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C. Aggarwal

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    MINI 26 - Circulating Tumor Markers (ID 148)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 14
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      MINI26.02 - Deep Sequencing Reveals the Significance of Plasma DNA Concentration and Mutational Burden in Advanced Non-Small-Cell Lung Cancer Patients (ID 1409)

      04:45 - 04:50 PM  |  Author(s): S. Hong, L. Zhang, Y. Wang, W. Fang, Y. Huang, H. Zhao, Y. Zhao, C. Xue, Y. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      Plasma cell-free DNA (cfDNA) contains genetic information from primary and metastatic cancer foci. We utilized multiplex deep sequencing technology to investigate the clinical significance of cfDNA concentration and mutational burden in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors (TKIs).

      Methods:
      Between January 2012 and February 2014, seventy-one eligible patients from Sun Yat-sen University Cancer Center were enrolled. All the patients provided written informed consent and donated 2 ml plasma before taking EGFR-TKIs. Plasma DNA was isolated and purified using QIAamp Circulating Nucleic Acid Kit. CfDNA concentration was determined by Qubit Fluorometer. A set of 234 primer pairs were designed to amplify sequences covering hotspots of 35 genes. The amplicon libraries were prepared and entered into deep sequencing on Ion Torrent PGM chip. Variants were called by established bioinformatics methods. Circulating DNA mutational burden was defined as the number of somatic variants other than EGFR mutations. Objective response rate (ORR) and disease control rate (DCR) between different groups were compared using Fisher’s exact test while progression-free survival (PFS) and overall survival (OS) between different groups were compared by Kaplan-Meier curves and log-rank tests. Multivariate stepwise Cox regression analyses were performed to identify independent prognostic factors.

      Results:
      Forty-nine out of 71 patients were observed to harbor at least one variant and at most 7 variants, involving 10 genes (totally 124 variants). Higher cfDNA concentration was associated with impaired DCR (18.6% vs 81.4%; p=0.008), PFS (median PFS, 3.5 vs 15.2 months; HR=3.03; p=0.001) and OS (median OS, 27.3 vs not-reached; HR=2.38; p=0.042) compared with low cfDNA concentration group. Higher mutational burden was associated with unfavorable ORR (31.6% vs 73.7%; p=0.004) and PFS (median PFS; 8.6 vs 17.8 months; HR=1.61; p=0.050) compared with low mutational burden group. EGFR mutation conferred better ORR, DCR and PFS compared with EGFR wild-type (Figure 1). Multivariate analyses revealed that apart from EGFR mutation status, cfDNA concentration and mutational burden were also associated with the efficacy and/or the prognosis of EGFR-TKIs.Figure 1



      Conclusion:
      We for the first time showed that cfDNA concentration and mutational burden might influence the efficacy and prognosis of patients receiving EGFR-TKIs. These findings call for the need for the multiplex genetic analysis of patients’ cfDNA to tailor their treatment.

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      MINI26.03 - Detecting C-MET Amplification in Blood and Tumor Tissue of Non-Small Cell Lung Cancer (ID 143)

      04:50 - 04:55 PM  |  Author(s): M. Fang, C. Xu

      • Abstract
      • Slides

      Background:
      To detect the consistency of the c-MET gene amplification in peripheral blood and tumor tissue of patients with non small cell lung cancer and discuss the clinical application value of c-MET gene amplification in peripheral blood.

      Methods:
      Real-time fluorescent quantitative PCR was used to test the tissues in 257 patients of non small cell lung cancers and the peripheral blood samples in 318 patients of non small cell lung cancer, of which 185 cases of peripheral blood specimens could match the tissue samples, and detected the c-MET gene amplification in them by comparison of amplifications consistency in blood and tissue samples, and analysed the correlation between c-MET gene amplification and clinical characteristics of patients.

      Results:
      The c-MET gene amplification rate was 9.75% in peripheral blood of 31 patients with non small cell lung cancer,and was 8.95% in 23 cancer tissues, the amplification consistency was 81.25% in peripheral blood-tumor tissue matched samples. The difference was statistically significant (P<0.05).

      Conclusion:
      The consistency of the c-MET gene amplification in peripheral blood and tissue is high. c-MET gene amplification of peripheral blood could be used for clinical diagnosis and treatment in cases when tissue specimen is hard to get.

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      MINI26.04 - Discussant for MINI26.02, MINI26.03 (ID 3376)

      04:55 - 05:05 PM  |  Author(s): R. Salgia

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI26.05 - Immunophenotyping of Circulating T Cells and TILs with Chemotherapy and Phased Ipilimumab in Non-Small Cell Lung Cancer (ID 2787)

      05:05 - 05:10 PM  |  Author(s): F. Dunphy, J. Yi, M. Onaitis, R. Osborne, D. Harpole, J. Crawford, T. D'Amico, K. Weinhold, N. Ready

      • Abstract
      • Presentation
      • Slides

      Background:
      Ipilimumab (Ipi) is a humanized CTLA-4 antibody that blocks binding of CTLA-4 with its cognate ligands, permitting T cell activation through CD28 binding. There is evidence that phased in Ipi added to chemotherapy (C) may enhance efficacy in non-small cell lung cancer NSCLC. This trial was undertaken to gain a better understanding of the changes that occur in T cells, regulatory T cells (Tregs), and myeloid-derived suppressor (MDSC) in both the blood and tumor micro-environment with CTLA-4 blockade.

      Methods:
      Patients with stage T > 4 cm and/or N1, N2 NSCLC were offered neoadjuvant carboplatin AUC6 plus paclitaxel 200 mg/m[2] every 21 days 3 cycles with ipilimumab 10 mg/kg day 1 cycles 2 and 3. Blood for immune profiling of circulating T cells was collected prior to cycle 1, after cycle 1 chemotherapy alone, and after cycle 3 chemotherapy plus Ipi. If patients underwent tumor resection and excess tumor was available, viable tumor infiltrating lymphocytes (TILS) were disaggregated and stored for later analysis. Phenotypic and functional polychromatic flow cytometry (PFC) analyses were performed on peripheral blood mononuclear cells (PBMC).

      Results:
      Blood was successfully collected at all 3 time points for the first 17/18 patients who initiated trial therapy. Excess tumor (0.96-5 gms) was collected on 5 patients and ample viable CD45+ TIL cells (9.4-26x10[6]) were isolated and viably cryopreserved. Phenotypic analyses revealed that both CD4+ and CD8+ cells from all 17 patients were highly activated following two cycles of ipilimumab (cycle 3) as evidenced by greatly increased frequencies of CD28, HLA-DR, PD-1, and intracellular CTLA-4 expressing cells. The frequencies of Tregs, defined by CD4+CD25+FoxP3+ expression, were highly variable among the 17 participants, with 8 showing increased Tregs, 7 showing decreased frequencies, and 2 remaining unchanged over the course of therapy. Seven of the 17 participants had levels of MDSC cells at or above 5%, with two patients achieving MDSC levels of 13% and 26.7%. Tumor associated antigen (TAA)-specific CD4+ or CD8+ cells were detected at baseline on 4 patients (24%), but their relative frequencies were unaltered by Ipi therapy. The most commonly recognized TAA was Survivin, followed by MAGEA3 and PRAME. No patients developed detectable de novo TAA reactivities while on Ipi therapy. We will report the phenotypic and functional parameters of TILs isolated from 5 tumors of the patients enrolled on the current trial at the time of presentation.

      Conclusion:
      TAA-specific CD4+ or CD8+ cells were unexpectedly detected in the blood at baseline in a subset of patients. We were able to determine what common NSCLC antigens the circulating CD4+ or CD8+ T cells were activated against, and this has the potential to be a blood based biomarker for trials studying immunotherapy such as vaccines. Neoadjuvant ipilimumab therapy neither facilitated the development of anti-TAA reactivities nor enhanced the frequencies of existing TAA-reactive T cells in PBMC. Neoadjuvant ipilimumab therapy effectively enhanced the frequencies of highly activated T cells, but had no consistent effect of the frequencies of Tregs.

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      MINI26.06 - Cytological Criteria Based in the Characterization of CTCs for Assessment the Response to Erlotinib (ID 2974)

      05:10 - 05:15 PM  |  Author(s): M.J. Serrano, J.M. Jurado, J. Valdivia, M. Mellado, J. Exposito-Fernandez, C. Bayarri, J.L. Garcia-Puche

      • Abstract
      • Presentation
      • Slides

      Background:
      During the past decade, circulating tumor cells (CTCs) have been accepted as new prognostic and predictive factors for some type of cancers. In non small lung cancer cells (NSCLC) their detection and characterization is especially important to identify treatment resistances that some patients develop. Here, we report the value of characterization of CTCs and established cytological criteria to assess a good response for EGFR- tyrosine-Kinase inhibitors

      Methods:
      From Feb 2012 to October 2014, 39 patients (median age 63 years) with metastatic lung cancer were included in this study. NSCL (26 Adenocarcinomas and 13 Squamous cell carcinoma) EGFR wild-type patients were being treated with second or higher lines therapies with erlotinib. 10 ml of blood were collected from each patient into a CellSave TM Preservatives Tubes (Veridex, LLC, Johnson & Johnson Company) blood collection tube, maintained at room temperature and processed within a maximum of 72 hr after collection according to the protocol established by our group .For CTCs enrichment from PBMCs we used “Carcinoma Cell Enrichment and Detection kit: MACS technology (Miltenyi Biotechnology), using magnetic beads labeled with a multi-CK-specific. After isolation of CTCs, samples containing CTCs CK+ were stained for EGFR in double immunofluorescence (IF) experiments, following our standard protocol.The assessment of treatment was evaluated by histological criteria (CyCaR: Cytological Criteria of assessment Response).This way, as favorable response was defined when the number of CTCS was reduced more than 50% at 6 or 12 weeks of starting erlotinib treatment

      Results:
      Before treatment 18/39 patients (46%) were identified as positive for CTC[CK+ ]with an average number of 3.5 cell (range 1-11); 9 of which were presented persistence of CTCs after treatment. 7/ 18 patients positive for the presence of CTC[CK + ]were positive to presence EGFR marker (CTC[CK+ /EGFR +).]. More important was, that we found A positive correlation between CTCs and survival: patients with CTC(CK+ /EGFR-) presented a shorter OS (34 vs 53 weeks) and PFS (13 vs 17 weeks) compared with those patients with CTC(CK+ /EGFR +) which responded favorably to erlotinib. Patients without cytological response criteria had a worse survival OS (28 vs 53 weeks, p=0.057) and PFS (11,5 vs 21,3 weeks, p=0.06).

      Conclusion:
      Our study suggests that the characterization of CTC based in the EGFR expression might be useful as a marker for the therapeutic selection and monitoring of lung cancer patients sensitive to treatment with inhibitors of tyrosin-kinase.

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      MINI26.07 - Circulating Tumor Cells (CTC) Enrichment as Liquid-Biopsy for Molecular and Genomic Characterization in ALK-Rearranged (ALK+) Lung Cancer (ID 3132)

      05:15 - 05:20 PM  |  Author(s): P.C. Ma, L. Yin, P. Joshi, Y. Feng, W. Zhang, M. Shapiro, M. McNamara, N. Hashemi Sadraei, N. Pennell, Q. He, N. Chen, E. Borden, M. Zborowski

      • Abstract
      • Presentation
      • Slides

      Background:
      Precision therapy with tyrosine kinase inhibitor (TKI) crizotinib and ceritinib against EML4-ALK (ALK+) non-small cell lung cancer (NSCLC) has advanced rapidly in recent years as a new paradigm in personalized cancer therapy. However, acquired drug resistance despite initial response still remains the rule, necessitating further investigations into mechanisms of resistance and novel therapies to overcome progressive resistant disease. Liquid-biopsy using peripheral blood circulating tumor cells (CTCs) as a minimally-invasive tool to determine patient’s disease status, tumor cells molecular-genomic make-up and evolution during therapies, is highly desirable. There is still an unmet need to develop affordable and robust technology platforms to empower such liquid-biopsy assay of CTC. There are relative advantages and pitfalls with various CTC platforms and a method to capture CTC in an unbiased fashion without pre-definition would be beneficial.

      Methods:
      We conducted pilot studies with adoption of two different CTC detection and enrichment platforms. First, we used the CellSearch[®] “positive-selection” platform through EpCAM immunomagnetic separation to profile 11 pts with ALK(+) NSCLC who were treated with crizotinib prospectively. Blood samples were collected (i) pretreatment, (ii) on TKI with CR/PR/SD, and (iii) at disease progression. Second, we evaluated a novel “negative-selection” CTCs capture-isolation platform, based on unbiased immunomagnetic removal of pan-leukocyte marker CD45+ cells coupled with RBC lysis, to enable CTC isolation without predefined CTC criteria. Pilot studies utilizing ALK+ H3122 cell line and ALK+ patients’ blood samples were performed for assay optimization and comparison. Whole genome sequencing using Illumina HiSeq x TEN was performed after whole genome amplification of the CTC tumor gDNA with paired-normal germline DNA for genomic interrogation.

      Results:
      Using ALK+ NSCLC patients’ peripheral blood samples, we demonstrated the presence of the EML4-ALK fusion (variant 1) in QPCR assay from the enriched CTC isolated using the CellSearch® platform. Also, CellSearch[®] enumeration in our pilot ALK+ cohort revealed a trend of correlation between the CTC numbers and disease status. The spike-in experiment in “negative selection” CTC platform enriched the spiked H3122 cells by 10,000 fold from the nucleated blood cells. Applying our “negative-selection” CTC assay to a patient with known EML4-ALK variant 1 (EML4-ex13/ALK-ex20) fusion lung cancer during disease progression on crizotinib, we detected the specific EML4-ALK variant 1 fusion in QPCR assay from the CTC enriched “eluate” fraction, but not in the “feed” fraction, whether the CellSearch® platform revealed any CTCs or not. In our index case of ALK-rearrangement NSCLC, we successfully performed whole genome sequencing analysis on the pretreatment negative-selection CTCs in comparison with the germline DNA and pretreatment lymph node tumor biopsied tissue tumor DNA. Our preliminary WGS results revealed similar genomic landscapes between the CTC and the biopsied tumor tissues.

      Conclusion:
      Taken together, our pilot CTC study results support the high sensitivity of the unbiased “negative selection” enrichment platform and its potential to empower molecular and genomic determinations in lung cancer. We also demonstrated the feasibility of the negative-selection CTC liquid-biopsy platform to achieve whole genome sequencing analysis of the captured CTCs.

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      MINI26.08 - A Correlative Plasma Biomarker Analysis of the Combination of Bevacizumab and Chemotherapy for Advanced Non-Small-Cell Lung Cancer (ID 1423)

      05:20 - 05:25 PM  |  Author(s): L. Ding, X. Hong, Q. Chen, K. Liu, X. Wan, N. Zhou, Y. Liang, H. Wu

      • Abstract

      Background:
      The addition of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, to a standard, first-line platin-based, two-agent chemotherapy regimen conferred a significant improvement in overall survival, progression-free survival, and response rate in patients with advanced non-squamous NSCLC (ns-NSCLC). The feasibility of the combination of bevacizumab and chemotherapy as the second-line or more therapy for ns-NSCLC is currently explored as well. However, no effective biomarker is validated to predict the response or clinical benefit of bevacizumab. This study aims to investigate the correlation between biomarkers and overall response to bevacizumab plus chemotherapy for patients with advanced ns-NSCLC.

      Methods:
      Patients with locally advanced or metastatic ns-NSCLC who were assigned to 7.5mg/kg 3-weekly doses of bevacizumab plus chemotherapy were eligible. Aaccording to investigators’ decision, chemotherapy regimens were pemetrexed (500mg/m[2]) with or without platinum (75mg/m[2]). Peripheral blood samples were collected at baseline and after 2[nd] cycle of therapy for the analysis of granulocyte colony-stimulating factor(G-CSF), vascular endothelial growth factor A(VEGF-A) and VEGF receptor-2 (VEGFR-2). Plasma samples concomitantly with the radiological evaluation of disease progression were collected as possible. Correlation between biomarkers and overall response rate (ORR) were assessed by using a logistic regression model.

      Results:
      Baseline blood samples were available from 45 patients (100%, 19 patients were therapy naive, 26 patients failed of prior therapies), while samples after 2[nd] cycle were obtained from 37 patients (82.22%). For the primary analysis, there was no significant association between baseline plasma biomarkers and best overall response to the treatment. But, patients with low baseline plasma G-CSF level showed a trend toward improving ORR versus patients with high G-CSF level (odds ratio [OR], 3.846; 95%CI, 0.868 to 17.044,p=0.076). Patients with high baseline plasma VEGF-A level showed a trend toward higher ORR versus patients with low VEGF-A levels (OR, 3.477; 95%CI, 0.857 to 14.113,p=0.081). No significant correlations were observed between plasma biomarkers and progression-free survival (PFS). In comparison to baseline, plasma VEGF-A level increased significantly at 2[nd] cycle or radiological disease progression (p<0.001). However, the magnitude of the difference did not correlate with ORR or PFS.

      Conclusion:
      Baseline or dynamic changes in plasma G-CSF, VEGF-A and VEGFR-2 did not correlate significantly with response of bevacizumab plus chemotherapy treatment for ns-NSCLC patients, while low baseline plasma G-CSF and high VEGF-A are possible candidate biomarkers for predicting response of bevacizumab plus chemotherapy for ns-NSCLC.

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      MINI26.09 - Correlation between Circulating Tumor Biomarkers and Positron-Emission Tomography in Advanced Non-Small Cell Lung Cancer (ID 2940)

      05:25 - 05:30 PM  |  Author(s): C. Genova, E. Rijavec, F. Biello, G. Barletta, C. Maggioni, S. Coco, I. Vanni, A. Truini, A. Alama, G. Buzzatti, S. Morbelli, G. Ferrarazzo, F. Bongioanni, G. Sambuceti, M. Massollo, F. Grossi

      • Abstract
      • Presentation
      • Slides

      Background:
      Circulating tumor cells (CTCs) and plasma circulating-free DNA (cfDNA) are promising candidates as non-invasive prognostic markers in malignant diseases. 18-fluorodeoxyglucose positron emission tomography integrated with computed tomography (18FDG-PET/TC) has a well-recognized diagnostic and prognostic value in non-small cell lung cancer (NSCLC). Very little is known about the mutual relationship between circulating biomarkers (CTCs and cfDNA) and 18FDG-PET/CT indicators in NSCLC.

      Methods:
      Peripheral blood samples from 28 patients affected by advanced/metastatic NSCLC were collected before starting first-line chemotherapy. CTCs were isolated by size using a filtration-based device (ScreenCell) and then identified and enumerated; cfDNA was isolated from plasma (QIAamp DNA Blood Mini Kit, Qiagen) and quantified by qPCR method using human telomerase reverse transcriptase (hTERT). All patients underwent 18FDG-PET/TC (Biograph 16 Siemens) at baseline. Maximum diameter (dmax) of the primary lesion (T), dmax of the greater lymph nodal (N), and metastatic (M) lesions were measured. Similarly, maximum and mean standardized uptake value (SUVmax, SUVmean) and size-incorporated SUVmax (SIMaxSUV) were computed for T, N and M, respectively; SIMaxSUV was calculated with the following formula for T, N, and M: SIMaxSUV= SUVMax*dmax. Presence (B+) and absence (B-) of metabolically active bone lesions (bone mets) were recorded. The association among CTCs, cfDNA and 18FDG-PET/CT-derived parameters was evaluated through multivariate analysis. T-test was performed to evaluate the difference in CTCs and cfDNA in B+ and B- groups, respectively.

      Results:
      Twenty-eight patients were evaluated; median age was 66 years (range: 51-80); male/female ratio was 18/10; 15 patients were current smokers, while 11 were former-smokers and 2 were never-smokers. Histo-types were grouped as it follows: adenocarcinoma= 22; squamous cell carcinoma= 5; not otherwise specified NSCLC= 1. Nine patients out of 28 had metabolically active bone lesions. Median CTC count was 7 CTCs/3ml (range: 0-47 CTCs/3ml), while median HTERT copy number was 109.0 (range: 16.7-1405-5).

      18FDG-PET/CT PARAMETERS MEAN STANDARD DEVIATION P
      T Size 44.93 20.25 0.175
      SUV max 10.16 4.48 0.036
      SUV mean 10.6 3.4 0.994
      SIMaxSuv 487.7 333.5 0.472
      N Size 22.2 10.9 0.313
      SUV max 7.4 4.0 0.318
      SUV mean 5.8 3.0 0.294
      SIMaxSuv 172.8 158.1 0.231
      M Size 23.9 15.0 0.083
      SUV max 7.5 4.1 0.318
      SUV mean 7.4 1.2 0.307
      SIMaxSuv 216.4 206.5 0.463
      At multivariate analysis, SUVmax of T was the only variable independently associated with cfDNA (p=0.036). No correlations were highlighted between CTCs and all PET-derived parameters. A trend towards significance between high HTERT and the presence of metabolically active bone lesions was observed (p=0.058).

      Conclusion:
      Our data demonstrate that the expression of cfDNA is correlated with the metabolic activity of the primary tumor lesion. Since SIMaxSUV was not correlated with HTERT, it appears that the expression of cfDNA depends from tumor metabolism rather than its burden. Further analyses on 18FDG-PET/TC-derived metabolic tumor volume are ongoing.

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      MINI26.10 - Discussant for MINI26.05, MINI26.06, MINI26.07, MINI26.08, MINI26.09 (ID 3377)

      05:30 - 05:40 PM  |  Author(s): B. Halmos

      • Abstract
      • Presentation

      Abstract not provided

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      MINI26.11 - Longitudinal Monitoring of EGFR Mutations in Plasma of EGFR Mutant NSCLC Patients Treated with EGFR TKIs: Korean Lung Cancer Consortium (ID 1130)

      05:40 - 05:45 PM  |  Author(s): J.Y. Lee, B. Yali, W. Xiumin, B.S. Hyeon, H.Y. Lee, J. Sun, S. Lee, J.S. Ahn, E.K. Cho, H.R. Kim, Y.J. Min, D. Kim, K. Park, X. Qing, M. Mao, M. Ahn

      • Abstract
      • Presentation
      • Slides

      Background:
      Detection of epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC) patients is mainly based on tissue biopsy, which is invasive and time consuming. Furthermore, there is still a need for serial monitoring of EGFR mutations and detection of EGFR tyrosine kinase inhibitors (TKIs) resistance. We hypothesized that plasma-based EGFR mutation analysis may be feasible for monitoring response to EGFR TKIs and could be used to predict the resistance.

      Methods:
      From January 2012 to October 2014, 200 EGFR mutant NSCLC patients were enrolled and treated with EGFR TKIs (141 patients for gefitinib, 46 patients for erlotinib, and 13 patients for afatinib). Plasma samples were prospectively obtained every 2 months from baseline until disease progression. The longitudinally collected plasma samples (n = 368) from 81 patients who progressed were analyzed using droplet digital PCR (ddPCR). We identified an association between serial EGFR mutant titers in plasma cell-free DNA (cfDNA) samples and the patient’s clinical response to EGFR TKIs.

      Results:
      Of a total 58 baseline cfDNA samples available for ddPCR, 43 (74%) samples demonstrated same mutation in the matched tumors (i.e. sensitivity: 70.8% (17/24) for L858R vs 76.5% (26/34) for exon 19 deletions). The concordance rate of plasma with tissue results of EGFR mutation was 88% for L858R and 86% for exon 19 deletion, respectively. Of the 54 patients with both before and after treatment plasma samples, 40 patients showed a dramatic decrease of mutant copies (greater than 50%) in blood in the first 2 months after treatment. We also found the secondary mutation (T790M) emerged in 28 patients around 3~13 months after treatment and in 4 patients before the treatment. Elevated circulating mutations (L858R/ex19/T790M) can be detected in 5 patients before disease progression as determined by CT scan.

      Conclusion:
      These results suggest that ddPCR is an appropriate method for determining plasma-based EGFR mutation status and may aid in monitoring response to EGFR TKIs and early detection of EGFR TKIs resistance.

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      MINI26.12 - Circulating Tumor DNA for Noninvasive Monitoring of Non-Small Cell Lung Cancer Patients Receiving EGFR-Targeted Therapies (ID 372)

      05:45 - 05:50 PM  |  Author(s): D. Tsui, M. Muhammed, A.S. Wong, O.M. Rueda, T. Forshew, R. Soo, H. Wong, B.C. Goh, T. Eisen, F. Marass, D. Gale, W. Liu, T.M. Chin, N. Rosenfeld

      • Abstract
      • Slides

      Background:
      Analysis of circulating tumor DNA (ctDNA) in plasma offers an opportunity to noninvasively monitor tumor burden and identify alternative drivers of disease progression in real-time. However, cancer progression during targeted therapy, such as EGFR-targeted therapies in non-small cell lung cancer (NSCLC), is driven by clonal evolution, and how this impacts the levels of targeted mutations in circulating tumor DNA (ctDNA) for monitoring disease burden is unclear.

      Methods:
      We collected serial plasma samples from 47 NSCLC patients receiving EGFR-targeted therapy (gefitinib) and hydroxychloroquine, and analysed mutations in EGFR, TP53, PTEN and PIK3CA in plasma by digital PCR and tagged-amplicon deep sequencing (TAm-Seq) of ctDNA.

      Results:
      We identified the same EGFR mutations in tumor and plasma samples in over 97% of patients, and found that patients with high pre-treatment levels of ctDNA are associated with worse progression-free survival and overall survival. Serial plasma analysis of 32 patients reveals clonal dynamics in ctDNA in response to treatment. In >72% of patients (23/32), EGFR mutations levels increased preceding clinical progression, with the resistant mutation T790M detected in around 50% of these patients (13/23) a median of 6 months before progression became clinically evident. In the remaining 9 of the 32 patients, EGFR-mutant ctDNA levels became uninformative during treatment, and in two patients we identified alternative driver mutations in ctDNA that correlated with progression. In one patient we also showed that the analysis of relative representations of resistant and sensitizing mutations may provide insight to the response to sequential treatment.

      Conclusion:
      Our results demonstrate the potential of ctDNA for noninvasive stratification and monitoring disease progression in NSCLC patients, and highlight that targeted therapy may drive the selection of alterative mutations. This may impact the representation of the targeted mutations in plasma for assessing disease burden. We therefore propose that effective ctDNA-based monitoring of targeted therapies in oncogene-addicted cancers requires tracking of multiple mutations beyond the targeted genes.

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      MINI26.13 - Serial ctDNA Assessment of Response and Resistance to EGFR-TKI for Patients with EGFR-L858R Mutant Lung Cancer from a Prospective Trial (ID 3107)

      05:50 - 05:55 PM  |  Author(s): Q. Zhou, J.-. Yang, Z.-. Chen, X.-. Zhang, H.-. Yan, J. Su, H.-. Chen, C.-. Xu, H.-. Tu, W.-. Zhong, X.-. Yang, Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Background:
      Plasma circulating tumor DNA (ctDNA) has been widely accepted as a form of liquid biopsy to detect EGFR mutations in NSCLC for its high concordance rate with tumor tissues. There are some retrospective studies about the ctDNA quantitative changes of EGFR mutations in EGFR-TKI treatment, but there is no report about serial ctDNA assessment of response and resistance to EGFR-TKI by detecting the dynamic changes of EGFR mutations during the whole course of EGFR-TKI treatment based on prospective clinical trial.

      Methods:
      Based on a randomized trial initiated to compare erlotinib with gefitinib in advanced NSCLC harboring EGFR exon 21 L858R mutation in tumor tissues (CTONG0901, NCT01024413), we prospectively collected serial plasma samples as preplanned schedule (baseline, one week after treatment, one month after treatment and then every 8 weeks until disease progression) and quantitatively detected EGFR L858R mutation in ctDNA by using fluorescence quantitative polymerase chain reaction. We made a serial ctDNA assessment of response and resistance to EGFR-TKI and its correlation with survival outcomes. Four patients’ serial plasma samples were selected to undergo next generation sequencing (NGS).

      Results:
      From 108 patients enrolled in the trial, serial plasma of 80 patients were collected as schedule and tested the quantity of L858R. As a whole, the quantity of L858R decreased to the lowest level when patients achieved best response to EGFR-TKI and increased to the highest level when disease progressed. Further analysis by Ward's Hierarchical Clustering Method showed that the dynamic changes of quantity of L858R could be categorized into two groups, Ascend Group and Stable Group (Figure 1A). Median progression-free survival (PFS) was 11.1 months (95%CI=6.6-15.6) and 7.5 months (95%CI=1.4-13.6) in two groups, respectively (HR=0.57, 95%CI=0.34-0.97, P=0.035) (Figure 1B). Median overall survival was 20.1 months (95%CI=15.7~24.5) vs. 16.4 months (95%CI=13.3~19.6) (HR=0.73, 95% CI =0.38~1.38, P=0.322). In multivariate Cox proportional hazards regression analysis, changing group was independent predictive factor for PFS. In plasma samples of 4 patients underwent NGS, similar dynamic changing characteristics were confirmed and more genetic mutations were found. Detailed data will be presented on site.Figure 1



      Conclusion:
      This is the first report about serial ctDNA assessment of response and resistance to EGFR-TKI by detecting the dynamic changes of EGFR mutation based on a prospective clinical trial. The quantity of plasma L858R has different changing patterns during EGFR-TKI treatment and higher L858R mutation abundance on EGFR-TKI resistance is correlated with longer PFS.

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      MINI26.14 - Noninvasive Identification of EGFR-T790M Mediated Resistant NSCLC Patients Using Plasma CfDNA (ID 1208)

      05:55 - 06:00 PM  |  Author(s): D. Zheng, X. Ye, Y. Sun, M. Zhang, J. Wang, J. Ni, H. Zhang, L. Zhang, J. Luo, J. Zhang, L. Tang, G. Chen, B. Su, G. Zhu, M. Hu, Y. Gu, J. Xu

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR-T790M mutation, which is the valuable target for the next generation of EGFR-TKI, accounts for about half of the acquired resistance to current EGFR-TKI therapy in the EGFR sensitive mutation positive NSCLC patients. Due to clinical challenge in obtaining re-biopsy tumor tissues, noninvasive detection of EGFR-T790M in plasma circulating free DNA (cfDNA) has been proved to be feasible. Yet a highly sensitive assay needs to be developed to avoid false-negative detection. We here explored whether droplet digital PCR (ddPCR) of cfDNA can an alternative assay to identify the EGFR-TKI resistance mediated by EGFR-T790M in the clinical practice.

      Methods:
      The digital PCR method was recently developed for EGFR sensitive mutations, and its high sensitivity and specificity were validated in plasma cfDNA from EGFR-TKI-naïve NSCLC patients. In this study, we applied this method to detect EGFR-T790M in plasma cfDNA from metastatic NSCLC patients who initially responded but acquired resistance to current EGFR-TKI treatment. For the concordance analysis, the paired re-biopsy or pleural effusion cytology samples after failed EGFR-TKI were also collected for EGFR-T790M testing.

      Results:
      25 consecutive NSCLC patients were enrolled and analyzed in this study according to these criteria: 1. Metastatic NSCLC patients with acquired EGFR-TKI resistance. 2. The re-biopsy tissue or cytology samples and paired plasma samples were available after disease progression on EGFR-TKI. Among these 25 patients, 13 were positive and 9 were negative for EGFR-T790M mutation in both tumor tissue and plasma samples. 3 patients positive for EGFR-T790M mutation in tumor tissue were detected negative in their plasma. The overall concordance rate between plasma and tumor tissue testing was 88.00% (22/25) (Kappa=0.757, 95%CI: 0.4996-1.0). The sensitivity and specificity for plasma testing of EGFR-T790M mutation by ddPCR were 81.25% (13/16) (95%CI: 54.35%-96.00%) and 100.00% (9/9) (95%CI: 66.37%-100%), respectively. Figure 1



      Conclusion:
      Detection of EGFR-T790M in plasma cfDNA by ddPCR is highly sensitive and specific when compared to the pairedre-biopsy tissue or cytology samples. This noninvasive method could complement current invasive biopsy approach or provide an alternative method to identify specific mutation mediated resistance in clinic.

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      MINI26.15 - Discussant for MINI26.11, MINI26.12, MINI26.13, MINI26.14 (ID 3378)

      06:00 - 06:10 PM  |  Author(s): R. Perez-Soler

      • Abstract
      • Presentation

      Abstract not provided

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    MTE 02 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (Ticketed Session) (ID 54)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Advocacy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/07/2015, 07:00 AM - 08:00 AM, 105
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      MTE02.01 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (ID 1979)

      07:00 - 07:30 AM  |  Author(s): C. Aggarwal

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The traditional obstacles to approval of oncologic therapeutic agents, especially targeted therapies that address a rare-biomarker defined group of patients are the long processes from initial drug discovery to clinical implementation, the difficulties in recruitment for these clinical trials and high number of screen failures and the overall low rate of enrollment in clinical trials. The Lung Master Protocol (Lung-MAP, S1400) is a precedent-setting clinical trial designed to advance the efficient development of targeted therapies for squamous cell cancer of the lung (SCCA). There are few new effective therapeutic options for patients with advanced lung SCCA. Immunotherapies, including nivolumab, have already shown clear benefit for patients with SCCA in 2015 leading to approval by the FDA which has been an unprecedented step forward for the treatment of patients, however we are still lacking predictive markers for these therapies that are reliably selecting patients more likely to benefit. Lung-MAP (S1400) is aiming to identify biomarker-drug pairs that will lead to successful therapeutic outcomes and registration of new agents. It is a registration-intent master protocol that includes a screening component and clinical trial component; the clinical trial component includes multiple sub-studies which independently evaluate investigational therapies. The clinical trial component is designed to be modular such that new sub-studies can be added either as other sub-studies close or as new biomarker-drug pairs are identified for testing in this patient population. Lung-MAP is utlilizing a broad NGS screening platform capitalizing on the expanding application of genomic sequencing in oncology that has through the Cancer Genome Atlas and other sequencing initiatives revealed targetable genetic aberrations including gene mutations, rearrangements, amplifications, and deletions, and creating an immense opportunity to implement personalized therapy with a high potential to improve patients outcomes. Immunotherapy has been integrated in the design of Lung-MAP from its launch in June of 2014. The original study design and structure is shown in the figure. Figure 1 The modular design of the study has allowed for the flexibility to adapt to the approval of nivolumab and the hault in further development of AMG102 (rilotumumab) with discontinuation of the corresponding sub-study by implementing timely modifications which include the following:1)Eligibility has changed from exclusively second line therapy to second-or more line therapy 2)Pre-screening, while patient receive first line therapy has been added to boost accrual 3)the unmatched arm has been changed to a single (not randomized) arm study with the anti-PD-L1 agent MEDI-4736. Theses changes are reflected in the figure. Each independently conducted and analyzed sub-study specifies investigator-assessed progression-free survival (IA-PFS) and overall survival (OS) as the co-primary endpoints for the phase 3 primary objectives. The primary objectives for the phase 3 are to determine if there is a statistically significant difference in OS and to determine if there is both a clinically meaningful and statistically significant difference in IA-PFS. The conduct of Lung-MAP relies on close collaboration (a public-private partnership) among the NCI and NCTN (spearheaded by SWOG), the pharmaceutical industry, the Foundation for the NIH (FNIH), Friends of Cancer Research, advocates, and FDA. This Master Protocol will improve genomic screening of SCC patients for clinical trial entry, and improve time lines for drug-biomarker testing, allowing for inclusion of the maximum numbers of otherwise eligible patients. The clinical trial continues to be updated following science and alterations in the therapeutic landscape, with adaptations in design and incorporation of new agents against matched targets and the implementation of novel immunotherapy approaches for the unmatched arm. Figure 2





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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P3.01-054 - Etirinotecan Pegol (NKTR-102) in the Treatment of Patients with Metastatic NSCLC after Failure of 2nd Line Treatment: A Phase II Study (ID 717)

      09:30 - 09:30 AM  |  Author(s): C. Aggarwal

      • Abstract
      • Slides

      Background:
      3rd line treatment options are limited for patient (pts) with metastatic NSCLC. NKTR-102 is a long-acting topoisomerase-I inhibitor designed to concentrate in tumors and provide continuous exposure throughout the chemotherapy cycle. Based on clinical activity of irinotecan in NSCLC, we conducted a Phase II single arm trial to evaluate efficacy of NKTR-102.

      Methods:
      Pts >18 yrs with histologically proven NSCLC who received 2 prior systemic therapy regimens were eligible. Measurable disease, ECOG PS ≤1 and adequate end organ function were required. NKTR-102, 145mg/m2 was administered IV q3 weeks till progression. Response was assessed q6 weeks by RECIST 1.1. Primary endpoint was overall response rate. Secondary endpoints were progression free survival (PFS), overall survival (OS) and safety. Simon two-stage design was implemented; if 0/12 responses were observed in the 1st stage, the study would be terminated for futility. If there was at least 1 objective response in the 1st stage, the study would continue to stage 2, enrolling an additional 25 pts, for a total of 37.

      Results:
      Between 01/2013 and 01/2015, 37 pts have been enrolled. Median age 63 yrs (18-82), 45% female, ECOG PS 0=8 pts, 92% current/former smokers, 9 pts with squamous cell, 28 had adenocarcinoma. Median time from diagnosis to initiation of NKTR-102 was 18 mos (6-72). Pts received a median of 3 cycles (1-13). All pts were evaluable for response rate and toxicity. One pt in Stage I (adenocarcinoma) had a partial response. Fifteen pts had stable disease, 7 pts are still on treatment. 3 pts had Grade 3 GI toxicity attributable to NKTR-102. 6 pts required a dose reduction to 120 mg/m2 due to diarrhea. There was no hematological toxicity. Median PFS was 2.3 mos. For pts with >1 yr follow up (n=20), median OS was 5.5 mos. Complete PFS and OS data will be presented.

      Conclusion:
      NKTR-102 is well tolerated and leads to stabilization of disease in third line treatment of metastatic NSCLC. These clinical data combined with a favorable safety profile warrant further clinical investigation of this agent. Clinical trial information: NCT01773109.

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