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Jianjun Zhang



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    ES 04 - Biology of Lung Cancer (ID 513)

    • Event: WCLC 2017
    • Type: Educational Session
    • Track: Biology/Pathology
    • Presentations: 1
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      ES 04.03 - Tumor Heterogeneity (ID 7598)

      11:40 - 12:00  |  Presenting Author(s): Jianjun Zhang

      • Abstract
      • Presentation

      Abstract:
      Heterogeneity is a universal phenotype across different cancer types, including non-small cell lung cancer (NSCLC). Tumor heterogeneity is present not only between different tumors from different patients or within the same patients (inter-tumor heterogeneity), but also between different cells within the same tumor (intra-tumor heterogeneity, ITH). ITH results from tumor evolution and in the meanwhile servers as a substrate for tumor evolution. ITH may be influenced by the host antitumor immune surveillance as well as anticancer therapies. Delineating cancer evolution and ITH may provide pivotal insight to our understanding of cancer development, progression and therapeutic resistance, and may eventually help us design more effective preventive and therapeutic strategies. Pioneering studies by multi-region profiling and by comparing paired primary and relapsed tumors have shed light on cancer genomic evolution and suggested the potential impact of genomic ITH on cancer biology and patient outcome. Tracking Non-Small Cell Lung Cancer Evolution through Therapy (TRACERx) is by far the largest study on genomic ITH of NSCLC using multi-region sequencing approach. The results from the first 100 patients enrolled in TRACERx were recently published in the New England Journal of Medicine. In this elegant study, 327 tumor regions from 100 tumors were subjected to high-depth whole exome sequencing (WES). Extensive genomic ITH was demonstrated at both nucleotide and chromosomal levels: a median of 30% of somatic mutations and 48% of copy number alterations (CNAs) were subclonal. Early clonal mutations were associated with smoking signatures in the majority of tumors, while subclonal mutations were significantly enriched for genomic signatures related to spontaneous deamination of methylated cytosines and APOBEC suggesting different mutational mechanisms in play at different times during cancer progression. A high proportion of subclonal CNAs was associated with an increased risk of recurrence and shorter disease free survival (DFS). However, no significant association with DFS was observed between the groups when stratified by proportion of subclonal mutations. The rich data from TRACERx and previous studies are provocative for the future translational and clinical research. Herein, we outline some of the concepts. First, TRACERx provided another piece of evidence that genomic heterogeneity is associated with survival of patients with localized NSCLC. However, it is somewhat surprising that more commonly regarded ITH in point mutations was not found to be associated with survival in this patient cohort, which is in contrast with previous reports in NSCLC and other malignancies. Given the relative small sample size, short postsurgical follow up (median follow up of approximately 18 months with 80% patients less than 2 years) and only 20 relapses, any imbalance in major prognostic factors such as stage, age, histology, smoking, and adjuvant therapy may have masked an actual association between mutational ITH and survival. Our group has recently completed multi-region deep WES on 30 stage IA NSCLC -15 patients relapsed within 3 years post-surgery (cases) and 15 patients have not relapsed with a minimum of 5-year postsurgical follow up (controls). Cases and controls are matched for stage, tumor size, gender, age, histology, smoking history etc. and none of the patients received neoadjuvant or adjuvant therapy. In this well-balanced case-control study, higher degree of point mutation ITH was found to be associated with shorter overall survival and shorter DFS. Nevertheless, the association between CNA ITH and DFS reported in the TRACERx study remained significant after adjusting for known prognostic factors suggests that chromosomal ITH may have greater impact on patient outcome than somatic mutations. This is probably because gain or loss of chromosomal segments or even whole chromosomes could affect hundreds or thousands of genes that may thus disrupt multiple key molecular processes, while point mutations usually affect single genes or pathways. Second, subclonal driver mutations are often detected by multi-region sequencing, which introduces a challenge to our current personalized oncology approach based on sequencing driver genes from single biopsies. Multi-region sequencing is not practical for patients with metastatic diseases or unresectable tumors. However, ctDNA is not spatially limited to certain tumor regions and may have the advantage in detecting subclonal mutations compared to single biopsies. With the rapid progress being made in liquid biopsy and sequencing technologies, sequencing ctDNA could become a practical alternative for multi-region tumor sequencing. Third, majority of studies on NSCLC ITH are based on primarily resected tumors. How chemotherapy, targeted therapy, radiation or immune therapy would impact ITH architectures remains unknown. One can hypothesize that residual tumor cells that survive neoadjuvant therapies could represent the subclones resistant to the these therapies. Therefore, investigating the residual tumors post-neoadjuvant treatment may provide valuable information on mechanisms of drug resistance. As such, well-designed window-of-opportunity neoadjuvant clinical trials would be invaluable for studying drug resistance. Forth, in addition to serving as a potential prognostic biomarker, ITH itself could become a potential therapeutic target. Given the important role of genomic instability in tumor evolution, modulating genomic stability such as targeting APOBEC family, a common cause of subclonal diversification of NSCLC, or inhibiting DNA repair pathways could become a novel therapeutic strategy. This strategy has been recently highlighted by the efficacy of PARP inhibitors in homologous recombination-deficient tumors. Last but not least, the majority of studies on ITH have mainly focused on the genomic ITH. However, ITH can be present at different molecular levels (genetic, epigenetic, gene expression etc.) of cancer cells and also of tumor microenvironment constituting of epithelial cells, blood and lymphatic vessels, cytokines, infiltrating immune cells etc. ITH of any of these components may impact tumor evolution and patient outcome. Our pilot study has demonstrated that a higher level of methylation ITH was associated with larger tumor size, advanced patient age and increased risk of postsurgical recurrence in NSCLC patients. Furthermore, we recently reported substantial T cell repertoire ITH in NSCLC with the majority of T cell clones restricted to individual tumor regions and that a higher degree of T cell repertoire ITH was associated with an increased risk of postsurgical recurrence and shorter DFS. Tumor evolution is a complex process, during which cancer cells accumulate molecular alterations that change their phenotypic features by interacting with the tumor microenvironment. In order to systematically understand the tumor ITH and evolution, future studies are required to depict the overall molecular (genetic, epigenetic, gene and protein expression) ITH of cancer cells as well as the tumor microenvironment components, ideally from longitudinally collected samples with or without treatments to dissect the evolutionary history of NSCLC and other malignancies leading to novel diagnostic, preventive and therapeutic strategies.

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    MA 01 - SCLC: Research Perspectives (ID 650)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MA 01.03 - The Potential of ctDNA Sequencing in Disease Monitoring and Depicting Genomic Evolution of Small-Cell Lung Cancer Under Therapy (ID 9682)

      11:10 - 11:15  |  Author(s): Jianjun Zhang

      • Abstract
      • Presentation
      • Slides

      Background:
      Although small cell lung cancer (SCLC) is sensitive to initial therapy, almost all patients relapse and survival remains poor. Outgrowth of treatment-resistant subclones could be responsible for recurrence. However, genomic evolution of SCLC after treatment hasn’t been well investigated, partially due to the challenge of obtaining longitudinal samples. CT is the standard modality for response assessment and disease monitoring. But it doesn’t always accurately assess the disease status. SCLC is characterized by early hemagenous spread, which makes circulating tumor DNA (ctDNA) analysis a promising modality for genomic profiling and disease monitoring of SCLC.

      Method:
      Targeted-capture deep sequencing (mean target coverage 538x-1866x) of 545 cancer genes was performed to 44 ctDNA samples collected before therapy as baseline and at different timepoints during treatment from 23 SCLC patients. Pretreatment tumor biopsies from 8 patients were also sequenced (mean target coverage 348x-1281x) of the same gene panel. DNA from peripheral blood mononuclear cells was served as the germline control.

      Result:
      Mutations were identified in all 44 ctDNA samples with a median of 16 mutations per sample (average mutation burden of 6.6/Mb). TP53 and RB1 were the most frequently mutated genes, detected in 91% (21/23) and 65% (15/23) patients, respectively. 74 mutations were identified from the 8 tumor biopsies, among which, 69 (93.2%) were detected in matched ctDNA. We inferred subclonal architecture of each ctDNA sample based on cancer cell fraction derived using PyClone. A median of 10 (ranging 2-26) subclones was inferred from each ctDNA sample and only 17% (2% to 60.%) of mutations were clonal mutations suggesting substantial genomic heterogeneity. Single gene mutations were not associated with survival. However, mean variant allele frequency of clonal mutations (clonal-VAF) at baseline was associated with progression-free survival (PFS) and overall survival (OS) independent of stage, age, or platinum sensitivity. The median PFS of patients with higher versus lower than median clonal-VAF was 5.2 months (95% CI, 4.6 to 5.8 months) versus 10.0 months (95% CI, 9.3 to 10.7 months), p=0.002. The median OS was 8.1 months (95% CI, 5.5 to 10.7 months) versus 24.9 months (95% CI, 0.0 to 51.2 months) in patients with higher versus lower than median clonal-VAF, respectively, p=0.004. Analysis of serial ctDNA before and during treatment showed that clonal-VAF closely tracked closely with treatment responses.

      Conclusion:
      ctDNA sequencing is a promising modality for genomic profiling and disease monitoring for SCLC patients. Clonal VAF may be a better ctDNA metric than single gene mutations.

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    MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MA 05.02 - STK11/LKB1 Loss of Function Genomic Alterations Predict Primary Resistance to PD-1/PD-L1 Axis Blockade in KRAS-Mutant NSCLC (ID 10367)

      15:50 - 15:55  |  Author(s): Jianjun Zhang

      • Abstract
      • Presentation
      • Slides

      Background:
      The genomic landscape of primary resistance to PD-1 blockade in lung adenocarcinoma (LUAD) is largely unknown. We previously reported that co-mutations in STK11/LKB1 (KL) or TP53 (KP) define subgroups of KRAS-mutant LUAD with distinct therapeutic vulnerabilities and immune profiles. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS mutant and wild-type LUAD patients and examine the relationship between genetic alterations in individual genes, tumor cell PD-L1 expression and tumor mutational burden (TMB) using cohorts form the SU2C/ACS Lung Cancer Dream Team and Foundation Medicine (FM).

      Method:
      The cohorts included 924 LUAD with NGS (FM cohort) and 188 patients with KRAS non-squamous NSCLC (SU2C cohort) who received at least one cycle of PD-1/PD-L1 inhibitor therapy and had available molecular profiling. Tumor cell PD-L1 expression was tested using E1L3N IHC (SU2C) and the VENTANA PD-L1 (SP142) assay (FM). TMB was defined as previously described and was classified as high (TMB-H), intermediate (TMB-I) or low (TMB-L).

      Result:
      188 immunotherapy-treated (83.5% nivolumab, 11.7% pembrolizumab, 4.8% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant NSCLC were included in the efficacy analysis. The ORR differed significantly between the KL (8.8%), KP (35.9%) and K-only sub-groups (27.3%) (P=0.0011, Fisher’s exact test). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 2.7m, HR=0.53, 95% CI 0.34-0.84, P<0.001, log-rank test) and OS (mOS 6.8m vs 15.6m, HR 0.53, 95% CI 0.34 to 0.84, P=0.0072, log rank test) compared to KRAS-mutant NSCLC with wild-type STK11. Loss-of function (LOF) genetic alterations in STK11 were the only significantly enriched event in PD-L1 negative, TMB-I/H compared to PD-L1 high positive (TPS≥50%), TMB-I/H tumors in the overall FMI cohort (Bonferroni adjusted P=2.38x10[-4], Fisher’s exact test) and among KRAS-mutant tumors (adjusted P=0.05, Fisher’s exact test) . Notably, PD-1 blockade demonstrated activity among 10 PD-L1-negative KP tumors, with 3 PRs and 4SDs recorded. In syngeneic isogenic murine models PD-1 blockade significantly inhibited the growth of Kras mutant tumors with wild-type LKB1 (K), but not those with LKB1 loss (KL), providing evidence that LKB1 loss can play a causative role in promoting PD-1 inhibitor resistance.

      Conclusion:
      Loss of function genomic alterations in STK11 represent a dominant driver of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant NSCLC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the STK11 status of individual tumors.

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    OA 07 - Biomarker for Lung Cancer (ID 659)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      OA 07.02 - Characteristics of Lung Cancer Cell-Free Tumor DNA (CfDNA) Shedding and Correlation with Tumor Burden as Measured by RECIST (ID 9663)

      15:55 - 16:05  |  Author(s): Jianjun Zhang

      • Abstract
      • Presentation
      • Slides

      Background:
      cfDNA is a promising biomarker for early recurrence detection and disease monitoring in the NSCLC curative setting. However, less is known about cfDNA shedding characteristics and correlation with tumor burden in advanced NSCLC.

      Method:
      We reviewed cfDNA results of NSCLC patients tested at our institution between November 2015 and December 2016 with Guardant 360, a comprehensive cfDNA assay that detects genomic alterations in 70-73 cancer genes. 141 cases with evaluable imaging were selected for this analysis, enriching for EGFR and KRAS mutated cases to facilitate comparisons of major genomic subtypes (Table 1). Tumor burden was approximated using the sum of longest diameters (SLD), per RECIST v1.1.

      Result:
      There was a statistically significant correlation of moderate strength between cfDNA maximum variant allele frequency (VAF) detected and SLD (Spearman’s rho = 0.35, p < 0.001). This correlation was strongest in KRAS mutant cases (rho = 0.52, p = 0.001) and weakest in EGFR mutated tumors (rho = 0.21, p < 0.24). Multi-variate regression that included stage, histology, and mutation status confirmed the predictive value of cfDNA VAF for SLD (p = 0.03). TP53 mutants had higher cfDNA VAF (Wilcox p < 0.001), even after accounting for SLD. Increased cfDNA VAF was also seen with EGFR mutants and patients with visceral metastasis, though possibly confounded by concomitant EGFR amplification and increased tumor burden, respectively. CNS metastasis was not associated with differential cfDNA shedding. Figure 1



      Conclusion:
      In this primarily metastatic cohort, cfDNA VAF correlated with radiographic assessment of tumor burden by RECIST. This correlation was partially mediated by the presence of key driver mutations. TP53 and EGFR mutant tumors and the presence of visceral metastasis are associated with higher cfDNA VAF. These findings have potential implications for the use of cfDNA in advanced-stage NSCLC disease monitoring, where RECIST is more clinically applicable than formal volumetrics.

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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)

      11:45 - 11:55  |  Author(s): Jianjun Zhang

      • 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)

      11:45 - 11:55  |  Author(s): Jianjun Zhang

      • 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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    P2.02 - Biology/Pathology (ID 616)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 2
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      P2.02-013 - Investigation of Genomic and TCR Repertoire Evolution of AAH, AIS, MIA to Invasive Lung Adenocarcinoma by Multiregion Exome and TCR Sequencing (ID 9192)

      09:30 - 09:30  |  Presenting Author(s): Jianjun Zhang

      • Abstract
      • Slides

      Background:
      Carcinogenesis may result from accumulation of molecular aberrations (molecular evolution) and escaping from host immune surveillance (immunoediting). It has been postulated that atypical adenomatous hyperplasia (AAH) represents preneoplastic lesion that may progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). However, due to lack of appropriate study materials, the molecular and immune landscape of AAH, AIS or MIA have not been well studied and the definition and management of these lesions remain controversial.

      Method:
      With the intent to delineate the pivotal molecular and immune events during early carcinogenesis of lung adenocarcinoma, we have collected 119 resected pre- and early neoplastic lung lesions including AAH (N=24), AIS (N=27), MIA (N=54) and ADC (N=14) from 53 patients including 41 patients presenting with multifocal lesions and 25 patients carrying more than one type of pathology. Two to five spatially separated regions from each lesion were subjected to whole exome sequencing and T cell receptor sequencing.

      Result:
      Mutation burden (average SNVs) was found to progressively increase from 1.32/Mb in AAH to 2.55/MB in AIS, 5.42/MB in MIA and 15.38/MB in ADC. Genomic heterogeneity has also become more complex with neoplastic progression with mean Shannon index of 1.53 in AAH, 1.78 in AIS, 1.56 in MIA and 1.79 in ADC. An increase in C>A transversions coincident with a decrease in A>G transitions and progressively increasing APOBEC enrichment scores (4.13 in AAH, 5.63 in AIS, 6.02 in MIA and 6.59 in ADC) were observed with neoplastic disease progression. Furthermore, phylogenetic analysis revealed varying evolutional processes in AAH, AIS, MIA and ADC with canonical cancer gene mutations in KRAS, ATM, TP53 and EGFR etc. as key drivers in a subset of patients. TCR sequencing demonstrated a progressive decrease in T cell density (average percent T cells among all nuclear cells: 12% in AAH, 8% in AIS, 7% in MIA and 4% in ADC) and a progressive decrease in productive TCR clonality (average productive TCR clonality: 0.0434 in AAH, 0.0427 in AIS, 0.0399 in MIA and 0.0395 in ADC) suggesting suppressive T cell repertoire in more advanced diseases.

      Conclusion:
      Our results provide molecular evidence supporting the model of early lung carcinogenesis from AAH, to AIS, MIA and ADC and demonstrated that with disease progression, genomic landscape of lung neoplastic lesions has become progressively more complex along with progressive immunosuppressive TCR repertoire.

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      P2.02-041 - Update on Prospective Immunogenomic Profiling of Non-Small Cell Lung Cancer (ICON Project) (ID 10156)

      09:30 - 09:30  |  Presenting Author(s): Jianjun Zhang

      • Abstract
      • Slides

      Background:
      Given the rapidly changing therapeutic landscape for non-small cell lung cancer (NSCLC), a thorough understanding of the tumor immune environment is critical to the appropriate selection of patients and testing of immuno-oncology agents. We established a project aimed at defining the comprehensive and integrated immunogenomic landscape in NSCLC, including immune, genomic and clinical data from 100 surgically resected lung cancers.

      Method:
      Tissue samples were collected at the time of surgery, and blood samples before and after surgery up to 1-year. Tissue samples were subjected to tumor infiltrating lymphocyte (TIL) isolation and expansion; generation of PDX models,WES and in-silico neoantigen prediction, RNA sequencing, RPPA, CyTOF, T cell receptor sequencing, and multiplex immunofluorescence evaluation of immune cells and markers. Blood samples were processed for cfDNA, microRNA, and cytokine profiling.

      Result:
      93 out of 131 enrolled patients with median age 67 years contributed samples to ICON; 44% males, 80% former smokers, 12% never smokers. Majority had adenocarcinoma (60%) and 26% SCC. 37 (40%) had stage I, 29 (31%) stage II, and 20 (22%) stage III disease; 14 patients received neoadjuvant chemotherapy. Median tumor size was 4.0cm and 79 (85%) underwent R0 and 9 (10%) R1 resection. TIL expansion was 68% successful. Phenotypic and functional analysis of TIL is ongoing. Preliminary analysis show suppression of intratumoral CD8[+] cells with low perforin levels and high CD8[+]PD1 levels as compared to normal tissue; however tumor CD8[+]CD28 co-stimulatory molecule expression was high. PDX success rate is 35%. IHC analyses show higher CD8[+]PD1, CD3, CD8[+]BTLA expression in SCC than in adenocarcinoma or normal tissue. WES and RNA sequencing show that median mutation burden is 9.3/MB in adenocarcinomas and 11.2/MB in SCC. Other immunogenomic analyses are in process.

      Conclusion:
      The ICON is an ambitious multi-team project designed to integrate multiple levels of tumor related data. Preliminary analysis demonstrates the project to be feasible, with a high rate of prospective sample acquisition. Tumor profiles from ICON will serve as a reference for upcoming neoadjuvant single and dual checkpoint immunotherapy trials. ICON Team: A. Weissferdt, A. Vaporciyan, A. Futreal, T. Karpinets, C. Yee, C. Haymaker, L. Federico, M.-A. Forget, G. Lizee, A. Talukder, J. Roszik, H. Tran, M. Vasquez, E. Prado, C. Behrens, E. Parra, J. Rodriguez-Canales, J. Fujimoto, L. Vence, J. Roth, I. Meraz, E. Roarty, L. Lacerda, L. Byers, S. Swisher, W. William Jr., P. Sharma, J. Allison, B. Fang, H. Wagner, E. Bogatenkova, I. Wistuba, J. Heymach and C. Bernatchez

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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 - 09:30  |  Author(s): Jianjun Zhang

      • 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
    • +

      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 - 09:30  |  Author(s): Jianjun Zhang

      • 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.