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Jian Bai



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    FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP12.05 - Molecular Landscape of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Chinese Advanced Non-Small Cell Lung Cancer (ID 3529)

      00:00 - 00:00  |  Author(s): Jian Bai

      • Abstract
      • Slides

      Introduction

      Immune checkpoint inhibitors (ICIs) have improved the prognosis of non-small cell lung cancer (NSCLC) patients. However, about 80% of patients do not respond at all ("primary resistance"), whereas others initially respond to immunotherapy, later relapse and develop therapy resistance ("acquired resistance"). Absence of PD-L1 expression is well regarded as a biomarker of primary resistance to ICIs, and tumor mutation burden (TMB), microsatellite instability (MSI), HLA genotype and tumor neoantigen burden (TNB) have also been reported in recent studies to be related to the resistance of immunotherapy. This research is to explore the molecular landscape of primary and acquired resistance in Chinese advanced NSCLC treated with anti-PD-L1/PD-1 antibodies based on results of whole exome sequencing (WES) and targeted sequencing (TS) containing comprehensive immune molecular markers.

      Methods

      WES (~39Mb CDS of over 18,000 genes) or TS (~1.6Mb CDS of 654 genes) were conducted on 50 samples from 45 patients received anti-PD-L1/PD-1 antibodies, including 18 baseline pretreatment and 32 resistant tumor samples (Figure 1A). The primary endpoints include objective response rate (ORR) and progression-free survival (PFS), and statistics was analyzed using Fisher’s exact test and Kaplan-Meier analysis.

      Results

      About 31% of patients (N=14) responded to anti-PD-L1/PD-1 antibodies in Chinese advanced NSCLC (Figure 1A, 1B), and 40% (N=18) had stable disease. TNB was a stronger prognosis predictor of ICIs than TMB in pretreatment samples (N=18, Figure 1C, 1D). Patients with high TNB had a significantly better objective response (P=0.007) and longer PFS (P=0.003) (Figure 1C). HLA supertype B27 (HR=0.350, P=0.021) and HLA B*15:02 (HR=0.330, P=0.018) were individually associated with a poor prognosis in total 45 patients received ICIs (Figure 1E, 1F). These results indicate that low TMB or presence of HLA B27 and HLA B*15:02 were associated with primary resistance to ICIs. For acquired resistance to ICIs, known mutations were found when disease progressed on ICIs (3/25), including B2M p.W80*, B2M p.L15Ffs*41 and JAK1 p.L235I (Figure 1G). One patient had PFS of 11.2 months with acquired B2M mutation p.L15Ffs*41 detected only in post-progression sample (Figure 1H).

      figure1_update20200827.png

      Conclusion

      In Chinese advanced NSCLC, low TNB and presence of HLA B*15:02 and supertype B27 are biomarkers of primary resistance to ICIs, implying TNB and HLA genotypes can help screen patients with greater clinical benefit from immunotherapy in addition to PD-L1. Known mutations of acquired resistance to ICIs are found in few samples, other molecular mechanisms need to be explored to understand acquired resistance to ICIs.

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      FP12.13 - Therapeutic Index Predicts Clinical Outcome of both Treated and Treatment-Naïve NSCLC Patients Receiving Targeted- and Immune-Therapy (ID 1931)

      00:00 - 00:00  |  Author(s): Jian Bai

      • Abstract
      • Slides

      Introduction

      Recent studies have reported that the more molecular matches, the better prognosis of clinical treatments is. “Matching score” based on a targeted panel is such an index to evaluate the prognosis of previously treated cancer patients receiving targeted- and immune-therapy, while no similar scoring system has been established for treatment-naïve patients. This research aims to construct a new therapeutic index (T-Index) to predict clinical prognosis for both treatment-naïve and treated NSCLC patients receiving targeted- and immune-therapy.

      Methods

      Whole exome sequencing (WES, ~39Mb CDS of over 18,000 genes) and targeted sequencing (TS, ~1.1Mb CDS of 457 genes) were conducted on tumor samples from 102 stage IV NSCLC patients (treated N=32, treatment-naïve N=70) before targeted- (N=84) and immune-therapy (N=18) from 2018 to 2019. Molecular feature shared by WES and TS (SNV/Indel, CNV and tumor mutation burden (TMB)), and WES-specific molecular features (HLA genotyping, tumor neoantigen burden (TNB), loss of heterozygosity (LOH) and intra-tumoral heterogeneity (ITH)) were analyzed to identify prognostic predictors, and T-Index of WES and TS was each calculated. The association of both T-Indexes with objective response rate (ORR) and progression-free survival (PFS) were analyzed and compared. The cutoff of 0.5 was chosen according to the minimum P value approach.

      Results

      ORR and PFS were significantly higher and longer in patients with T-Index>0.5 than those with T-Index<=0.5 in previously treated patients (N=39) using WES (p=7e-0.4 for ORR, p=0.005 for PFS), but not using TS (p=0.388 for ORR, p=0.119 for PFS) (Figure 1A and 1C). In the treatment-naïve patients (N=70, targeted N=62, immunotherapy N=8), ORR in patients with T-Index>0.5 was significantly higher than those with T-Index<=0.5 using both WES (73.5% vs. 31.8%, p=0.002, Figure 1B)and TS (73.9% vs. 36.4% p=0.004, Figure 1D). A higher T-Index was also an independent predictor of longer PFS in WES(8.4mo vs. 5.5mo,p=0.012)and TS(9.5mo vs. 7.4mo,p=0.035)for treatment-naïve patients (Figure 1B and 1D).figure-20200825.png

      Conclusion

      Our results showed that T-Index by WES including non-canonical biomarkers, TNB, HLA genotyping, LOH and ITH, is significantly associated with clinical outcome whether in treatment-naïve or previously treated patients. Since TS are more practical for companion diagnostics in clinical, a new version of sequencing panel which covers non-canonical biomarkers related to immunotherapy listed above is needed to be developed and tested with the study going forward.

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    JICC01 - Joint IASLC-CAALC-CSCO Session: The Truth and Myth of Oral Anti-VEGFR Inhibitors for Advance NSCLC (ID 276)

    • Event: WCLC 2020
    • Type: Workshop
    • Track: N.A.
    • Presentations: 1
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      JICC01.12 - Molecular Landscape of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Chinese Advanced Non-Small Cell Lung Cancer (ID 4276)

      07:00 - 09:00  |  Author(s): Jian Bai

      • Abstract

      Introduction
      Immune checkpoint inhibitors (ICIs) have improved the prognosis of non-small cell lung cancer (NSCLC) patients. However, about 80% of patients do not respond at all ("primary resistance"), whereas others initially respond to immunotherapy, later relapse and develop therapy resistance ("acquired resistance"). Absence of PD-L1 expression is well regarded as a biomarker of primary resistance to ICIs, and tumor mutation burden (TMB), microsatellite instability (MSI), HLA genotype and tumor neoantigen burden (TNB) have also been reported in recent studies to be related to the resistance of immunotherapy. This research is to explore the molecular landscape of primary and acquired resistance in Chinese advanced NSCLC treated with anti-PD-L1/PD-1 antibodies based on results of whole exome sequencing (WES) and targeted sequencing (TS) containing comprehensive immune molecular markers. Methods
      WES (~39Mb CDS of over 18,000 genes) or TS (~1.6Mb CDS of 654 genes) were conducted on 50 samples from 45 patients received anti-PD-L1/PD-1 antibodies, including 18 baseline pretreatment and 32 resistant tumor samples (Figure 1A). The primary endpoints include objective response rate (ORR) and progression-free survival (PFS), and statistics was analyzed using Fisher’s exact test and Kaplan-Meier analysis. Results
      About 31% of patients (N=14) responded to anti-PD-L1/PD-1 antibodies in Chinese advanced NSCLC (Figure 1A, 1B), and 40% (N=18) had stable disease. TNB was a stronger prognosis predictor of ICIs than TMB in pretreatment samples (N=18, Figure 1C, 1D). Patients with high TNB had a significantly better objective response (P=0.007) and longer PFS (P=0.003) (Figure 1C). HLA supertype B27 (HR=0.350, P=0.021) and HLA B*15:02 (HR=0.330, P=0.018) were individually associated with a poor prognosis in total 45 patients received ICIs (Figure 1E, 1F). These results indicate that low TMB or presence of HLA B27 and HLA B*15:02 were associated with primary resistance to ICIs. For acquired resistance to ICIs, known mutations were found when disease progressed on ICIs (3/25), including B2M p.W80*, B2M p.L15Ffs*41 and JAK1 p.L235I (Figure 1G). One patient had PFS of 11.2 months with acquired B2M mutation p.L15Ffs*41 detected only in post-progression sample (Figure 1H).

      Conclusion
      In Chinese advanced NSCLC, low TNB and presence of HLA B*15:02 and supertype B27 are biomarkers of primary resistance to ICIs, implying TNB and HLA genotypes can help screen patients with greater clinical benefit from immunotherapy in addition to PD-L1. Known mutations of acquired resistance to ICIs are found in few samples, other molecular mechanisms need to be explored to understand acquired resistance to ICIs.