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E. Roarty



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    OA 09 - EGFR TKI Resistance (ID 663)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 09.05 - Identification of Novel Potentially Targetable Genomic Alterations in Paired Tumors with Acquired EGFR TKI Resistance by NGS (ID 9088)

      11:00 - 12:30  |  Author(s): E. Roarty

      • Abstract
      • Presentation
      • Slides

      Background:
      While previous reports have established MET and HER2 amplification as two mechanisms of non-T790M driven EGFR TKI resistance in EGFR mutant NSCLC, resistance occurs in the absence of these modifications in a significant number of patients. Therefore, there exists an unmet need to define additional mechanisms of resistance to EGFR TKIs. We hypothesized that targeted next-generation sequencing could detect additional targetable activating mutations in paired tumor samples from patients with acquired resistance to first or second generation EGFR TKIs.

      Method:
      We conducted an analysis of clinical and molecular data prospectively collected from 285 EGFR-mutant NSCLC patients enrolled into the MD Anderson Lung Cancer GEMINI database. Of 157 patients treated with first-line therapy (erlotinib, gefitinib, or afatinib), we identified 75 patients with TKI-acquired resistance with matched pre/post-TKI tumor samples. Matched tumor samples were analyzed with targeted gene sequencing. Recurrent alterations were defined as an alteration occurring more than 2 times. Recurrent acquired mutations were expressed in Ba/F3 and EGFR mutant (T790M+/-) NSCLC cells. Mutation expressing Ba/F3 cell lines were assayed for IL-3 independence, and mutation expressing NSCLC cell were screened against combination targeted TKIs.

      Result:
      EGFR mutant NSCLC patients treated with first-line therapy had a median PFS of 14 months; and, of the patients with pre/post-TKI tumor molecular data, 47% of patients were T790M negative. There were 30 recurrent acquired alterations identified in 13 different genes. Genes included ARAF, BRAF, EGFR, FGFR, GNAS, JAK2, MCL1, PDGFRα, PIK3CA, RAF1, RB1, SMAD4, and TP53. Of the alterations identified, most occurred in 1 of 4 targetable genes: BRAF (N=3), FGFR (N=5), PDGFRα (N=3), or PIK3CA (N=2). Both previously reported and novel mutations were identified, and preliminary screening of mutant expressing Ba/F3 cell lines found that of the mutations tested (BRAF WT & G469H, FGFR2 A371G, PDGFRα WT & L682F, and PIK3Ca E545K) all grew independent of IL-3. HCC827 and H1975 cell lines expressing acquired mutations in BRAF, FGFR, PDGFRα, or PIK3CA were more sensitive to combination targeted therapy compared to EGFR TKIs or mutation specific TKIs alone unlike control cell lines, supporting the possibility that targeting these mutations would be of therapeutic benefit.

      Conclusion:
      Analysis of patient data identified 30 recurrent genomic alterations in 13 different genes including novel alterations in BRAF, EGFR, FGFR, PDGFRα, RB1, and SMAD4, many of which were found to be activating mutations. Our analysis identified potentially targetable mutations of BRAF, FGFR, PDGFRα, and PIK3CA which merits further pre-clinical and clinical investigation.

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    OA 13 - Immuno-Biology (ID 677)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      OA 13.05 - Immune, Molecular and T Cell Repertoire Landscape of 235 Resected Non-Small Cell Lung Cancers and Paired Normal Lung Tissues (ID 8766)

      11:00 - 12:30  |  Author(s): E. Roarty

      • Abstract
      • Presentation
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types responding to immune checkpoint blockade, likely through harnessing of the anti-tumor T cell response. However, the lung is continuously exposed to the outside environment, which may result in a continuous state of inflammation against outside pathogens unrelated to the tumor microenvironment. Therefore, further investigation into the T cell repertoire and T cell phenotypes across normal lung and tumor is warranted.

      Method:
      We performed T cell receptor (TCR) sequencing on peripheral blood mononuclear cells (PBMC), normal lung, and tumor from 225 NSCLC patients, among which, 96 patients were also subjected to whole exome sequencing (WES) of PBMC, tumor and normal lung tissues. We further performed Cytometry by Time-of-Flight (CyTOF) on 10 NSCLC tumors and paired normal lung tissues to phenotype immune and T cell subsets.

      Result:
      Comparison of the T cell repertoire showed 9% (from 4% to 15%) of T cell clones were shared between normal lung and paired tumor. Furthermore, among the top 100 clones identified in the tumor, on average 57 (from 0 to 95) were shared with paired normal lung tissue. Interestingly, T cell clonality was higher in the normal lung in 89% of patients suggesting potential differences in the immune response and immunogenicity. A substantial number of somatic mutations were also identified not only in NSCLC tumors (average 566; from 147 to 2819), but also in morphologically normal lung tissues (average 156; from 50 to 2481). CyTOF demonstrated striking differences in the immune infiltrate between normal lung and tumor, namely a lower frequency of PD-1+CD28+ T cells (both CD4+ and CD8+) in the normal lung (2.7% versus 3.0% in tumor). In addition, a unique GITR+ T cell subset (0.96%) was entirely restricted to the normal lung. Conversely, increases in regulatory T cell frequency (CD4+FoxP3+) were observed in the tumor (10.4% vs 1.7% in normal lung), further highlighting the differences in T cell phenotype and response across normal lung and tumor.

      Conclusion:
      These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be residential T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes including increases in immunosuppressive T cells within the tumor which may further highlight the differences in the anti-tumor immune response.

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    P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P2.04-014 - Computing the Impact of Immunotherapy on NSCLC Landscape: The Advanced Non-Small Cell Lung Cancer Holistic Registry (ANCHoR)  (ID 9505)

      09:30 - 16:00  |  Author(s): E. Roarty

      • Abstract

      Background:
      Anti-PD-1 and anti-PD-L1 antibodies including pembrolizumab, nivolumab and atezolizumab have entered clinical practice in the management of metastatic NSCLC as monotherapy and immunotherapy-based combinations. We have established a real-world Advanced Non-Small Cell Lung Cancer Holistic Registry (ANCHoR) to understand how the emergence of immunotherapy impacts choice of treatment, clinical outcomes, and patient reported outcomes (PROs) in the different histo-molecular subtypes of metastatic NSCLC. The objectives of ANCHoR are to determine the treatment choice and treatment sequence by PD-L1 status in the various histo-molecular categories of NSCLC and to understand the impact of such treatment choice on response rates, progression-free survival (PFS), and overall survival (OS). Additionally we will measure the impact the treatment choices have on the PROs by utilizing the validated instruments, EuroQol-5D version 5L (EQ-5D-5L) and MD Anderson Symptom Inventory module specific to lung cancer (MDASI-LC).

      Method:
      The study will enroll patients with metastatic NSCLC diagnoses who are treated at MD Anderson Cancer Center (MDA) between January 1, 2017 and December 31, 2020. The study period will end on June 30, 2021 to allow a minimum of six months of follow-up. Trained abstractors will collect demographic, diagnostic, clinical, molecular (biomarker and PD-L1), treatment (regimens utilized in sequence and reason for discontinuation), response and survival (including PFS and OS), health care resource utilization and PRO (EQ-5D-5L and MDASI-LC) information that will be integrated in a comprehensive database. Information from the MDA electronic medical record will be extracted and populated in the GEnomic Marker-guided therapy INItiative (GEMINI) database and the PRO database which are linked. EQ-5D-5L followed by MDASI-LC will be completed directly by the patients and these will be automatically populated in the web-based PRO database at treatment initiation, at the time of response assessments and when switching lines of therapy.

      Result:
      Interim analysis will be conducted every six months to measure the impact of immunotherapy over time. Study results will be presented using descriptive statistics for continuous variables (mean, standard deviation, median, and interquartile range), categorical variables (frequency and proportions), and time-to-event variables (Kaplan-Meier). Regression models will be used for estimating the relationship between dependent variable and one or more predictors. Cox proportional hazards model will be used to estimate hazard ratios for time-to-event outcomes.

      Conclusion:
      The ANCHoR study is the first comprehensive registry of its kind that will enable the quantification of the changing impact of immunotherapy on the real-world NSCLC treatment landscape.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-062a - Single Institutional Experience of the Use of PD-1 Inhibitors to Non-Small Cell Lung Cancer Patients with Preexisting Autoimmune Diseases (ID 10307)

      09:30 - 16:00  |  Author(s): E. Roarty

      • Abstract

      Background:
      Safety of PD-1/PD-L1 pathway inhibitors in patients with preexisting autoimmune disease is not well defined since these patients are generally excluded from immunotherapy trials. In this study we aimed to provide our institutional experience for the safety of PD-1 inhibitors in NSCLC patients with a history of autoimmune diseases.

      Method:
      In a retrospective study we collected genomic, demographic, clinical and pathologic data from patients with a history of autoimmune disease who received PD-1 inhibitors for their stage IV NSCLC as standard of care at MD Anderson Cancer Center (MDACC). Qualifying autoimmune diseases included autoimmune thyroiditis, rheumatologic, neurologic and dermatologic autoimmune conditions.

      Result:
      Between March 2016 and February 2017, 975 NSCLC patients were treated with PD-1 inhibitors, as standard of care at MDACC and 14 of those patients had preexisting autoimmune disease (5 rheumatoid arthritis, 3 seronegative arthritis, 3 psoriasis, 2 hashimoto thyroiditis, and 1 polymyalgia rheumatica). Three patients experienced flare of the autoimmune disease (2 psoriasis, and 1 rheumatoid arthritis) while on therapy and two of those patients were symptomatic from their preexisting autoimmune disease prior to the treatment. Median duration of exposure to therapy prior to flare was 21.4 weeks (range 7-48 weeks). These patients did not require treatment break or steroid use for autoimmune disease flare. 35% (5/14) of patients developed at least one immune related adverse effect (irAEs, one grade 2 and four grade 3) unrelated to the underlying autoimmune disease. There were no grade 4-5 irAEs observed. Updated results from larger patient cohort will be reported at the conference.

      Conclusion:
      In our single center experience, symptomatic flare of underlying autoimmune diseases was uncommon. However, patients with history of immune disease may be at higher risks for immune related toxicities during therapy with PD-1 pathway inhibitor. Further studies are needed to identify the safety profile of the PD-1 directed therapies in patient subsets with preexisting autoimmune diseases.

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    P3.03 - Chemotherapy/Targeted Therapy (ID 719)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P3.03-027 - LKB1 Loss Is Associated with Resistance to Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer Mouse Models (ID 10259)

      09:30 - 16:00  |  Author(s): E. Roarty

      • Abstract

      Background:
      LKB1 is a protein kinase that is mutated and down-regulated in 20-30% of non-small cell lung cancer (NSCLC). LKB1 mutations co-occur with KRAS alterations in 7%-10% of NSCLC, resulting in an aggressive phenotype with short survival. Because LKB1 activates AMPK, the master sensor of cellular energy, many of the best known functions of LKB1 are attributed to its ability to control metabolic alterations in the cells. However LKB1 also plays an important role in regulating angiogenesis, likely as a strategy to overcome energetic depletion of tumor microenvironment. Bevacizumab, the human anti-VEGF antibody, improves the PFS and OS of NSCLC patients combined with chemotherapy, but often the benefit is transient and therapeutic resistance occurs. Our laboratory has previously identified alterations in cell metabolism and in vasculature of LKB1-deficient tumors when compared to LKB1 wild type in NSCLC.

      Method:
      LKB1 KO murine NSCLC cell lines were generated using CRISPR/Cas9 system in a KRAS[G12D] mutant background (LKR10 & LKR13). Syngeneic NSCLC models were established via s.c. injection of LKB1 intact and KO murine cells in immunocompetent mice. After tumors reached 150 mm[3] mice were randomly assigned to treatment groups consisting of vehicle, mouse anti-VEGF and nintedanib. Tumor volumes were measured and compared using student’s t test and samples were collected for vasculature analysis. Survival curves will be calculated using log rank test. Hypoxia experiments were preformed and apoptosis was measured using annexin V and 7ADD staining.

      Result:
      Treatment with anti-VEGF or nintedanib significantly inhibited tumor progression in LKB1 wt KRAS[G12D] mutant mouse model (p<0.001) but did not show any therapeutic effect in the LKB1 KO KRAS[G12D] group. Furthermore in the LKB1 wt group, the median survival of anti-VEGF and nintedanib treated mice was 111 days and 84 days respectively and 37 days in the vehicle group. No improvement in survival was detected in the LKB1 KO group after treatment with anti-VEGF. In vitro studies showed that LKB1 loss is associated with a decrease in oxygen consumption and enhanced glycolysis. Furthermore LKB1 KO NSCLC cells showed a decrease in apoptosis under hypoxic and low nutrient conditions compared to LKR13 LKB1 wt cells.

      Conclusion:
      NSCLC LKB1-deficient tumors showed resistance to anti-angiogenic therapy and this effect is driven by the regulation of metabolic adaptations that allow cells to survive under hypoxic and low nutrient conditions.