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Siraj M Ali



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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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      MA16.05 - MET Kinase Domain Rearrangements (KDRE) in Non-Small Cell Lung Cancer (NSCLC) Identified Through Comprehensive Genomic Profiling (CGP) (ID 13401)

      14:00 - 14:05  |  Author(s): Siraj M Ali

      • Abstract
      • Presentation
      • Slides

      Background

      MET is a known oncogenic driver in NSCLC, and activation via various means including gene amplification, exon 14 skipping, and fusion has been reported to be targetable in the clinical setting. However, the prevalence and characteristics of NSCLCs harboring MET kinase fusions as well as diverse KDRE have not been comprehensively assessed.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Hybrid-capture based CGP was performed on 32,643 FFPE or 3,076 blood-based ctDNA NSCLC specimens during the course of clinical care. Tumor mutational burden (TMB) was determined on 0.83-1.1 megabases (Mb) of sequenced DNA and is reported as mutations/Mb.

      4c3880bb027f159e801041b1021e88e8 Result

      In 35,719 unique NSCLC patient cases assayed, RE retaining the MET kinase domain were detected in 63 (0.2%) cases. These included MET fusions with an identified 5’ fusion partner (n=8, 12.7%), probable MET fusions with an unidentified fusion partner (n=32, 50.8%), MET kinase domain duplications (KDD, n=7, 11.1%), MET exon 14 skipping rearrangements (n=6, 9.5%), and MET rearrangements of the 5’ terminus (n=10, 15.9%). Fusion partners identified include CAPZA2 (2 cases), CAV2, CD47, INPPL1, LHFPL3, PRKAR2B and SPECC1. MET kinase-inactivating rearrangements were also detected in the larger cohort (n=10, 0.03%). MET KDRE cases harbored at least one targetable NSCLC NCCN guidelines driver alteration in 27.0% (n=17) of cases including EGFR activating subs (L858R, L861Q) or exon 19 deletions (n=8), MET exon 14 skipping short variants (n=6), ALK fusions (n=2), and a BRAF V600E mutation. KRAS short variants were detected in 6 additional cases. MET amplification also co-occurred in 36.5% of cases with MET KDRE (n=23, median copy number 16). The median TMB in cases with MET KDRE was 6.1 mut/Mb, as compared to a median of 7.0 mut/Mb for NSCLC samples overall. Clinical treatment information for a subset of cases will be presented, including paired cases in which the MET KDRE may represent an acquired mechanism of resistance to EGFR- or ALK-targeted therapy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Potentially targetable MET rearrangements retaining the kinase domain were observed in 0.2% of NSCLCs, which may be an underestimate considering that these assays sequence all MET exons, but do not specifically bait MET intronic breakpoints. These data suggest that MET KDRE, including, but not limited to fusions and KDD, may represent a distinct subset of driver alterations and potential resistance mechanisms. The value of testing for and potentially targeting these alterations as part of routine clinical care in NSCLC warrants further investigation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.13 - Targeted Therapy (Not CME Accredited Session) (ID 979)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.13-26 - Outcomes of Patients with Metastatic Lung Cancer Presented in a Multidisciplinary Molecular Tumor Board (ID 12838)

      12:00 - 13:30  |  Author(s): Siraj M Ali

      • Abstract
      • Slides

      Background

      With the adoption of broad genomic profiling, interpretation of genomic data in NSCLC has become increasingly complex. Approved targeted therapies against oncogenic driver mutations have improved clinical outcomes for patients whose lung cancers harbor these genomic alterations. However, for other patients, the benefit of broad genomic sequencing is not fully proven. Multidisciplinary molecular tumor boards (MTB) may improve clinical outcomes by appropriately matching targeted treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed clinical, pathologic, and molecular data of metastatic lung cancer patients presented at the UC Davis MTB from January 2016 through May 2017. Genomic alterations were identified by hybrid capture-based comprehensive genomic profiling to a median coverage depth of >500X for 315 cancer-related genes (FoundationOne®).

      4c3880bb027f159e801041b1021e88e8 Result

      Out of 48 patients presented, 19 (39.6%) had lung cancer. Fourteen patients (73.7%) had adenocarcinoma, 1 SCLC, 1 squamous, 2 neuroendocrine, and 1 mixed histology. Seventeen patients were available for follow-up.

      Median number of prior treatments was 2 (range: 0-7) and median number of prior targeted therapies was 2 (range: 0-5). On average, each tumor sample had 5.3 genomic alterations (range 2 – 14). Every sample had ³1 actionable mutation, in that matched targeted therapy was available in the form of an FDA-approved drug for NSCLC, FDA-approved drug in another tumor type, or genomically informed clinical trial. Tumors harbored an EGFR mutation (N=7), HER2 amplification (N=2), BRAF V600E (N=2), or mutation in BRCA1 (N=1), KIT (N=1), or PTCH1 (N=1). All 7 patients with an EGFR mutation had previously received EGFR-targeted therapy, six with progressive disease (PD) on prior EGFR-TKI.

      Thirteen patients (76.5%) received targeted therapy, including FDA-approved therapy for NSCLC (N=4), FDA-approved therapy for another tumor type (N=6), or a genomically informed clinical trial (N=3). The other four patients were either on an immunotherapy clinical trial (N=2) or could not tolerate treatment (N=2). Out of the 13 patients who received targeted therapy, 4 patients had a partial response (31%) (3 EGFR, 1 BRAF V600E), all other patients had stable disease or PD. Median PFS on MTB-selected treatment was 4.8 months (range: 25% 2.2 – 75% 10.7 months).

      8eea62084ca7e541d918e823422bd82e Conclusion

      MTB at an academic medical center matched a high percentage of patients to either a targeted treatment or clinical trials with targeted therapies or immunotherapy. A subset of patients had clinical benefit to targeted therapies in this pretreated population. Multidisciplinary expertise at MTB can guide treatment for NSCLC, but new targeted treatments are needed to improve clinical outcomes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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