Author of

• 25921

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  P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall

  • 26291

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    P1.01-58 - Variants Distribution and Heterogeneity of Outcomes to Crizotinib in ALK-Rearranged Chinese Non-Small Cell Lung Cancers (ID 13940)

    16:45 - 18:00  |  Author(s): Yang Gao
    • Abstract
    • Slides

    Background
    

    ALK-rearranged NSCLC is a unique molecular subgroup with high sensitivity to ALK inhibitors. Crizotinib, a FDA-approved tyrosine kinase inhibitor for ALK-rearranged NSCLCs, showed remarkable response in ALK-positive NSCLC. However, the magnitude and duration of clinical responses to crizotinib among different ALK variants are found to be heterogeneous, and studies about the clinical outcomes showed contradict conclusions.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    We collected sequencing information from 110 ALK-positive Chinese NSCLC patients, whose tissue or plasma biopsies were sequenced in a CLIA-certified genomic profiling laboratory. Sequencing results were reviewed with the intent of studying ALK rearrangement distribution and clinical outcomes to crizotinib.

    4c3880bb027f159e801041b1021e88e8 Result
    

    A total of 134 ALK rearrangements were identified in this cohort, with 39 unique rearrangements. EML4 was the most common ALK rearrangement partner, with variant 3 (v3) as the most frequent variants (42.7%) of EML4-ALK fusion, accounting for 71.6% (96/134) of all the rearrangements in 87.3% (96/110) patients. For EML4-ALK positive patients after crizotinib treatment (n=96), survival analysis revealed that patients with EML4-ALK only displayed favorable PFS (10.0 vs 7.2 months, p=0.037) and OS (36.0 vs 20.0 months, p=0.037) than those combined with other fusions. In vitro data reported that variant v3 and v5 was structurally stable and less sensitive to ALK inhibitors due to the lack of TAPE domain. In this study, patients harboring v3 and v5 displayed significantly inferior OS than those with other variants (31 vs 37.6 months, p=0.010). For all the ALK-rearranged patients (n=110), no significant difference was observed between the survival of EML4-ALK and non-EML4-ALK (PFS, 9.4 vs 14.5 months, p=0.61; OS, 35.1 vs 35.5 months, p=0.58), below and above 40-years (PFS, 7.3 vs 11.3 months, p=0.23; OS, 25.4 vs 35.5 months, p=0.69).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    This study demonstrated the distribution pattern of ALK rearrangements in Chinese NSCLCs, and illustrated the clinical outcomes of ALK-positive patients in different sub-groups. We hope this study could improve basic knowledge of ALK rearrangement and might be helpful for clinicians in choosing patients for appropriate medical treatment. Moreover, these findings advocate for more comprehensive ALK genomic profiling and validation of current results of clinical outcomes in large populations.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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• 25957

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  P3.03 - Biology (Not CME Accredited Session) (ID 969)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall

  • 27476

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    P3.03-01 - BRAF V600 and Non-V600 Mutations in Chinese Lung Cancer (ID 13759)

    12:00 - 13:30  |  Presenting Author(s): Yang Gao
    • Abstract
    • Slides

    Background
    

    BRAF gene mutation, especially V600E, was frequently mutated in cancer. Vemurafenib and dabrafenib has already been approved in melanoma as well as NSCLC and preclinical studies have demonstrated promising results in non-V600 NSCLC. But the landscape of BRAF non-V600 mutation in Chinsese lung cancer was rarely descripted.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    7,417 normal-paired samples from lung cancer patients were analyzed using hybridization capture-based next generation sequencing and alterations including single nucleotide variants (SNVs), short insertions/deletions (indels), copy number variations (CNVs) and structural variations (SV) were analyzed.

    4c3880bb027f159e801041b1021e88e8 Result
    

    BRAF was altered in 1.8% (133 of 7,417) of all tumors. BRAF V600 (gain of function, GOF) and non-V600 mutations (GOF: G469V/R/E/A, K601N/E, L597V/R, T599dup/T599R, N486_P490del, L525R, and loss of function/LOF: D594N/G, N581S/I, G466V/A, K483E, G596R), has previously been reported to increase MEK/ERK activation, were detected in 52.3% (58/111) and 47.7% (53/111) of BRAF functional mutation patients. CNVs and SVs were both observed at a frequency of 0.9% (1/111). Two patients have two GOF mutations (V600E/T599R). We also found that 82.0% (91/111) of the BRAF functional mutation carriers also owned the other actionable or driver mutation, the most frequent one was TP53 (68.1%), then was EGFR (18.7%), KRAS/NRAS (14.3%), PIK3CA (11.0%) as well as CDKN2A/B (9.9%).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    BRAF gene mutations, non-V600 especially, was extensively mutated in Chinese lung cancer. This work supports a broad profiling approach in lung cancers and suggests that non-V600E BRAF alterations represent a subgroup of lung cancers in which targeted therapy should be considered.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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