacking. Here we report the multi-centered prospective clinical validation of a ctDNA NGS panel for stratification of patients with advanced untreated NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      InVisionFirst™ (Inivata) is a ctDNA NGS assay for detection of genomic alterations in 36 genes commonly mutated in NSCLC and other cancers. 264 patients with untreated advanced NSCLC were prospectively recruited by 41 US centers. 178 patients had tumour tissue available for molecular profiling (predominantly by NGS) and the remaining 86 patients without tissue were included to compare ctDNA profiles obtained from patients with and without tissue for profiling.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 204 patients (77.3%) had detectable ctDNA alterations. Using tissue results as the reference, overall concordance for the full 36 genes in the InVisionFirst™ panel with matched tissue profiling was 97.8% with 82.9% PPV, 98.5% NPV, 70.6% sensitivity and 99.2% specificity. Considering a subgroup of 8 genes that can influence routine clinical patient management (EGFR, ALK, ROS1, ERBB2, MET, BRAF, KRAS, STK11) the PPV was 93.7%, 96.8% NPV, 72.4% sensitivity and 99.4% specificity. Excluding patients with undetectable ctDNA, these figures become 93.7% PPV, 98.4% NPV, 87.3% sensitivity and 99.3% specificity. The observed pattern of genomic changes seen in ctDNA was consistent across patients with and without tissue for profiling. Across the whole study, 44 patients with actionable alterations were identified by ctDNA testing compared to only 36 by tissue testing. 47% of patients tested by ctDNA had an actionable alteration or an alteration that is generally mutually exclusive for such actionable changes such as KRAS or STK11.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The InVisionFirst™ assay demonstrates excellent concordance with tissue profiling in this multi-centered prospective clinical validation study. The performance of this assay in terms of overall sensitivity and specificity appears comparable if not higher than other established commercial ctDNA assays. Utilization of InVisionFirst™ ctDNA testing led to the detection of 22% more actionable alterations than standard of care tissue testing in this study supporting its use for the molecular stratification of patients with advanced NSCLC. Further analyses on the features associated with detectable ctDNA signatures are ongoing.

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-24 - Prospective Efficacy of Osimertinib in Circulating Tumour DNA (ctDNA) T790M-Mutant NSCLC Patients (ID 14031)

      16:45 - 18:00  |  Author(s): Nitzan Rosenfeld

      • Abstract
      • Slides

      Background

      Liquid biopsy circulating tumor DNA (ctDNA) analysis in advanced EGFR-mutant NSCLC patients is an approved tool for molecular profiling and disease surveillance when tissue is not available. Long-term efficacy of osimertinib in patients with the T790M resistance mutation positive detected only by ctDNA (without tissue information) has not been fully validated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In a prospective study, EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKI, in whom a repeat tissue biopsy was not feasible, were assessed for ctDNA T790M mutational status using InVisionSeqTM. T790M-positive NSCLC patients received osimertinib (80 mg daily; extended access program or approval) at RECIST progression. The objectives were to assess: proportion of patients with acquired ctDNA-T790M positive; overall survival (OS) of the overall EGFR-mutant population as well as OS comparison for T790M +ve/-ve. Also, for those T790M-positive NSCLC patients who received osimertinib in a real world data we assessed: response rate (RR) according to RECIST 1.1 by investigator and progression free survival (PFS), calculated from the date of osimertinib initiation until the date of progression or death (whichever came first), or the date of last follow-up are also reported.

      4c3880bb027f159e801041b1021e88e8 Result

      We recruited 82 patients (71% female, median age 64 years, 72% Del19 EGFR mutation, 71% never-smokers). The ctDNA T790M mutation was detected in 55% (N=45) of NSCLC patients. Median OS of EGFR-mutant population was 38.2 months (mo.). According to T790M status, median OS was 41.2 months and 30.4 mo. for T790M-positive and T790M-negative NSCLC patients, respectively. Both cohorts had already received a median of 3 previous treatment lines. In 40 T790M-positive NSCLC patients who receive osimertinib, RR was 55% (PR: 55%, SD 27.5% and PD: 12.5%) and median PFS of 8.5 mo. Median OS on osimertinib among 10 patients with brain and/or leptomeningeal metastases at baseline was of 13.4 months.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In patients with acquired resistance to first- or second-generation EGFR TKIs, ctDNA T790M detection by InVisionSeq™ is equivalent to what has been reported in tissue biopsy. Osimertinib has clinical benefit in patients for which the T790M resistance mutation is detected only through a liquid biopsy procedure.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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