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Rajwanth Veluswamy



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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-15 - NSCLC Response Determinants to Chemoimmunotherapy: Deep Profiling of Tumors Following Neoadjuvant Cemiplimab and Chemotherapy (Now Available) (ID 1021)

      08:00 - 18:00  |  Author(s): Rajwanth Veluswamy

      • Abstract
      • Slides

      Background

      Clinical trials have demonstrated synergistic effects of combination chemoimmunotherapy in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC), however, our understanding is limited as to why and for whom PD-1 blockade with or without chemotherapy is effective, as is our understanding of the mechanism of synergy between these therapies.

      While most patients with resectable NSCLC receive neoadjuvant or adjuvant chemotherapy, this intervention only changes the natural course of disease for ~5% of patients. Early studies have demonstrated major pathologic responses to neoadjuvant immunotherapy ± chemotherapy.

      Method

      To investigate the immunodynamic effect of PD-1 blockade and chemotherapy, and identify potentially more effective immune modifying targets or combinations, we will use novel immunophenotyping platforms to characterize the effect of this combination on the tumor. This trial will enroll 52 patients with Stage Ib-IIIa NSCLC into three cohorts receiving 2 cycles of 1) platinum-doublet chemotherapy, 2) the PD-1 antibody cemiplimab, or 3) combination chemoimmunotherapy. Following surgery, patients will receive additional adjuvant chemoimmunotherapy; in total all patients will receive 4 cycles of standard platinum-doublet chemotherapy and 8 cycles of cemiplimab. All patients will undergo pre-treatment biopsies of their tumor, and blood will be collected at 6 time-points before and after surgery.

      The primary endpoint for this clinical trial is major pathologic response, defined as ≤10% viable tumor within resection. Secondary endpoints include: delay of surgery, disease-free survival, overall response rate, overall survival, measurement of adverse events, and change in CD8 T-cell infiltration.

      Exploratory endpoints include in-depth analysis of the pre-treatment tumor biopsies and post-treatment surgical specimens, and paired blood. We will characterize proteomic and transcriptomic changes in the stromal and immune compartment of tumors at the histologic level using a multiplexed ion-beam imaging (MIBI)—a novel multiplex immunohistochemistry platform capable of analyzing >50 markers on a single section of tissue—and at the single-cell level using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq), a novel platform combining the proteomic data-potential of mass cytometry (CyTOF) and the transcriptomic data-potential of single cell RNA sequencing including TCR sequencing. Feasibility of this multi-pronged approach has been demonstrated on untreated NSCLC (unpublished data, submitted as abstract to WCLC by our group).

      To probe for biomarkers correlating with response or resistance to therapy, we will perform unbiased analysis of peripheral blood lymphoid and myeloid populations by CyTOF, and measure nearly 100 soluble factors in serum using Olink.

      Result

      This trial opened to accrual April 2019.

      Conclusion

      Section not applicable.

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    MA02 - Miscellaneous Topics in the Management of Early Stage Lung Cancer (ID 116)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      MA02.09 - Prognostic Impact of Immune Cell Biomarkers in Surgically Resectable Non-Small Cell Lung Cancer (Now Available) (ID 2646)

      10:30 - 12:00  |  Author(s): Rajwanth Veluswamy

      • Abstract
      • Presentation
      • Slides

      Background

      Immune cells within the tumor microenvironment (TME) play an important role in the development, progression and eventual outcomes of non-small cell lung cancer (NSCLC). The relative balance of immune effector and regulatory cell subpopulations may tilt the TME to be either detrimental or supportive of tumorogenesis and will have a profound impact on the tumor’s eventual destiny. In early-stage lung cancer, the role of individual immune cell subtypes in the TME on survival outcomes following surgical resection is unknown.

      Method

      This project made use of The Cancer Genome Atlas (TCGA) Program data. We computed sample-specific scores for different immune cells using xCell, a new model for estimating different immune cell types from RNAseq data, for all stage I-IIIA NSCLCs. Then, we assessed the association between each cell type and survival with Cox Regression, while adjusting for important clinical variables (i.e., stage, age, gender, smoking status). We stratified the analysis according to histological subtype.

      Result

      There were 910 surgically resected early-stage NSCLC analyzed, of which 438 were adenocarcinomas (LUADs) and 472 were squamous cell (LUSC) samples. Higher levels of natural killer cells, neutrophils, and mast cells within tumors were associated with significantly improved survival in LUAD patients, whereas no immune cell type was associated with survival for LUSC patients or the combined analysis.

      Figure 1: Adjusted Survival According to Estimated Immune Cell Infiltration

      figure 1 adjusted survival according to estimated immune cell infiltration.png

      Hazard ratios are adjusted for stage, gender, age and smoking status

      Conclusion

      Innate and adaptive immune cells within the TME may have prognostic value in early-stage NSCLC patients undergoing surgical resection. However, the role of individual immune cells may vary according to histological subtype. Prospective research should continue to assess the association of the immune cell composition of the TME with clinical outcomes.

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    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA07.10 - The Influence of Sex on Immunotherapy Efficacy in Non-Small Cell Lung Cancer (Now Available) (ID 712)

      13:30 - 15:00  |  Author(s): Rajwanth Veluswamy

      • Abstract
      • Presentation
      • Slides

      Background

      Patient’s sex impacts clinical outcomes for multiple cancers, including non-small cell lung cancer (NSCLC). A recent meta-analysis demonstrated sex may also impact response to novel immunotherapeutic agents, where men appear to derive greater benefit than women. However, the role of important clinical confounders of immunotherapy response that differ according to sex was not accounted for. The aim of this project was to investigate the effect of sex on immunotherapy benefit for NSCLC patients using a large, nationally representative database while adjusting for important clinical confounders.

      Method

      Advanced metastatic NSCLC patients diagnosed between 2013-2015 were identified in the National Cancer Database (NCDB). A Cox Proportional Hazards model was used to assess the interaction between sex and immunotherapy treatment for overall survival. This model was also adjusted for histology, stage, age, race, tumor size, comorbidities and other treatment (i.e. chemotherapy, radiation).

      Result

      Of 103,525 advanced NSCLC patients, 69,120 (67%) had adequate follow-up information for survival analysis. Of these, 37,423 (54.1%) were males and 31,697 (45.9%) females; 4,012 patients received immunotherapy as first-course treatment. In the adjusted model, both males (Hazard Ratio [HR]adj: 0.77, 95% Confidence Interval [CI] 0.73-0.81) and females (HRadj: 0.80, 95% CI 0.76-0.85) receiving immunotherapy had improved survival compared to those not receiving immunotherapy. The interaction between sex and immunotherapy was not significant (p=0.2539) after adjusting for clinical variables. Among the covariates, younger age, adenocarcinoma histology, Black race, smaller tumor size, lower comorbidity score and additional cancer treatment (either chemotherapy or radiation) were independently associated with better survival (p<0.0001 for all comparisons).

      Conclusion

      Patient sex does not appear to affect the benefit of immunotherapy in advanced NSCLC patients after adjusting for potential clinical confounders. Other clinical factors may play a role in immunotherapy response and should be explored in future research.

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    P1.17 - Treatment of Early Stage/Localized Disease (ID 188)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.17-14 - Prognostic Value of Immune Cell Biomarkers in Surgically Resectable Non-Small Cell Lung Cancer: A Meta-Analysis (Now Available) (ID 2658)

      09:45 - 18:00  |  Author(s): Rajwanth Veluswamy

      • Abstract
      • Slides

      Background

      Immune cells within the tumor microenvironment (TME) play an important role in the development, progression and outcomes of non-small cell lung cancer (NSCLC). We conducted the first meta-analysis of studies assessing the role of individual immune cells in surgically resected stage I-III NSCLC to evaluate the prognostic value of immune cell biomarkers.

      Method

      PubMed was searched to identify eligible studies assessing clinical outcomes of surgically resected stage I-III NSCLC patients according to immune cell subsets: CD3+ T cells, CD4+ T Helper cells, CD8+ T cytotoxic cells, CD20+ B cells, FoxP3+T Regulatory cells, Natural Killer cells (CD56/CD57+), macrophages (CD68+), and Mast Cells. Meta-analysis was performed using a linear mixed-effects model to determine overall survival (OS) and disease free survival (DFS), and was reported according to whether or not the study adjusted for clinical covariates. I2 was used to assess heterogeneity across studies.

      Result

      42 articles (7,906 patients) were included in this analysis. Higher levels of CD20+ B cells were associated with better OS, while increased FoxP3+ T regulatory cells and Mast Cells were associated with worse OS in unadjusted studies. However, in studies adjusting for clinical variables, CD8+ T cytotoxic cells and Natural Killer cells were also found to be associated with improved OS, while mast cells no longer were significantly detrimental. CD20+ B cells were associated with better DFS in unadjusted studies; in adjusted studies, CD8+ T cytotoxic cells were associated with better survival and FoxP3+ T Regulatory cells were associated with worse survival, with CD20+ B cells no longer significantly associated survival. I2 did not show substantial heterogeneity between studies.

      Table 1: Meta-Analysis Survival Estimates

      OS

      DFS

      Biomarker

      Unadjusted HR (95% CI)

      N, Heterogeneity (%)

      Adjusted HR

      (95% CI)

      N, Heterogeneity (%)

      Unadjusted HR (95% CI)

      N, Heterogeneity (%)

      Adjusted HR

      (95% CI)

      N, Heterogeneity (%)

      CD3+

      T cells

      0.98

      (0.87-1.12)

      6 articles

      I2= 0.00

      0.71

      (0.37-1.37)

      3 articles

      I2= 0.00

      0.98

      (0.86-1.12)

      5 articles

      I2= 0.00%

      -------

      -------

      CD4+

      T Helper cells

      0.64

      (0.37-1.10)

      4 articles

      I2= 13.65

      0.80

      (0.50-1.28)

      4 articles

      I2= 0.00

      0.72

      (0.39-1.32)

      3 articles

      I2= 0.00%

      0.59

      (0.11-3.12)

      1 article

      CD8+

      T Cytotoxic cells

      0.99

      (0.95-1.04)

      14 articles

      I2= 0.00

      0.71

      (0.52-0.96)

      12 articles

      I2= 20.95

      0.94

      (0.77-1.16)

      8 articles

      I2= 16.65%

      0.60

      (0.41,-0.87)

      9 articles

      I2= 20.43%

      CD20+

      B cells

      0.45

      (0.22-0.93)

      5 articles

      I2= 52.29

      0.16

      (0.04-0.64)

      1 article

      0.57

      (0.33,-1.00)

      4 articles

      I2= 0.00%

      0.51

      (0.20-1.32)

      1 article

      FoxP3+

      T Regulatory cells

      1.78

      (1.20-2.64)

      9 articles

      I2= 14.93

      2.38

      (1.56-3.65)

      6 articles

      I2= 0.00

      1.45

      (0.81-2.59)

      3 articles

      I2= 0.00%

      2.07

      (1.10-3.90)

      3 articles

      I2= 0.00%

      Natural Killer cells

      0.66

      (0.35-1.25)

      3 articles

      I2= 13.63

      0.50

      (0.26-0.95)

      4 articles

      I2= 0.00

      1.35

      (0.39-4.66)

      1 article

      0.59

      (0.27-1.28)

      2 articles

      I2= 0.00%

      Macrophages

      1.11

      (0.65-1.90)

      5 articles

      I2= 18.11

      1.04

      (0.69-1.55)

      6 articles

      I2= 0.00

      -------

      -------

      1.88

      (0.87-4.08)

      4 articles

      I2= 43.97%

      Mast Cells

      1.81

      (1.01-3.15)

      3 articles

      I2=0.00

      2.01

      (0.88-3.92)

      3 articles

      I2=43.99

      2.30

      (1.20-4.70)

      1 article

      1.50

      (0.60-3.60)

      1article

      HR= Hazard Ratio, CI = Confidence Interval

      Conclusion

      Immune cell subsets are able to provide prognostic information in early-stage NSCLC undergoing surgical resection. When evaluating these immune biomarkers, adjustment for clinical covariates can have a profound impact on survival estimates.

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    P2.17 - Treatment of Early Stage/Localized Disease (ID 189)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.17-11 - Evaluating PD-L1 as a Prognostic Biomarker in Surgically Resectable Non-Small Cell Lung Cancer (ID 1959)

      10:15 - 18:15  |  Author(s): Rajwanth Veluswamy

      • Abstract

      Background

      Identifying biomarkers that can predict which early stage non-small cell lung cancers (NSCLCs) are likely to recur following surgical resection is critical to improving survival outcomes. Programmed Cell Death Ligand-1 (PD-L1) is an immune regulatory protein expressed on tumor cells that inhibits T effector response against tumors. Therefore, high PDL-1 expression on tumor cells may enable evasion of the anti-tumor response and be associated with worst outcomes. We conducted a meta-analysis to determine if PDL-1 expression is associated with survival in surgically resected early stage NSCLCs.

      Method

      PubMed was searched to identify eligible studies comparing survival of surgically resected stage I-III NSCLC patients according to PD-L1 tumor expression. Included studies were grouped according to measurement criteria of PDL-1 expression: 1%, 5%, 50% cutoffs or as a continuous variable expressed as H-score. The latter is calculated from the percentage of cells expressing PDL1 multiplied by the intensity of staining. Meta-analysis was performed using a linear mixed-effects model to determine overall survival (OS). I2 was used as a measure of heterogeneity across studies.

      Result

      Of the 519 articles queried, 31 articles met eligibility criteria, accounting for 6,713 patients. Nine studies (n=2,407) used H score, where higher PD-L1 expression was associated with worse OS (hazard ratio [HR]meta: 1.68, 95% confidence interval [CI]: 1.17-2.41, I2= 15.45%). Five studies used a 1% cutoff (n=1,073), 14 studies reported using a 5% value (n=2,310) and 6 studies (n=1,572) used a 50% cutoff for evaluating high vs. low PD-L1 expression. PD-L1 expression was not statistically significantly associated with survival according to these cutoffs and there was high inter-study heterogeneity (HRmeta: 1.47, 95% CI 0.89-2.41; I2= 17.57%; HRmeta: 1.09, 95% CI 0.79-1.52; I2= 35.49%; HRmeta: 1.21, 95% CI 0.61-2.40; I2= 58.26% for 1%, 5%, 50%, respectively).

      Conclusion

      Higher PD-L1 expression in early stage NSCLCs as measured by H scores was associated with worse post-surgical survival. The measurement of PD-L1 expression as a continuous variable (i.e. H score) may provide more accuracy for predicting survival outcomes over percentage cutoffs. Future research is needed to validate PD-L1 expression as a predictive biomarker of survival for early-stage NSCLCs undergoing surgical resection.