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Xiaoxiao Peng



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    JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)

    • Event: WCLC 2019
    • Type: Joint IASLC-CSCO-CAALC Session
    • Track:
    • Presentations: 1
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      JCSE01.25 - TP53/KMT2C Co-Mutation as a Novel Biomarker for Immunotherapy in Non-Small Cell Lung Cancer Patients (ID 3862)

      07:00 - 11:15  |  Author(s): Xiaoxiao Peng

      • Abstract
      • Slides

      Abstract
      Background
      Immune checkpoint inhibitors (ICIs) have shown remarkable antitumor effects in non-small cell lung cancer (NSCLC), however only a subset of patients respond. Genomic alterations (GAs) detected by targeted next-generation sequencing (NGS) is increasingly used in clinical practice, but its correlation with recognized immune biomarkers and predictive value for ICIs response in NSCLC is unclear.

      Methods
      FFPE tumor and matched blood samples of 637 NSCLC patients (84 squamous cell and 553 non-squamous cell) were collected for targeted NGS panel sequencing from December 2017 to January 2019. GAs including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. TMB high (TMB-H) was defined as ≥10 muts/Mb. Positive PD-L1 expression was defined as ≥1% of tumor cells with membranous staining (22C3/28-8, DAKO). Genomic data and ICIs treatment outcome from a 240 NSCLC patient cohort was derived from cBioPortal (MSKCC, J Clin Oncol 2018).

      Results
      In 637 NSCLC patients, the prevalence of PD-L1≥1% was 26.5% and the median TMB was 4.6 muts/Mb (IQR, 2.3-10). Recurrent TP53, KRAS, LRP1B and KEAP1 mutations were significantly correlated with higher TMB (p value). TP53, KRAS and KEAP1 mutations were significantly enriched in the TMB-H/PD-L1+ subset while STK11 mutations were enriched in TMB-H/PD-L1- subset (p value). KMT2C, also known as MLL3, belongs to the mixed‐lineage leukemia (MLL) family of histone methyltransferases and its GAs was found in 5% of our cohort. Tumors with KMT2C and TP53 co-mutations (co-MUT) had a significantly higher TMB (15.1 muts/Mb) than TP53/KMT2C single-MUT (8.7 muts/Mb) and TP53/KMT2C co-WT (3.1 muts/Mb) tumors. Moreover, TMB-H/PD-L1+ subset was enriched in KMT2C and TP53 co-MUT (25%) comparing to TP53/KMT2C single-MUT (14.7%) and TP53/KMT2C co-WT (3.3%) tumors. Survival analysis from public clinical trials confirmed that patients with TP53/KMT2C co-MUT had remarkable clinical benefit to ICIs in both progression free survival (PFS) and durable clinical benefit (DCB). The median PFS was 7.3, 4.2 and 2.5 months for TP53/KMT2C co-MUT, TP53/KMT2C single-MUT and TP53/KMT2C co-WT patients, respectively (p=0.0032). TP53/KMT2C co-MUT was an independent variable of PFS (TP53/KMT2C co-MUT vs. TP53/KMT2C co-WT, HR: 0.47, 95%CI: 0.25-0.89, p=0.0199). Furthermore, TP53 with KMT2C or KRAS co-MUT expanded the patient population benefiting from ICIs (mPFS = 7.2 months, p=0.00042; DCB = 51.2%, p= 0.0195).

      Conclusion
      This study provides evidence that TP53/KMT2C co-MUT may serve as a predictive biomarker for ICIs in NSCLC. GAs detected by targeted NGS could illuminate insight for immunotherapy.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-20 - TP53/KMT2C Co-Mutation as a Novel Biomarker for Immunotherapy in Non-Small Cell Lung Cancer Patients (ID 2081)

      10:15 - 18:15  |  Author(s): Xiaoxiao Peng

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have shown remarkable antitumor effects in non-small cell lung cancer (NSCLC), however only a subset of patients respond. Genomic alterations (GAs) detected by targeted next-generation sequencing (NGS) is increasingly used in clinical practice, but its correlation with recognized immune biomarkers and predictive value for ICIs response in NSCLC is unclear.

      Method

      FFPE tumor and matched blood samples of 637 NSCLC patients (84 squamous cell and 553 non-squamous cell) were collected for targeted NGS panel sequencing from December 2017 to January 2019. GAs including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. TMB high (TMB-H) was defined as ≥10 muts/Mb. Positive PD-L1 expression was defined as ≥1% of tumor cells with membranous staining (22C3/28-8, DAKO). Genomic data and ICIs treatment outcome from a 240 NSCLC patient cohort was derived from cBioPortal (MSKCC, J Clin Oncol 2018).

      Result

      In 637 NSCLC patients, the prevalence of PD-L1≥1% was 26.5% and the median TMB was 4.6 muts/Mb (IQR, 2.3-10). Recurrent TP53, KRAS, LRP1B and KEAP1 mutations were significantly correlated with higher TMB (p value). TP53, KRAS and KEAP1 mutations were significantly enriched in the TMB-H/PD-L1+ subset while STK11 mutations were enriched in TMB-H/PD-L1- subset (p value). KMT2C, also known as MLL3, belongs to the mixed‐lineage leukemia (MLL) family of histone methyltransferases and its GAs was found in 5% of our cohort. Tumors with KMT2C and TP53 co-mutations (co-MUT) had a significantly higher TMB (15.1 muts/Mb) than TP53/KMT2C single-MUT (8.7 muts/Mb) and TP53/KMT2C co-WT (3.1 muts/Mb) tumors. Moreover, TMB-H/PD-L1+ subset was enriched in KMT2C and TP53 co-MUT (25%) comparing to TP53/KMT2C single-MUT (14.7%) and TP53/KMT2C co-WT (3.3%) tumors. Survival analysis from public clinical trials confirmed that patients with TP53/KMT2C co-MUT had remarkable clinical benefit to ICIs in both progression free survival (PFS) and durable clinical benefit (DCB). The median PFS was 7.3, 4.2 and 2.5 months for TP53/KMT2C co-MUT, TP53/KMT2C single-MUT and TP53/KMT2C co-WT patients, respectively (p=0.0032). TP53/KMT2C co-MUT was an independent variable of PFS (TP53/KMT2C co-MUT vs. TP53/KMT2C co-WT, HR: 0.47, 95%CI: 0.25-0.89, p=0.0199). Furthermore, TP53 with KMT2C or KRAS co-MUT expanded the patient population benefiting from ICIs (mPFS = 7.2 months, p=0.00042; DCB = 51.2%, p= 0.0195).

      Conclusion

      This study provides evidence that TP53/KMT2C co-MUT may serve as a predictive biomarker for ICIs in NSCLC. GAs detected by targeted NGS could illuminate insight for immunotherapy.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.