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Lingzhi Hong



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    FP07 - Pathology (ID 109)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP07.10 - Circulating Tumor DNA Analysis in NSCLC with MET exon 14 Skipping Alterations (ID 3418)

      00:00 - 00:00  |  Author(s): Lingzhi Hong

      • Abstract
      • Slides

      Introduction

      MET exon 14 skipping alteration (METex14) is an established oncogene driver in non-small cell lung cancers (NSCLC). Small molecule inhibitors (crizotinib, tepotinib, capmatinib and savolitinib) have shown efficacy in this patient population. Circulating tumor DNA (ctDNA) is an effective approach to detect METex14, as utilized in the VISION trial, which showed comparable outcome to tissue biopsy in patients treated with tepotinib. Here, we present the mutation and co-mutation landscape of the METex14 NSCLC detected by ctDNA.

      Methods

      Guardant360® results (Guardant Health) from patients with a diagnosis of advanced lung cancer were retrospectively reviewed and treatment-naïve and previously treated patients were included. Each subject was counted once regardless of multiple ctDNA tests performed. METex14 was considered positive when a deletion or non-synonymous mutation flanking exon 14 of MET was identified.

      Results

      A total of 345 lung cancer patients with METex14 were identified, including adenocarcinoma (79.1%), squamous cell carcinoma (9.8%), NSCLC NOS (7.8%), small-cell lung cancer (2%), and large-cell lung cancer (1.2%). The median age was 77 (range: 41-94) years, and 59% were female. The prevalence by functional sites were: 5’ splice donor site (45.8%), 3’ splice acceptor site (31.0%), D1010 splice mutation (18.3%), Y1003 – CBL mediated MET degradation (4.0%), others (0.9%). No significant gender differences were observed regarding the functional sites. The most frequent mutation type was base substitution (58.4%), followed by indel (41.6%). Whole-exon deletion was not found in this dataset (Table 1). The most frequent oncogene co-alterations included MET amplifications (9.0%), EGFR (7.2%) amplifications, KRAS mutation (6.9%, 15/24 subclonal), CDK4 (4.3%) amplifications and BRAF mutation (4.0%, 11/14 subclonal), while ALK-, ROS1-, RET-, and NTRK-fusions (1.4%) were uncommon. Additionally, TP53 mutations were detected in 53.8% of cases.

      Table 1. Functional site by mutation types of METex14 in lung cancer (N=345)
      n (%)
      Acceptor site 107 (31.0)
      Indel 96 (27.8)
      Base substitution 11 (3.2)
      Donor site 158 (45.8)
      Indel 46 (13.3)
      Base substitution 112 (32.5)
      Y1003 14 (4.0)
      Insertion 1 (0.3)
      Base substitution 13 (3.8)
      D1010 63 (18.3)
      Base substitution 63 (18.3)
      Others 3 (0.9)

      Conclusion

      In this real-world cohort of 345 cases of METex14-mutant NSCLC, detected using Guardant360, up to 21% were non-adenocarcinomas. The distribution of alterations of METex14 identified using liquid biopsy were similar to previously reported cohorts from tissue biopsies. Other driver oncogene alterations co-occur with METex14 at a low frequency.

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    P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P14.26 - Diminished Efficacy of PD-(L)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma is Impacted by KRAS Mutation Status (ID 2343)

      00:00 - 00:00  |  Author(s): Lingzhi Hong

      • Abstract
      • Slides

      Introduction

      STK11 and KEAP1 mutations (STK11m and KEAP1m) are commonly mutated in lung adenocarcinoma (LUAD). STK11m have been associated with resistance to immune checkpoint inhibition (ICI) in KRAS-mutant (KRASm) LUAD. However, whether STK11m status also impacts clinical outcomes to ICI in KRAS wild-type (wt) LUAD is unknown. Whether KEAP1m impact outcomes to ICI in KRASm and KRASwt LUAD is also unknown.

      Methods

      We analyzed clinical outcomes of patients (pts) with LUAD treated with ICI according to KRAS and STK11 and KEAP1 mutation status in two independent cohorts (Cohort 1 [DFCI/MGH] and Cohort 2 [MSKCC/MDACC]). TCGA and xCell data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 co-mutation status.

      Results

      Of 1261 pts with advanced LUAD treated with ICI, 42.5% had a KRASm, 20.6% and 19.2% had pathogenic STK11 and KEAP1 mutations, respectively. Co-occurring mutations in KRAS/STK11, KRAS/KEAP1, and STK11/KEAP1 were found in 10.9%, 8.4%, and 9.4% of cases, respectively. In both Cohort 1 and Cohort 2, STK11 and KEAP1 mutations were associated with significantly worse clinical outcomes to ICI among KRASm cases, but not among KRASwt cases (Table 1). The presence of an STK11 and KEAP1 mutation in KRASm NSCLCs was confirmed to be independent predictors of shorter PFS (STK11: HR 1.51, P=0.006; KEAP1: HR 2.01, P<0.01) and shorter OS (STK11: HR 1.81, P <0.001; KEAP1: HR 2.41, P<0.0001) in multivariable analysis in the combined cohort (Cohort 1 + Cohort 2). Gene ontology analysis from TCGA revealed that among KRASm but not KRASwt LUAD, STK11m was associated with the downregulation of MHC class II-related genes, including CD74 (P<0.01), HLA-DOA (P<0.01), HLA-DRB5 (P=0.03), HLA-DRB1 (P=0.03), and HLA-DMB (P<0.01). KEAP1m was associated with a significant downregulation of positive regulators of type I interferon and inflammatory cytokine production, such as STING (P<0.001), DDX58 (P<0.01), TLR4 (P<0.01), and TLR7 (P<0.01) among KRASm but not KRASwt LUAD. Cell subset transcriptome analysis showed that STK11m was associated with a significantly lower proportions of M1 macrophages among KRASm but not KRASwt LUAD (P<0.01). KEAP1m was associated with a significantly lower proportions of CD8+ T cells (P<0.001) and B cells (P<0.01) among KRASm but not KRASwt LUADs.table 1.jpg

      Conclusion

      The deleterious impact of STK11 and/or KEAP1 mutations on ICI efficacy in patients with advanced LUAD differs according to KRAS mutation status. KRAS/STK11 and KRAS/KEAP1 co-mutations identify subsets of lung cancers with distinct therapeutic outcomes and immune profiles.

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