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Y. Yatabe

Moderator of

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    MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 14
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      MINI05.01 - A Progression Free Survival Score for EGFR Mutant Non-Small Cell Lung Cancer Patients Treat with First Line EGFR Tyrosine Kinase Inhibitors (ID 493)

      16:45 - 18:15  |  Author(s): Y. Chen, M. Lin, W. Fang, C. Lie, H. Chang

      • Abstract
      • Presentation
      • Slides

      Background:
      As epidermal growth factor receptor (EGFR) mutation a strong predictor of EGFR tyrosine kinase inhibitor (TKI) responsiveness, there are still around 10% TKI-naïve patients early refractory to first line TKIs. We aimed to find clinical predictors of TKIs responsiveness in EGFR-mutant non-small cell lung cancer (NSCLC) patients and create a scoring system as progression free survival (PFS) prediction.

      Methods:
      This retrospective study evaluated 262 patients harboring EGFR mutation received TKIs as first line therapy for NSCLC between January 2011 and December 2013. Patients were assigned to test (N=131) and validation (N=131) by time sequence. Patients with age ≤ 40, uncommon EGFR mutation, poor performance status, more sites of distal metastasis, and lymphocyte to monocyte ratio ≤3 were independently associated with poor progression free survival. These five factors were included in the scoring system and 3 predictive groups were formed by total score. Table. 1 Univariate and Cox regression analysis of progression free survival

      Univariate analysis Multivariate analysis
      PFS (M) P value P value
      Age >40 ≤40 11.6 3.3 0.001 0.002
      BMI >24 ≤24 14.9 9.1 0.027 0.928
      Gender Male Female 9.3 12.0 0.292
      DM YES NO 9.1 11.5 0.500
      Smoking Never Former / current 11.5 7.6 0.413
      Performance status ECOG 0-2 ECOG 3-4 11.5 2.7 0.009 0.012
      Mutation Common Uncommon 11.5 4.1 <0.001 <0.001
      Tumor type Adenocarcinoma Non-adenocarcinoma 11.1 9.8 0.789
      No. of distal metastasis 0 1-2 >2 21.4 11.3 6.1 <0.001 <0.001 0.015 <0.001
      Malignant effusion Yes No 9.1 11.6 0.031 0.946
      Lymphocyte to monocyte ratio >3 ≤3 13.4 7.4 <0.001 0.047


      Results:
      Progression free survival in the test group were 15.7 months(m) for 0-1 points, 9.3 m for 2 points, 4.0 m for 3-6 points (p <0.001). In the validation test, Progression free survival in there predictive groups each were 13.7 m, 9.5 m, 4.8 m (p <0.001). Between the test and validation groups, no significant differences were found in each one of the three predictive groups. Figure 1



      Conclusion:
      The score appears valid and reproducible. It can stratify NSCLC patients harboring EGFR mutation using first line EGFR-TKIs into long, intermediate and short PFS groups.

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      MINI05.02 - Impact of ABCG2 Polymorphisms on the Clinical Outcome of TKIs Therapy in Chinese Advanced Non-Small-Cell Lung Cancer Patients (ID 591)

      16:45 - 18:15  |  Author(s): X. Chen, D. Chen, S. Yang, Y. Pan, X. Li, S. Ma

      • Abstract
      • Presentation
      • Slides

      Background:
      ATP binding cassette superfamily G member 2 (ABCG2) has been demonstrated to be associated with the effect of chemotherapy/targeted therapy in non-small-cell lung cancer (NSCLC) and the single nucleotide polymorphisms (SNPs) of ABCG2 gene are supposed to affect the expression of ABCG2 protein. The purpose of this study was to investigate the correlation between SNPs of ABCG2 and outcome of tyrosine kinase inhibitions (TKIs) therapy in Chinese advanced NSCLC patients.

      Methods:
      SNP genotyping(34 G/A, 421 C/A, 1143 C/T and -15622 C/T)of ABCG2 gene in 100 patients was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The clinical characteristics of 100 patients were collected. A total of 70 patients were treated with TKIs(gefitinib, erlotinib and icotinib). The association between ABCG2 polymorphisms and clinical characteristics was evaluated. Kaplan-Meier survival curves were plotted for overall survival (OS) and analyzed with the log-rank test. Cox proportional hazards model was applied to evaluate the association between OS and clinical or genomic characteristics and estimated the adjusted HR and its 95 %CI.

      Results:
      The three polymorphisms of the ABCG2 34 G/A, 421 C/A and 1143 C/T occurred more frequently compared with -15622 C/T in Chinese advanced NSCLC patients. The allele A of 421C>A happened frequently in EGFR mutation positive patients (33.3% vs 9.1%, P=0.038). There was no association between ABCG2 polymorphisms and other clinical characteristics (p> 0.05).The median OS of patients with 34G>A mutant type (GA+AA) was 31.0 (95%CI: 22.9-39.1) months , which was significantly longer than those with wild type (GG) , 18.0 (95%CI: 14.9-21.1) months (p=0.005). No significant difference of OS was found in 421 C/A and 1143 C/T polymorphisms (p> 0.05).

      Conclusion:
      Our findings demonstrate a strong association between the ABCG2 34G>A polymorphism and the overall survival of NSCLC patients treated with TKI. It may be a possible predictor of the clinical outcome of TKIs therapy in NSCLC patients.

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      MINI05.03 - P53 Disruptive Mutation Is a Negative Predictive Factor in EGFR M+ NSCLC Treated with TKI (ID 903)

      16:45 - 18:15  |  Author(s): A.C. Lueers, N. Neemann, R. Prenzel, D. Scriba, K. Wilborn, U. Stropiep, M. Falk, C. Hallas, M. Tiemann, F. Griesinger

      • Abstract
      • Presentation
      • Slides

      Background:
      p53 mutations are common in lung cancer, and have also been described in EGFR mutated patients. The impact of p53 mutations in EGFR M+ patients is controversial, especially if classified as “disruptive” and “non-disruptive” according to their functional effect on the p53 protein as proposed by Poeta and colleagues. The aim of the study was therefore to systematically analyze EGFR and p53 mutations within a cohort of patients with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and to investigate a potential impact of p53 mutations on treatment outcome.

      Methods:
      267 patients from a single center diagnosed with lung cancer stage IV were studied for the presence of EGFR as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing. P53 mutations were detected by Sanger Sequencing. Clinical characteristics including smoking status were available for all patients.

      Results:
      267 consecutive patients at the lung cancer center of the Pius-Hospital Oldenburg were studied. The overall EGFR mutation rate was 19% (51/267) in all patients, 80% (41/51) showing common mutations of exon 19 or 21. P53 disruptive mutation showed in 16% (8/51) and p53 nondisruptive mutation occurred in 11% (22/51) whereas p53 WT was found in 47% (24/51). In 8/51 (16%) patients p53 analysis was not successful. OS was 37 months in p53 disruptive mutation and p53 WT patients compared to 19 months in p53 nondisruptive mutation (p<0,05). PFS on 1st line TKI therapy was 18 months in p53 nondisruptive mutation and p53 WT patients and 6 months in p53 disruptive mutation (p<0,024). Similar results could be shown in the EGFR common mutation subgroup but not in the uncommon mutation subgroup.

      Conclusion:
      Significant differences in PFS and OS in EGFR M+ patients were observed depending on p53 mutation status. P53 mutational status is only predictive when disruptive and non-disruptive P53 mutations are differentiated. P53 should be tested prospectively in EGFR M+ patients as management of patients on 1st line TKI may be different.

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      MINI05.04 - Survival Outcome Assessed According to Tumor Burden & Progression Patterns in Patients with EGFR Mutant NSCLC Undergoing EGFR-TKIs (ID 886)

      16:45 - 18:15  |  Author(s): Y.K. Cha, H.Y. Lee, M. Ahn, Y. Choi, J.H. Lee, K. Park, S. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      Mutations in the epidermal growth factor receptor (EGFR) are associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). However, clinical predictors of the survival benefit of EGFR-TKI treatment in NSCLC with EGFR activating mutations have not been well elucidated. Therefore, this study evaluated clinical predictors of survival outcome in patients with EGFR mutant NSCLC who were treated with EGFR-TKIs. Mutations in the epidermal growth factor receptor (EGFR) are associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). However, clinical predictors of the survival benefit of EGFR-TKI treatment in NSCLC with EGFR activating mutations have not been well elucidated. Therefore, this study evaluated clinical predictors of survival outcome in patients with EGFR mutant NSCLC who were treated with EGFR-TKIs.

      Methods:
      A total of 224 patients with EGFR-mutant lung adenocarcinomas that were treated with EGFR-TKIs were retrospectively reviewed. Treatment outcomes were evaluated based on clinical factors, number of metastasis site and progression patterns.

      Results:
      The clinical factors associated with reduced progression-free survival (PFS) and overall survival (OS) by univariate analysis were ECOG performance status (PS) ≥ 2, intra- and extrathoracic metastasis, presence of extrathoracic metastasis, high number of metastasis sites, metastasis to liver or adrenal gland at baseline, and rapid progression of primary tumor at the time of progressive disease (PD). In multivariate analysis, factors that remained significantly associated with shorter PFS were ECOG PS ≥ 2 (Odds ratio [OR] 2.189 [95% CI, 1.374 – 3.437]; P < 0.001) and rapid progression of primary tumor at PD (OR 1.800 [95% CI, 1.059 – 3.058]; P = 0.030).

      Conclusion:
      Thus, tumor burden, expressed as the number of metastasis sites at the time of EGFR-TKI treatment, and rapid progression of primary tumor at PD are predictive of inferior survival in patients with lung adenocarcinoma with activating EGFR mutations.

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      MINI05.05 - Discussant for MINI05.01, MINI05.02, MINI05.03, MINI05.04 (ID 3531)

      16:45 - 18:15  |  Author(s): F. Cappuzzo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI05.06 - A Phase Ib/II Study of Afainib plus Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib (ID 667)

      16:45 - 18:15  |  Author(s): J.Y. Lee, S.H. Lim, H. Kim, K.H. Yoo, K.S. Jung, H. Song, M. Kwak, M. Han, J. Sun, S. Lee, J.S. Ahn, K. Park, M. Ahn

      • Abstract
      • Presentation
      • Slides

      Background:
      Afatinib (A) is a potent irreversible EGFR TKI and nimotuzumab (N) is a humanized anti-EGFR mAb. In this phase Ib/II study, we aimed to assess the safety and activity of A plus N in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib.

      Methods:
      Major inclusion criteria were advanced NSCLC with activating EGFR mutation or disease control for at least six months with previous gefitinib or erlotinib therapy. In the phase Ib study using classic 3+3 dose escalation method, patients were treated with A 40mg/d or 30mg/d in combination with N 100mg/w or 200mg/w. One cycle was composed of 4 weeks of treatment. In the phase II study, patients were treated with A plus N in the level of RP2D defined in the phase Ib study.

      Results:
      Overall, fifty pts were enrolled and treated: 13 in phase Ib and 37 in phase II. At the starting dose level (A 40mg/d + N 100mg/w), one out of 6 pts experienced end-of-cycle 1 DLT (G3 diarrhea), and the dose was up to the next level of A 40mg/d + N 200mg/w. Out of 6 pts at this level, 2 pts experienced DLTs (G3 diarrhea and G3 neutropenia, respectively), and RP2D was accordingly determined as A 40mg/d + N 100mg/w. In the whole treatment duration of the phase II, there was no treatment related death and 10 pts (20%) experienced any grade 3 adverse event, including diarrhea and skin rash. Out of evaluable 50 pts in the phase Ib/II study, the response rate was 36% (18 achieved partial response out of 50) and the median PFS was 4.4 months (95% CI:3.2-5.5 months).

      Conclusion:
      A and N showed an acceptable safety profile and promising antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib.

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      MINI05.07 - Circulating Tumor Cells and Evaluation of Targeted Therapy Effect in EGFR Mutation/ALK Translocation Metastatic Non-Small Cell Lung Cancer (ID 1403)

      16:45 - 18:15  |  Author(s): C. Su, X. Li, S. Ren, C. Zhou

      • Abstract
      • Presentation
      • Slides

      Background:
      Targeted therapies have considerably improved the prognosis of patients with non-small cell lung cancer (NSCLC).Although not precision enough, RESIST criteria was still the most often used response assessment method to reflecting the clinical benefits. We propose a non-invasive, folate receptor (FR)–based circulating tumor cell (CTC) detection approach to interpret treatment response of targeted therapy between baseline and follow-up CTC values in EGFR mutation/ALK translocation advanced NSCLC.

      Methods:
      One hundred and thirty eight patients were enrolled in our study. Peripheral blood was analyzed for CTCs enumeration on negative enrichment by immunomagnetic beads. Changes of CTCs levels were correlated with radiological response. Sequential analyses were conducted to monitor CTC signals during therapy and correlate radiological effects with treatment outcome.

      Results:
      CTCs were detected (≥8.7CTC) in 84.8% of patients. Pretreatment and pro-treatment blood samples from all 118 EGFR-mutant (19deltion:56, L858R:57, G719x:3, L861Q:1, 19 deletion + L858R:1), 14 ALK translocation lung cancer patients and 6 EGFR wild type patients were collected. Of 89 eligible and evaluable patients, baseline CTC counts were not associated with response to treatment by RECIST (P=0.353). There is no difference between exon 19 deletion and L858R of baseline CTC values. (19deletion:19.4 CTCs, L858R:20.9 CTCs,P=0.222) The change of CTCs values increased correlation with radiological response (P=0.042) after treatment of targeted therapy. There is no significant difference between exon 19 deletion and L858R of CTCs values pre and pro EGFR-TKI treatment.(3.32 vs.12.1, P=0.783)

      Conclusion:
      This study confirms the predictive significance of CTCs in patients with EGFR mutation/ALK translocation NSCLC receiving targeted therapy. The change of CTCs value correlated significantly with radiological response. This strategy may enable non-invasive, specific biomarker assessment method for using CTC decreases as an early indication of response to targeted therapy and monitoring in patients undergoing targeted cancer therapies.

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      MINI05.08 - Comparison of the Efficacy of Dacomitinib v Erlotinib for NSCLC Pts with Del 19/L858R (ID 775)

      16:45 - 18:15  |  Author(s): S.S. Ramalingam, K.J. O'Byrne, T. Mok, M. Boyer, P.A. Jänne, Z. Goldberg, C.B. Mather, I. Taylor, H. Zhang, L. Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background:
      To date there have been limited randomized comparisons of EGFR tyrosine kinase inhibitors (TKI) in EGFR mutant NSCLC. Dacomitinib is a potent, irreversible EGFR inhibitor that demonstrated robust activity in a phase 2 study for patients with common activating EGFR mutations. Additionally, preclinical data suggests greater activity in patients with common EGFR activating mutations in exon 19 or 21. ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) each compared the clinical activity of dacomitinib (D) versus erlotinib (E) in advanced NSCLC including patients with common activating EGFR mutations; pooled results are presented.

      Methods:
      Patients (pts) with locally advanced/metastatic NSCLC were randomized following progression with 1 or 2 prior chemotherapy regimens to treatment with dacomitinib (D) (45 mg PO QD) or erlotinib (E) (150 mg PO QD). The Phase 2 study (A7471028) was open label while the Phase 3 ARCHER 1009 study was double-blind and double dummy. Archived tumor tissue, ECOG performance status (PS) of 0-2, adequate organ function and informed consent were required. Results of the two studies were previously reported individually. Analyses were performed by pooling patients with common EGFR activating mutations from both studies to compare efficacy of D versus E.

      Results:
      121 patients with any EGFR mutation were enrolled into the two studies with 1 patient randomized but not treated; 101 (53 on D) pts had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median PFS was 14.6 months (95%CI 9.0–18.2) for D and 9.6 months (95%CI 7.4–12.7) for E and unstratified HR 0.717 (95%CI 0.458–1.124) with 1-sided p=0.073. The median OS was 26.6 months (95%CI 21.6–41.5) for D and 23.2 months (95%CI 16.0–31.8) for E and unstratified HR 0.737 (95%CI 0.431–1.259) with 1-sided p=0.132. The corresponding pooled analyses were conducted separately in exon 19 and exon 21. The adverse-event profile did not differ between the activating mutation subset and the overall population. Figure 1



      Conclusion:
      Dacomitinib may be associated with an improved PFS and OS compared to Erlotinib in patients with exon 19/21 EGFR mutations. A prospective P3 study comparing D to another EGFR TKI in 1L EGFR mutated NSCLC is ongoing to verify these observations (NCT01774721).

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      MINI05.09 - Discussant for MINI05.06, MINI05.07, MINI05.08 (ID 3323)

      16:45 - 18:15  |  Author(s): R. Martins

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI05.10 - EGFR-TKI Alone or with Concomitant Radiotherapy for Brain Metastases in Lung Adenocarcinoma Patients with EGFR Gene Mutations (ID 1566)

      16:45 - 18:15  |  Author(s): Y. Chen, J. Yang, X. Li, D. Hao, X. Wu, Y. Yang, X. Hu, C. He, W. Wang, J. Liu, J. Wang

      • Abstract
      • Presentation
      • Slides

      Background:
      Radiotherapy is the principal treatment modality for patients with brain metastases (BM), however, tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) shows therapeutic efficacy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. This study was conducted to compare the outcome of TKI alone with TKI plus concomitant radiotherapy in treatment of BM from EGFR-mutated lung adenocarcinoma patients.

      Methods:
      The inclusion criteria were as following: patients newly diagnosed with EGFR-mutant lung adenocarcinoma, presented with BM, TKI as first-line therapy, and ECOG PS 0-2.

      Results:
      From January 1, 2009 to September 1, 2014 at Zhengzhou University Affiliated Cancer Hospital, 516 lung adenocarcinoma patients with EGFR gene mutations were reviewed, and 132 cases (25.6%) with newly diagnosed BM were enrolled for the analysis. Among the 132 patients, more than half of them (n = 72; 54.5%) harbored a deletion in exon 19, 97 patients (73.5%) showed multiple intracranial lesions, and 50.8% (n = 67) had asymptomatic BM. 79 patients (59.8%) were treated with TKI alone, 53 with TKI plus concomitant radiotherapy (45 with whole brain radiotherapy, and 8 with stereotactic radiosurgery). The objective response rate of BM was significantly higher in TKI plus radiotherapy group (67.9%) compared with TKI alone group (27.8%, P<0.001). The median time to intracranial progression was 22.3 months. The median intracranial progression-free survival in patients who received TKI plus radiotherapy was 24.7 months, much longer than those treated with TKI alone which was 19.0 months, P = 0.005. Multivariate analysis showed brain radiotherapy (P = 0.012) and intracranial lesion number (P = 0.070) as important prognostic factors for intracranial progression-free survival. In addition, the data of overall survival will be presented at the conference.

      Conclusion:
      For EGFR-mutated lung adenocarcinoma patients with BM, TKI plus concomitant radiotherapy achieved higher response rate of BM and significant improvement in intracranial progression-free survival compared with TKI alone. Figure 1



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      MINI05.11 - Exon 19 Deletion Prolongs Survival in Brain Metastases from Non-Small Cell Lung Cancer (ID 417)

      16:45 - 18:15  |  Author(s): H. Li

      • Abstract
      • Presentation
      • Slides

      Background:
      Approximately 20-40% of non–small–cell lung cancer (NSCLC) patients develop brain metastasis (BM) and the survival is very poor with a median overall survival of 4-6 months following whole brain radiotherapy treatment. Recent studies have shown that oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were effective for the treatment of BM from NSCLC with EGFR mutation. However, the relationship between EGFR mutations and prognosis of NSCLC patients with BM remains to be determined. In this study, we investigated the impact of EGFR mutation status on the survival of BM patients from NSCLC

      Methods:
      730 NSCLC patients were retrospectively reviewed. 136 patients had developed BM during their course of disease. 33 of these 136 BM patients (24.3%) were confirmed to have exon 19 deletions, while 33 had exon 21 point mutation (L858R) (24.3%). Overall survival was evaluated by Kaplan-Meier method. Log-rank test and Cox proportional hazards model were used to analyze the impact of pretreatment and treatment variables on survival.

      Results:
      The median survival of NSCLC with BM was 8 months. Log-rank test analysis showed that ECOG PS at BM (p=0.000), control of primary tumor (p=0.005), pathology (p=0.01), EGFR mutations (p=0.045) and 19 exon deletion (p=0.007) were associated with a longer survival. In Cox proportional hazards model, EGFR exon 19 deletion (HR=0.558, 95%CI=0.325-0.957, p=0.034), control of primary tumor (HR=2.033, 95%CI=1.098-3.766, p=0.024), and ECOG PS at BM (HR=2.033,95%CI=1.145-1.287, p=0.006) were found to be independent prognostic factors. Moreover, there were significantly differences in the survival between different groups according to RTOG recursive partitioning analysis (RPA) classification system in this cohort of patients (p=0.000)

      Conclusion:
      Exon 19 deletion is an independent prognostic factor in BM from NSCLC. Our findings suggest that the status of exon 19 deletion may be integrated into the prognostic scoring classification system for NSCLC.

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      MINI05.12 - Erlotinib Combined with Chemotherapy versus Erlotinib Alone Treating Advanced Lung Adenocarcinoma with Brain Metastases (NCT01578668) (ID 620)

      16:45 - 18:15  |  Author(s): H. Yang, Y. Zhang, M. Zhao, X. Xu

      • Abstract
      • Presentation
      • Slides

      Background:
      Erlotinib has a synergistic effect with pemetrexed when treating non-squamous non-small cell lung cancer. The aim of our study was to confirm the efficacy and safety of erlotinib (E) in combination with pemetrexed/cisplatin (E-P) in Chinese lung adenocarcinoma with brain metastases.

      Methods:
      This study is a prospecive, non-randomized cocurrent controlled study. Lung adenocarcinoma patients with brain metastases, who were erlotinib or pemetrexed treatment-naive and had adequate organ functions, were assigned in parallel to receive either erlotinib 150 mg/day or erlotinib on days 4-21 plus pemetrexed 500 mg/m[2] on day 1 and cisplatin 20 mg/m[2] on day 1-3 every 21 days up to 6 cycles and subsequent oral erlotinib, until progressive disease or unacceptable toxicity. The primary endpoint was intracranial overall response rate (ORRi). Previous data showed that about 56% of the patients treated with E and 78% of the patients treated with E-P, achieved an ORRi. We estimated the minimum sample size of 65 with 70% power (two-sided alpha 0.05).

      Results:
      69 lung adenocarcinoma patients with brain metastases had received E (n=35) or E-P (n=34) from Jan 2012 through Nov 2014. Demographics and patient characteristics were well balanced between two groups, including EGFR status, gender, age, smoking status, ECOG performance status, brain metastases and number of prior treatments. ORRi, in the E-P arm was superior to that in the E arm (79% vs. 48%, P=0.008) (Table S). Especially in the patients with EGFR wild type or treated as first-line treatment could achieve much better ORRi. Patients treated with E-P arm, compared with E arm as first-line treatment, were associated with better intracranial PFS (PFSi) (median PFSi, 9 months vs. 2 months, P=0.02) and systemic PFS (median PFS, 8 months vs. 2 months, P=0.006).The most frequent adverse events related with erlotinib were higher in the combination arm. No new safety signals were detected. The side effects were tolerable and no-drug related deaths. Table S The ORRi between the E-P and E arm

      group (n) ORRi (n,%)
      Total patients E (35) 17,48.6%
      E-P (34) 27, 79.4%
      P value 0.008
      EGFR mutation E (18) 10,55.6%
      E-P (14) 12,85.7%
      P value 0.124
      EGFR negative E (7) 1, 14.3%
      E-P (11) 7, 63.6%
      P value 0.066
      EGFR unknown E (10) 6,60.0%
      E-P (9) 8,88.9%
      P value 0.303
      First-line treatment E (16) 7,43.7%
      E-P (18) 14 ,77.7%
      P value 0.08


      Conclusion:
      The combination of erlotinib and pemetrexed/cisplatin is effective and improved PFS as first-line treatment in Chinese lung adenocarcinoma with brain metastases. Toxicities are tolerable and the erlotinib-related side-effects were higher.

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      MINI05.13 - Treatment of EGFR/ALK-Driven Non-Small Cell Lung Cancer (NSCLC) Brain Metastases: Impact of First-Line Whole Brain Radiotherapy on Outcome (ID 1251)

      16:45 - 18:15  |  Author(s): M.K. Doherty, G. Korpanty, P. Tomasini, M. Alizadeh, K. Jao, C. Labbe, C. Mascaux, P. Martin, S. Kamel-Reid, M. Pintilie, G. Liu, P. Bradbury, R. Feld, N. Leighl, C. Chung, F. Shepherd

      • Abstract
      • Presentation
      • Slides

      Background:
      Brain metastases (mets) in EGFR/ALK-driven NSCLC are common, and frequently pose treatment dilemmas. Effective systemic therapy with tyrosine kinase inhibitors (TKIs) controls extracranial disease in up to 70% of patients, but often radiotherapy is required for intracranial control. As whole brain radiation (WBRT) may be associated with neurocognitive toxicity, we aimed to evaluate the impact of molecularly targeted therapy and stereotactic radiotherapy (SRS) for EGFR/ALK-driven NSCLC on intracranial disease control with and without WBRT.

      Methods:
      This retrospective analysis included patients treated with EGFR/ALK-positive NSCLC at Princess Margaret Cancer Centre from 1998-2015, with brain mets at lung cancer diagnosis or during treatment/follow-up. Demographic data were collected from electronic patient records. Time to intracranial progression (TTIP) and overall survival (OS) were calculated from date of diagnosis of brain mets, using the cumulative incidence function and Kaplan-Meier methods respectively; differences between groups were tested with Gray’s or log-rank test.

      Results:
      From 1998-2015, 162 patients with brain mets from EGFR/ALK-driven NSCLC were identified: 138 in the EGFR cohort, 23 in the ALK cohort and one included in both cohorts for analysis, whose tumour carries both an EGFR mutation and ALK rearrangement. Table 1 contains clinical characteristics and treatment details. In the EGFR cohort, initial brain mets treatment consisted of systemic therapy alone in 19 patients (17 TKI, 2 chemotherapy), SRS +/- surgery in 27 patients and WBRT +/- SRS/surgery in 88 patients. 1-year intracranial progression rates were 26%, 32% and 12%, respectively, and median TTIP was 18, 16 and 40 months [p=0.12]. Median OS was 26, 27 and 34 months respectively [p=0.49]. In the ALK cohort, initial brain mets treatment consisted of systemic therapy alone in 4 patients (1 TKI, 3 chemotherapy), SRS/surgery alone for 4 patients and WBRT +/- SRS/surgery for 15 patients. 1-year intracranial progression rates were 50%, 50% and 13%, respectively, and median TTIP was 18, 14 and 69 months [p=0.028]. Median OS was 35 months, not reached and 51 months, respectively [p=0.75]. Multivariable analysis for the whole group showed that age [p=0.021], number of brain mets [p=0.012] and extracranial control [p=0.008] were significantly associated with OS, but not WBRT [p=0.61].

      Conclusion:
      In this cohort of patients with brain mets from EGFR/ALK-driven NSCLC, patients treated with WBRT trended to longer TTIP. Although not statistically significant, our data also show a trend towards longer survival in patients who received WBRT. These observations require further validation in this patient population.

      EGFR (N=139) ALK (N=24)
      Median Age (Range) 59(29-86) 53(31-77)
      Female Sex 93(67%) 15(62%)
      Ethnicity Asian Caucasian Other 58(42%) 63(45%) 18(13%) 7(29%) 13(54%) 4(17%)
      Smoking Never Smoker Former/Current Smoker Unknown 108(77%) 30(22%) 1(1%) 19(79%) 5(21%) 0
      ECOG PS (Diagnosis) 0 1 2-4 66(48%) 67(48%) 6(4%) 7(29%) 14(58%) 3(13%)
      Brain Mets at Stage IV diagnosis 93(67%) 13(52%)
      Number of Brain Mets 1 2-4 5+ N/A 32(23%) 39(28%) 62(45%) 6(4%) 9(38%) 6(24%) 9(38%) 0
      Symptomatic Brain Mets No Yes 78(56%) 61(44%) 16(67%) 8(33%)
      Initial Brain Mets treatment WBRT WBRT+SRS/Surgery SRS+/-Surgery Systemic Therapy None 71(51%) 17(12%) 27(19%) 19(14%) 5(4%) 13(54%) 3(12%) 4(17%) 4(17%) 0


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      MINI05.14 - Discussant for MINI05.10, MINI05.11, MINI05.12, MINI05.13 (ID 3324)

      16:45 - 18:15  |  Author(s): B.J. Solomon

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MINI 22 - New Technology (ID 134)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 13
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      MINI22.01 - Detecting ALK, ROS1 and RET Fusion Genes in Advanced Non-Small Cell Lung Cancer (NSCLC) Using a Novel Multiplexed NCounter-Based Assay (ID 2254)

      16:45 - 18:15  |  Author(s): N. Reguart, A. Gimenez-Capitan, M.A. Molina, P. Galvan, L. Pare, S. Viteri, C. Teixidó, S. Rodriguez, J. Castellví, E. Aldeguer, N. Viñolas, R. Rosell, A. Prat

      • Abstract
      • Presentation
      • Slides

      Background:
      Gene fusions of anaplastic lymphoma kinase (ALK), ROS1, and RET are targetable oncogenes present in approximately 9% of advanced NSCLC. Current assays for detecting gene fusions are based on FISH (FDA-approved companion diagnostic test for ALK), immunohistochemistry (IHQ) and qRT-PCR. These tests, however, are complex and have disadvantages in terms of turnaround, sensitivity, cost and throughput. The nCounter platform allows joint detection, in a single tube, without any enzymatic reaction and in 72 hours, of multiple fusion genes by transcript-based method from formalin-fixed paraffin-embedded (FFPE) samples.

      Methods:
      A custom set consisting of 5´and 3´ probes and/or fusion-specific probes to detect ALK, ROS1 and RET fusion transcripts was evaluated. A panel of ALK-ROS-RET positive cell lines (H2228, H3122 [EML4-ALK], SU-DHL-1 [NPM-ALK], HCC78 [SLC34A2-ROS], BaF3 pBABE [CD74-ROS], LC2/ad [RET]) and control fusion negative cell lines (PC9, H1975 [EGFR mut], H460, H23 [KRAS mut]) were used for nCounter validation. To determine the minimum of tumor surface area for detection, ALK translocated cell line H2228 was tested in FFPE at increasing cell numbers (2500, 5000, 10.000, 25000, 50000) corresponding to a surface area of 0.27, 0.55, 1.1, 2.75 and 5.5 mm2, respectively, in the FFPE block. A total of 38 FFPE samples positive by FISH, IHC and/or qRT-PCR for ALK (n=30), ROS (n=7) and RET (n=1) were also analyzed. Total RNA was isolated from cell lines and FFPE and < 225 ng were used for hybridization. Raw counts were normalized using positive controls, negative controls and 4 house-keeping genes (GAPDH, GUSB, OAZ1 and POLR2A) as described in Lira et al. J Mol Diagn 2013. Positive and negative ALK fusion translocation was defined by a 3’/5’ ratio score of > 2.0 and ≤ 2.0 respectively. Response to crizotinib by RECIST criteria was retrospectively collected in patients with ALK-positive NSCLC.

      Results:
      nCounter sensitivity to predict fusion transcripts ALK, ROS and RET in cell lines by using both methods (3’/5’ and direct reporter probes) was 100%. Results indicate that samples containing as few as 10% positive tumor cells and a 2.75 mm2 tumor surface area were sufficient for adequate gene fusion detection. The accuracy of prediction (AUC) of ALK 3’-5’ ratio score in 45 independent samples was 82.6% (95% CI 69.3-95.6) with a kappa coefficient score of 0.637. Among 28 samples ALK-FISH-positive, ALK 3’-5’ scoring was positive in 27 samples (96%). One sample was non-evaluable by ALK 3’-5’ scoring. Among the 17 samples ALK-FISH-negative, ALK 3’-5’ score was negative and positive in 10 (59%) and 7 (41%) samples, respectively. All patients with ALK-FISH-negative samples but ALK 3’-5’ score positive (n=7) were positive for ALK IHC and 5 of them were treated with crizotinib. Response assessment was available in 3 of these patients and response rate was 100%. One patient non-evaluable by FISH but positive 3’-5’ scoring also responded to crizotinib.

      Conclusion:
      The ALK/ROS1/RET nCounter-based assay is a highly sensitive screening modality that might identify FISH-negative/non-evaluable NSCLC patients who could benefit from ALK inhibitors.

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      MINI22.02 - Clinically Adoption of MSK-IMPACT, a Hybridization Capture-Based next Generation Sequencing Assay, for the Assessment of Lung Adenocarcinomas (ID 2881)

      16:45 - 18:15  |  Author(s): M.E. Arcila, A. Zehir, H. Yu, A. Drilon, B.T. Li, G.J. Riely, N. Rekhtman, O. Lin, D. Hyman, M. Berger, C.M. Rudin, M.G. Kris, M. Ladanyi

      • Abstract
      • Presentation
      • Slides

      Background:
      Mutation analysis plays a central role in the management of lung adenocarcinomas (LUAD). The use of multiple single gene or mutation specific assays, broadly adopted in many laboratories to detect clinically relevant genomic alterations, often leads to delays if sequentially performed, tissue exhaustion, incomplete assessment and additional biopsy procedures. Comprehensive assays using massively parallel “next-generation” sequencing (NGS) offer a distinct advantage when addressing the increased testing needs of genotype-based therapeutic approaches. Here we describe our experience with a 410 gene, clinically validated, hybrid-capture-based NGS assay applied to testing of LUAD.

      Methods:
      Consecutive LUAD cases submitted for routine mutation analysis within a 1 year period were reviewed. Unstained slides of formalin fixed, paraffin embedded tissue were received for each case (range 15-20 slides/case). Corresponding H&E stained slides were reviewed and cell counts were performed in a subset of cases with limited material to establish minimal tissue requirements. Testing was performed by a laboratory-developed custom hybridization-capture based assay (MSK-IMPACT) targeting all exons and selected introns of 410 key cancer genes (J Mol Diagn 17:251-264, 2015). Barcoded libraries from tumor / normal pairs were captured and sequenced on an Illumina HiSeq 2500 and analyzed with a custom analysis pipeline.

      Results:
      A total of 469 specimens were received for comprehensive testing (98 cytology samples, 239 needle biopsies, 132 large biopsies/resections) of which 93% (436/469) were successfully tested. Thirty four cases (7%, 34/469) failed due to very low tumor content or low DNA yield. Cell counts for failed samples averaged 239 cells / slide (range 10-270) while all successfully tested had over 1,000 cells / slide each. Failure rate was similar for cytologies and biopsies. An average of 10 genomic alterations were detected per patient (range 1-96). The most frequently mutated genes were TP53, EGFR, KRAS, KEAP1 and STK11. Copy number gains of NKX2-1 and EGFR genes and CDKN2A loss were most common. EGFR mutations and ALK fusions were detected in 28% and 4% of cases, respectively. Among the 299 EGFR / ALK WT cases, MSK-IMPACT uncovered targetable genomic alterations that would have remained undetected through focused EGFR/ALK testing alone. These included fusions in RET (10) and ROS1 (13), mutations in ERBB2 (11) and BRAF (19) and amplifications in MET (12, unrelated to EGFR), MDM2 (26) and CDK4 (20) among others. The higher than expected rates of RET and ROS1 fusions are related to enrichment of previously tested cases known to be negative for other driver alterations.

      Conclusion:
      Comprehensive hybrid-capture based NGS assays such as MSK-IMPACT are an efficient testing strategy for LUAD across sample types. This upfront broad approach enables more optimal patient stratification for treatment by targeted therapeutics.

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      MINI22.03 - Next Generation Immunohistochemical Stains; True Multiplex (Quadruple) Immunohistochemical Panel for Non-Small Cell Lung Carcinoma (ID 2119)

      16:45 - 18:15  |  Author(s): C.C. Solomides, R. O'Neill, L. Behman, T. Shingler, J. Ashworth-Sharpe, B. Kelly, E. Roberts, L. Morrison

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the most common cancer worldwide and has the highest mortality rate. Carcinomas comprise 95% of all lung cancers, the vast majority of which are non-small cell lung carcinomas (NSCC). It is critical to further distinguish adenocarcinomas from squamous carcinomas in order to optimize the efficiency of the precision medicine analysis for the detection of active molecular targets for therapies. Currently Thyroid Transcription Factor-1 (TTF-1) and Napsin-A are the most commonly used immunohistochemical (IHC) stains to identify primary lung adenocarcinoma, and p40 and cytokeratin 5/6 (CK5/6) are used for squamous cell carcinoma. IHC stains for these markers, are performed either individually (IHC brown staining) or in combination as dual immunostains (i.e. TTF-1 + Napsin-A and p40 + CK5/6, utilizing brown and red chromogens). Here we present a novel, truly multiplex immunohistochemical approach that combines staining with the above four antibodies on a single tissue section utilizing four different chromogens to accurately diagnose primary lung adenocarcinomas, squamous cell carcinomas, and combined adenosquamous carcinomas of the lung.

      Methods:
      Developmental reagents from Ventana Medical Systems, Inc. were leveraged for this study. Detection of CK 5/6 and p40 [BC28] was used to identify squamous cell carcinoma cells. Detection of Napsin A and TTF-1 was used to identify adenocarcinoma cells. Detection was accomplished using secondary antibody:enzyme conjugates and orthogonal chromogenic detection chemistries to simultaneously detect all 4 biomarkers. Fully automated multiplexed detection was performed on a Benchmark XT with 4 microns thick sections from formalin fixed paraffin embedded, non-small cell lung cancer specimens obtained from both the Ventana Medical Systems, Inc. tissue bank and from the Thomas Jefferson University’s Department of Pathology, Anatomy and Cell Biology laboratories. Detection of each marker in multiplex was compared to individual detections using diaminobenzidine deposition according to established Ventana Medical Systems, Inc. protocols. All detections were reviewed by a board certified pathologist.

      Results:
      Adenocarcinomas (7 of 7) and the adenocarcinoma components of the adenosquamous carcinomas (6 of 6) stained positive for TTF-1 (yellow nuclear stain) and Napsin-A (pink cytoplasmic granular stain). Squamous cell carcinomas (5 of 5) and the squamous cell carcinoma components of the adenosquamous carcinomas (6 of 6) stained positive for p40 (blue nuclear stain) and CK5/6 (brown cytoplasmic stain). The colors were clear, distinct, easily differentiated and recognizable. There was no discrepancy between the expression of the individual antibodies and the expression of the same antibodies in the multiplex setting.

      Conclusion:
      Increasingly, the diagnosis of lung cancer is established by examination of small tissue specimens obtained by minimally invasive techniques. It is critical to employ these tissues at maximum efficiency in order to render an accurate pathologic diagnosis and to perform theranostic studies, either genomic or IHC, to demonstrate genetic mutations that make patients eligible for molecularly targeted agents. This new quadriplex IHC offers the capability with a single 4 micron section to accurately diagnose primary lung adenocarcinoma, squamous cell carcinoma or adenosquamous carcinoma and while conserving tissue for additional molecular testing.

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      MINI22.04 - Discussant for MINI22.01, MINI22.02, MINI22.03 (ID 3550)

      16:45 - 18:15  |  Author(s): J. Botling

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI22.05 - Quality Control Process for NGS to Minimize False Positives (ID 2989)

      16:45 - 18:15  |  Author(s): C.D. Morrison, J. Conroy, A. Papanicolau-Sengos, M.K. Nesline, J. Mastroianni

      • Abstract
      • Presentation
      • Slides

      Background:
      Next generation sequencing (NGS) has exceptional sensitivity, but at the expense of false positives. This can result in a less than optimal positive predictive value and eventually the futile treatment of patients. We have developed a unique set of quality control filters for both Ion Torrent and Illumina that minimize false positives, but have little negative impact on sensitivity. To address this paradoxical association of sensitivity and false positives, we developed a dual platform methodology of NGS using both the Ion Torrent and Illumina to solve this classical dilemma.

      Methods:
      A series of filters were developed to determine quality cutoffs for variant calls to minimize false positives that included the minimum quality score threshold (QUALT), minimum percent variant reads (MPVR), minimum variant reads (MVR), minimum variant reads threshold (MVRT), minimum variant allelic frequency threshold (MVAF), minimum variant reads positive predictive value (MVR-PPV), and systematic errors (SE). A parallel system of using the MiSeq and PGM to sequence all specimens within an IT systems control and a Classify Callsmatrix solution for mutational analysis was designed. Unique cohorts of patients with prior exome sequencing as part of TCGA were used as gold standard controls with matching fresh frozen and FFPE samples.

      Results:
      Table 1 provides the results of filters developed to maximize sensitivity versus PPV. Using our targeted sequencing panel the PGM consistently outperformed the MiSeq for the standard performance characteristics of sensitivity and PPV for both frozen and FFPE samples. Both platforms have systematic false positives that are unique and gene specific.

      Table 1 Platform Tissue VAF setting QUAL Cutoff MVRT Cutoff MVAF Cutoff Mean Sensitivity Range Sensitivity Mean PPV Range PPV
      PGM FF 0.2% None None None 100% 93-100% 88% 70-96%
      PGM FF 0.2% >99 >=20 >.035 99% 93-100% 95% 78-100%
      PGM FFPE 0.2% None None None 99% 93-100% 58% 2-94%
      PGM FFPE 0.2% >99 >=21 >.018 97% 63-100% 92% 40-100%
      MiSeq FF 1% None None None 97% 79-100% 49% 31-66%
      MiSeq FF 1% >99 >=5 >.017 95% 66-100% 82% 66-95%
      MiSeq FFPE 1% None None None 94% 43-100% 10% 2-37%
      MiSeq FFPE 1% >99 >=10 >.028 92% 39-100% 62% 6-100%
      Table 2 provides the results for dual platform sequencing which show a marked reduction in false positives while maintaining sensitivity.
      Table 2 FF FF FF FF FFPE FFPE FFPE FFPE
      SNV(s) SNV(s) Indels Indels SNV(s) SNV(s) Indels Indels
      Percent VAF Percent VAF Percent VAF Percent VAF
      Assay Sensitivity 99.8% 2.87% 100.0% 2.90% 98.3% 3.56% 100.0% 3.60%
      Assay PPV 97.5% 2.87% 91.0% 2.90% 96.7% 3.56% 91.0% 3.60%


      Conclusion:
      Single platform NGS is plagued by false positives. Dual platform sequencing is a reliable method of diminishing false positives with minimal to no impact on sensitivity.

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      MINI22.06 - The Challenge of Molecular Testing for Clinical Trials in Advanced Non-Small Cell Lung Cancer Patients: Analysis of a Prospective Database (ID 1240)

      16:45 - 18:15  |  Author(s): S. Lepers, A. Ottevaere, C. Oyen, L. Peeters, E.K. Verbeken, C. Dooms, K. Nackaerts, J. Vansteenkiste

      • Abstract
      • Presentation
      • Slides

      Background:
      Molecular testing has become important in managing advanced non-small cell lung cancer (NSCLC), both in clinical practice, as well as in clinical trials. For the latter, tissue samples often have to be analysed in a central laboratory. We evaluated the turnaround time and possible delay in start of therapy in this process.

      Methods:
      We reviewed our prospective database on all molecular testing cases for clinical trial suitability in patients with advanced NSCLC between March 1, 2011 (start) and October 31, 2014. The following time points were considered: T1 (request for tissue sections from the pathology lab); T2 (receipt of sections and shipment); T3 (arrival of sections in central lab (CL)); T4 (receipt of biomarker result from CL).

      Results:
      251 patients were considered for biomarker-driven trials. Twenty-three cases did not have further analysis, as the request for central molecular testing was cancelled: insufficient tissue (n=11); exclusion criterion (n=10); patient refusal (n=2). Results for the remaining 228 patients were: failure of central biomarker analysis due to insufficient quantity of tissue (n=18), or quality of tissue (n=3, i.e. decalcification or poor fixation). Valuable results were obtained for 207 patients. In 91 of 228 (39.9%) samples sent, a biomarker of interest was documented. This led to 34 clinical trial inclusions. Other patients were no longer eligible due to loss of performance status (n=20), loss of contact (n=14), no trial slot available at the appropriate time (n=18), or exclusion criteria (n=5). The mean waiting time between signing informed consent (T1) and receiving results of the biomarker analysis (T4) was 25.1 calendar (SD 17.3) days (Table). The preparation of the unstained slides by the pathology lab took about 9.1 (SD 6.8) days, the time of the biomarker testing itself accounted for 12.8 (SD 7.3) days. For 18 of 228 (7.9%) patients, repeated sample shipments were needed because of insufficient tumor cells, their mean waiting time between informed consent and receiving the biomarker result was 62.2 (SD 38.4) days. Table: Waiting times (t) in molecular testing for 228 patients.

      Time interval Mean StDev Median Range
      Pathology lab (T2-T1) 9.1 6.8 7.0 1 - 70
      Shipment (T3-T2) 1.8 1.6 1.0 0 - 17
      Analysis (T4-T3) 12.8 7.3 12.0 2 - 58
      Request to result (T4-T1) 25.1 17.3 22.0 7 - 184


      Conclusion:
      While molecular testing is important in many NSCLC trials, our results show that waiting times for central laboratory analysis can cause an important delay in treatment initiation, and even ineligibility for the trial(s) under consideration. Start of therapy based on properly validated local testing, with a posteriori central biomarker testing to guarantee the integrity of the trial, would be more rewarding for quite some patients.

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      MINI22.07 - An in Vitro Biomimetic Multi-Organ Microfluidic Chip System to Test Lung Cancer Metastasis (ID 1144)

      16:45 - 18:15  |  Author(s): Q. Wang, Z. Xu, E. Li, Z. Guo

      • Abstract
      • Slides

      Background:
      Lung cancer is the leading cause of cancer mortality worldwide, and metastatic spread of cancer to distant organs is the main reason for lung cancer deaths. They spread to different distant organs, exhibit an outstandingly different situation of clinical characteristics and will be medically and surgically incurable. Thus, there is a clear need for a reliable and efficient in vitro culture model to enable transition to invasion and journey to distant organs of these critical steps in cancer metastatic progression.

      Methods:
      Here we report a biomimetic multi-organ microfluidic chip system more closely reconstituting the structural tissue arrangements, functional complexity and dynamic mechanical microenvironments and reproducing survival, growth, transition to invasion and journey to distant multi organs in lung cancer metastasis. To reconstitute the actual growth conditions of lung cancer in vivo, we created a thin, porous, flexible membrane, integrated microfluidic chip emulating the in vivo tissue structure and enabling heterotypic cell interactions, while maintaining cell compart-mentalization. The human bronchial epithelial cells and stromal cells were cultured on opposite sides of the membrane. Once the cells were grown to confluence, air was introduced into the epithelial compartment to create an air-liquid interface and more precisely mimic the lining of the lung air space. Then lung cancer cells were cultured on the human epithelial compartment to mimic lung cancer formation and the multi organ chambers were linked with side channels that supply lung cancer cells to the brain, bone or liver cells chamber to mimic lung cancer metastasis. In addition, the system provided analyzing cell physiology and visualizing complex cell behaviors in a more physiologically relevant context.

      Results:
      A biomimetic multi-organ microfluidic chip system was created. The quick formation of lung cancer cells that grow away from their natural margins and then attack adjacent components and spread to other organs were observed at all times and the cells characterizations were also detected accurately and effectively. In this multi-organ pathogenesis system, it might be possible to provide an ultrahigh level of reproducibility, authenticity and sensitivity.

      Conclusion:
      This microdevice provides a proof of principlefor this novel biomimetic strategy that is inspired by the integrated chemical, biological, and mechanical structures and functions of the living multi organs. This versatile system enables direct visualization and quantitative analysis of diverse biological processes of the intact lung cancer metastasis in ways that have not been possible in traditional cell culture or animal models.

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      MINI22.08 - Development of a Protein Viewer for Displaying Variants of Unknown Significance in Relation to Actionable Mutations and Protein Domains (ID 2917)

      16:45 - 18:15  |  Author(s): A. Papanicolau-Sengos, M. Qin, L. Wei, J. Wang, M.K. Nesline, C. Hoeflich, K. Lahrs, J. Mastroianni, C.D. Morrison

      • Abstract
      • Presentation
      • Slides

      Background:
      Next-generation sequencing (NGS) can be used to interrogate multiple areas of the tumor genome. Several hot-spot panels have been developed to identify variants amenable to targeted therapies and enrollment into clinical trials. Variants of unknown significance (VUS) in the vicinity of hot-spots are routinely discovered. To better understand these obscure VUS, we built a Protein Viewer that displays the relationship of known actionable variant(s) to the VUS.

      Methods:
      We developed a web-based protein viewer that can be deployed across multiple browsers. The tool supports the visual representation of 23 genes which are interrogated by our NGS platform. We used the longest mRNA transcript (hg19) to define the protein domains. All actionable variants as reported by an knowledge database were included, with the selected VUS differentially highlighted. VUS is defined as a non-actionable variant that is not reported in dbSNP.

      Results:
      Approximately 50% of all stage III and IV lung cancer patients tested by our NGS platform have one or more VUS. After the variant information is loaded in the Protein Viewer, a two-dimensional image of the full length protein with actionable variants and VUS is displayed (Figure 1). The Viewer is utilized at RPCI to present cases at our molecular tumor board for quick visualization and discussion. Figure 1 Figure 1: Protein Viewer with a PIK3CA VUS harboring a Q546H (pink) in a lung adenocarcinoma. Top panel with PIK3CA exons 2-21 boundaries (vertical lines) with protein domains (blue rectangles along axis). Bottom panel with the zoom feature which allows more discreet visualization of the VUS, a neighboring Q546K actionable variant (green), and additional actionable variants for ovarian cancer (green rectangles).



      Conclusion:
      Understanding the relationship of VUS to protein domains and proximity to previously known actionable sites is a potentially powerful way to evaluate and determine whether a patient might be a candidate for targeted therapy. Because the exact effect of the VUS on the function of the protein is still impossible to discern (tyrosine kinase inhibitor sensitivity/ resistance/no effect), the next generation of protein viewers should incorporate 3D and protein folding/domain interaction prediction capabilities.

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      MINI22.09 - Discussant for MINI22.05, MINI22.06, MINI22.07, MINI22.08 (ID 3534)

      16:45 - 18:15  |  Author(s): P. Mazzone

      • Abstract
      • Presentation

      Abstract not provided

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      MINI22.10 - A New Approach to Large Scale Proteomic Profiling to Uncover Tumor Phenotypes (ID 2166)

      16:45 - 18:15  |  Author(s): R. Ostroff, K. Delisle, W.A. Franklin, L. Gold, D.T. Merrick, S. Williams, Y.E. Miller

      • Abstract
      • Presentation
      • Slides

      Background:
      Genomic profiling is a powerful method for identifying mutations that drive tumors and matching patients to targeted therapies. However, this may only be a transient solution and resistance commonly emerges as the mechanism of targeted inhibition is overcome. Proteomic profiling of the tumor provides a dynamic tool to survey altered protein expression and deregulated pathways, which in turn may implicate specific treatments or identify novel therapeutic targets. Mass spectrometry offers highly multiplexed proteomic measurements, but extensive sample pre-processing and low sample throughput can lead to extended analysis times of weeks or months. Thus a need exists for a high throughput, sensitive and quantitative platform for proteomic analysis.

      Methods:
      We used the SOMAscan proteomic platform, which measures 1129 proteins with a median limit of detection of 40 fM and 5% CV, to analyze protein lysates from 63 lung tumor samples. The assay does not require sample pre-fractionation, and this study (which generated over 142,000 protein measurements) represents less than one day of SOMAscan throughput. The study consisted of matched tumor/non-tumor protein lysates prepared from 18 squamous cell carcinoma and 45 adenocarcinoma fresh-frozen resected specimens, 86% of which were Stage I/II. The paired log~2~ tumor/non-tumor ratio was calculated and hierarchical clustering heat maps and dendrograms were constructed to identify related protein regions and tumor phenotypes.

      Results:
      Common proteomic changes and unique tumor phenotypic groups were identified by unbiased clustering algorithms. Large, consistent tumor/non-tumor differences of at least 4-fold were observed for 35 proteins in at least 20 (32%) of the tumors. Some of these proteins were more than 100-fold higher in individual tumors. The two most commonly elevated proteins were thrombospondin 2 and MMP12, which were increased in 81% and 61% of the tumors, respectively. We have previously reported higher levels of MMP12 in the serum of lung cancer patients, and the current data supports a tumor-associated origin for circulated MMP12. A second analysis identified sub-phenotypes of tumors clustered by common protein alterations independent of histological classification or mutation status. Many of these tumor subsets had increased expression of known oncology drug targets.

      Conclusion:
      Broad, unbiased high-throughput proteomic profiling of tumor tissue may reveal individual phenotypes that hold the potential to respond to targeted therapies and to monitor therapeutic efficacy throughout treatment. Measuring proteins complements mutation analysis by enabling therapeutic selection beyond driver mutation targets, including immune modulator therapies, repurposing existing drugs and enriching clinical trials with likely responders. While genomics is a fixed snapshot, blood- and tissue-based serial proteomic measurements respond to change and can lead to the personalized adaptation of treatment and identification of novel therapeutic targets.

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      MINI22.11 - A Clinical Platform for Examining Mechanism-Driven Chemotherapeutic Agents (ID 724)

      16:45 - 18:15  |  Author(s): C.P. Erkmen, E. Dmitrovsky, V.A. Memoli, K.H. Dragnev

      • Abstract
      • Presentation
      • Slides

      Background:
      There is a clinical need to establish whether those pathways activated in vitro and in animal models, are also activated in human lung cancer. We established a window-of-opportunity clinical trial platform in lung cancer where novel agents are administered in the preoperative period. Intratumoral drug concentrations are correlated with molecular marker changes. Our four completed window-of-opportunity clinical trials established that optimal intratumoral drug concentrations are needed for the desired pharmacodynamic effects, providing direction for optimal dose and schedule. To further evaluate the value of this window-of-opportunity platform, we investigate the impact on standard postoperative outcome measures.

      Methods:
      39 consecutive patients enrolled under the window-of-opportunity platform were matched to 39 contemporary patients undergoing the same operation by the same surgeon. Co-morbidities and stage of lung cancer and postoperative complications were compared using univariate and multivariate analysis. Wilcoxon Scores (Rank Sums) for variable data elements and Fisher’s Exact Test was used for analysis.

      Results:
      When comparing window-of-opportunity patients to control patients, there was no difference in age, pack years of smoking, or incidence of comorbidities including diabetes, coronary artery disease, hypertension, chronic obstructive pulmonary disease, and previous cancer. There was no difference in the stage distribution, (stage I: 28 vs. 22, stage II: 5 vs. 3, stage III: 5 vs. 2 stage IV: 1 vs. 1, p=0.1642). There was also no difference in the incidence of postoperative pneumonia (4 vs. 9, p=0.2235), other infection (2 vs. 3, p=0.8208), atelectasis (2 vs. 4, p=0.6748), myocardial infarction (0 vs. 0, p=1.000), reoperation for bleeding (1 vs. 1, p=1.000), pulmonary embolism (1 vs. 2, p=1.000) or number patients experiencing any complication (14 vs. 8, p=0.131118). There was no difference in the distribution of survival at 2 years (27 vs. 30) or 5 years (10 vs. 15), p=0.2266.

      Conclusion:
      The window of opportunity platform does not increase the perioperative risk of complications in early stage NSCLC patients undergoing surgery. By evaluating drug effect and the potential toxicities, window-of-opportunity trials validate mechanisms established in the laboratory and facilitate bi-directional translation research.

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      MINI22.12 - Molecular Characterisation of SCLC Using Both Circulating Tumour DNA and Circulating Tumour Cells Isolated from the Same Whole Blood Sample (ID 251)

      16:45 - 18:15  |  Author(s): D.G. Rothwell, N. Smith, D. Morris, H.S. Leong, Y. Li, L. Carter, F. Blackhall, C. Miller, C. Dive, G. Brady

      • Abstract
      • Presentation
      • Slides

      Background:
      Small Cell Lung Cancer (SCLC) is an aggressive, highly metastatic disease with dismal prognosis. Response rates to first line chemotherapy are generally high, but progression free survival is short due to development of chemotherapy resistance via mechanisms not well understood. Due to the difficulty in collecting tissue biopsies in SCLC, blood, which can be sampled simply and routinely, provides a means of inferring the current genetic status of a patients tumour via analysis of circulating tumour cells (CTCs) or circulating tumour DNA (ctDNA). These offer a minimally invasive opportunity to study drug resistance mechanisms, evaluate tumour heterogeneity and potentially reveal new drug targets in this disease. However, accurate assessment of both CTCs and ctDNA requires all blood cells be maintained intact until samples are processed, particularly when analytes present are at very low concentrations. Here we describe and validate a blood collection protocol that does not require on-site processing, and which is amenable for analysis of both CTCs and ctDNA following storage at ambient temperature in CellSave vacutainers for up to 96 hours after blood collection.

      Methods:
      To evaluate the suitability of using CellSave preserved samples for circulating free DNA (cfDNA) analysis, we undertook a 20 healthy normal volunteers (HNV) study and 45 patient sample study, with parallel EDTA and CellSave bloods collected. For each sample cfDNA was isolated between 4 hours and 96 hours post-draw and cfDNA yields determined. A potential issue with using CellSave blood was that the CellSave preservative could act as a DNA damaging agent and effectively increase background sequencing errors. To test this, the EDTA and CellSave cfDNA samples were subjected to next generation sequencing (NGS) to estimate the overall mutation burden. In addition, the utility of CellSave ctDNA for targeted NGS was also determined. Finally, SCLC-specific copy number aberrations (CNA) were analysed in ctDNA and CTCs isolated from the same CellSave blood sample from individual SCLC patients.

      Results:
      We demonstrate that yields of cfDNA obtained from 96-hour whole blood CellSave samples are equivalent to those obtained from conventional EDTA plasma processed within 4 hours of blood draw. Targeted and genome-wide NGS revealed comparable DNA quality and resultant sequence information from cfDNA within CellSave and EDTA samples, thereby validating CellSave blood as a viable source of ctDNA. We also demonstrate that CTCs and ctDNA can be isolated from the same patient blood sample, and give the same patterns of CNA allowing direct comparison of the genetic status of patients’ tumours.

      Conclusion:
      In summary, we have demonstrated the suitability of whole blood CellSave samples for both CTC and ctDNA molecular analysis in SCLC. The ability to generate informative molecular profiles of both CTCs and ctDNA from a simple whole blood sample, up to 4 days post-draw represents a significant methodological improvement for clinical benefit. We posit that as minimally invasive, liquid biopsies become increasingly employed for cancer patient management, the ability to routinely and simply draw blood and ship samples to accredited biomarker assessment laboratories will greatly facilitate the delivery of personalised cancer medicines.

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      MINI22.13 - Discussant for MINI22.10, MINI22.11, MINI22.12 (ID 3480)

      16:45 - 18:15  |  Author(s): E. Haura

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 03 - New Kinase Targets (ID 89)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL03.03 - EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Sensitivity to Afatinib or Neratinib but Not to Other EGFR-TKIs (ID 1748)

      10:45 - 12:15  |  Author(s): Y. Yatabe

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs),whereas exon 20 insertions (Ins20) are known to be resistant to these drugs. However, little is known about the role of mutations in exon 18. Inspired by clinical observation that a patient with adenocarcinoma harboring exon 18 deletion (Del18: delE709_T710insD) responded to afatinib, this study aimed to establish a rational therapeutic strategy for lung cancers harboring exon 18 mutations.

      Methods:
      The mutational status of lung cancers registered in Aichi Cancer Center (ACC) database between 2001 and 2015 was reviewed. Three representative mutations in exon 18, Del18, E709K, and G719A, were introduced into Ba/F3, NIH3T3, and HEK293 cells using retroviral vector. The 90% inhibitory concentrations (IC90s) of first generation (1G) (gefitinib and erlotinib), second generation (2G) (afatinib, dacomitinib, and neratinib), and third generation (3G) TKIs (AZD9291 and CO1686) in these cells were determined and compared with the corresponding IC90s in cells expressing exon 19 deletion (Del 19) and with the trough concentration (C~trough~) at the recommended doses for each drug. Clinical data on the treatment response of tumors harboring exon 18 mutations were collected from the ACC and Catalogue of Somatic Mutations in Cancer (COSMIC) databases.

      Results:
      Among the 1355 EGFR mutations registered in the ACC database, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Of note, exon 18 mutations including G719X, E709X, and Del18 were present in 3.2% (n=43), accounting for 38% of the remaining. According to the COSMIC database, exon 18 mutations accounted for 4.1% (654/16,138) of all EGFR mutations present from exons 18-21. Mutations at codons 709 and 719 accounted for 84% of all exon 18 mutations. Ba/F3 cells expressing Del18, E709K, or G719A grew in the absence of interleukin 3, and NIH3T3 cells transfected with these mutations formed foci with marked pile-up, indicating that these mutations act as oncogenic drivers. IC90s of 1G and 3G TKIs in cells transfected with Del18, E709K and G719A were much higher than those in cells transfected with Del19 (by >50-, >25-, and >11-fold, respectively). In contrast, IC90 of afatinib in these three mutations ranged from only 2- to 6-fold greater than that in Del19 and was <1/40 of its C~trough~. Notably, cells transfected with exon 18 mutations exhibited higher sensitivity to neratinib (by 25-fold for E709K, by 5-fold for G719A, and by a comparable extent for Del 18) than those expressing Del19. Western blot analyses showed that these differential sensitivities corresponded to different degrees of suppression of EGFR phosphorylation in HEK293 cells. Furthermore, analyses of the ACC and COSMIC databases clearly indicated that patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (~80%) than to 1G TKIs (35-56%).

      Conclusion:
      Our data indicated that lung cancers harboring exon 18 mutations, although rare, should not be overlooked in clinical practice and that these cases are best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits do not detect all exon 18 mutations.

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    ORAL 07 - Lung Cancer Pathogenesis (ID 91)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL07.08 - Discussant for ORAL07.05, ORAL07.06, ORAL07.07 (ID 3470)

      10:45 - 12:15  |  Author(s): Y. Yatabe

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 22 - Moving Beyond a Smoking Related-Cancer to the Young, Never-smokers and Inherited Disease (ID 117)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL22.07 - Oncogenic Profiling in Lung Adenocarcinoma Emerged in the Youth (ID 686)

      10:45 - 12:15  |  Author(s): Y. Yatabe

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR, Kras mutations and EML4-ALK translocations were frequently positive in adenocarcinoma among lung cancer, and in fewer cases HER2, BRAF mutations or RET, ROS1 translocations were identified. Although adenocarcinomas emerged in the youth are estimatedly associated with some driver oncogenes including these mutations/translocations, the detail remains unknown.

      Methods:
      We retrospectively screened 55 consecutive patients who were diagnosed as stage I-IV adenocarcinoma at the age of 40 years or less in 2009-2014. We analyzed clinical and genetic characteristics among them.

      Results:
      Out of 55 patients, 21 (38%) were male, 24 (44%) were never-smoker, and 38 (69%) were stage IV, with the median age of 36 years (range; 26-40). Forty-five patients (82%) were identified some driver oncogene. 26 (47%) had EML4-ALK translocation, 13 (24%) had EGFR mutation, and 2 (4%) had Kras mutation. We examined rare oncogenes in 10 out of 14 triple-negative patients, which revealed three patients had HER2 mutation and two had RET translocation.

      Conclusion:
      82% of adenocarcinomas emerged in the youth were identified some targetable driver oncogenes. Not only EGFR mutation or EML4-ALK translocation, rare oncogene examination is necessary especially among these populations.

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-074 - ITPKA Expression in Lung and Other Cancers, Regulated via Gene Body Methylation, Functions as an Oncogene (ID 1026)

      09:30 - 17:00  |  Author(s): Y. Yatabe

      • Abstract
      • Slides

      Background:
      Lung cancer is the leading cause of cancer mortality and accounts for 1.6 million deaths annually in the world. Lung cancers may be classified into non-small cell (NSCLC) and small cell (SCLC) lung cancers, which individually account for approximately 85% and 15%, respectively, of lung cancer cases. Despite recent advances in cancer therapy, the overall 5-year survival rate of lung cancer remains low. There remains an urgent need for discovery of novel approaches for early diagnosis and therapy. Inositol-trisphosphate 3-kinase A (ITPKA) regulates inositol phosphate metabolism and calcium signaling by phosphorylation of the second messenger inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) to inositol-1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4) (1). ITPKA has a very limited tissue expression, mainly in brain and testis. ITPKA, previously known as a neuron-specific F-actin bundling protein, has recently been shown to be overexpressed in lung adenocarcinoma and associated with increased metastatic potential (2). However, our understanding of the role and regulation of ITPKA in cancers is limited. Reference: 1. Shears SB. How versatile are inositol phosphate kinases? The Biochemical journal. 2004; 377:265-80. 2. Windhorst S, Kalinina T, Schmid K, Blechner C, Kriebitzsch N, Hinsch R, et al. Functional role of inositol-1,4,5-trisphosphate-3-kinase-A for motility of malignant transformed cells. International journal of cancer Journal international du cancer. 2011;129:1300-9.

      Methods:
      To identify potential oncogenes that are involved in the pathogenesis of lung cancer, cDNA microarray analysis was performed to search for up-regulated genes in primary lung adenocarcinomas. Inositol-trisphosphate 3-kinase A (ITPKA) was found to be overexpressed in lung ADC.

      Results:
      Using gain-of-function and loss-of-function approaches, we demonstrated that ITPKA contributes to cancer development. We also showed that methylation level in the ITPKA gene body is highly tumor-specific, and is positively correlated with its expression. Furthermore, DNMT3B-mediated methylation of the CpG island in ITPKA gene body regulates its expression via modulation of the binding of transcription activator SP1 to the ITPKA promoter. ITPKA gene body methylation first appeared at the in situ carcinoma stage and progressively increased during the multistage pathogenesis of lung carcinoma. Figure 1



      Conclusion:
      Altogether, deregulation of ITPKA may promote oncogenic transformation and function as a universal or near universal hallmark of malignancy. A novel regulatory mechanism of oncogene expression was demonstrated via gene body methylation which manipulates the binding of transcriptional factor(s) to its promoter and controls gene expression.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P2.01-059 - Does Pemetrexed/Platinum Fit All Patients with Non-Squamous Non-Small Cell Lung Cancer? A Retrospective Study of Clinical Factors and Outcomes (ID 2308)

      09:30 - 17:00  |  Author(s): Y. Yatabe

      • Abstract
      • Slides

      Background:
      Pemetrexed/platinum is one of the standard treatment regimens for patients with advanced non-squamous non-small cell lung cancer(NSCLC). The aim of this study was to examine the association between survival of lung cancer patients treated with pemetrexed/platinum and clinical factors.

      Methods:
      The medical records of advanced or relapsed non-squamous NSCLC patients treated with pemetrexed/platinum at our hospital between January 2010 and December 2013 were reviewed. Basic characteristics, histological subtypes of NSCLC, driver mutation status, TTF1 staining status and status of treatment with taxane were evaluated for association with the survival from pemetrexed/platinum started day to deaths.

      Results:
      Two hundreds nine records were reviewed. The median age was 62 (28-79), 60% were male, 40% were never smoker, 89% had an ECOG PS0-1 and 11% had a PS 2-3. The median value of CEA and CYFRA were 10.5 ng/ml and 3.0 ng/ml, respectively. 93% were diagnosed as adenocarcinoma and 7% were diagnosed as other subtypes (large, adenosquamous, sarcomatoid and not otherwise specified). 79% (81/102) had a positive TTF1 staining. 26% had EGFR mutation, 7% had ALK fusion and 11% had KRAS mutation. 36% of patients were received bevacizumab with pemetrexed/platinum. 35% of patients were treated with cisplatin. The response rate of pemetrexed/platinum was 34.8%. Median overall survival was 537days. 65% of patients were treated with taxane and the response rate was 15.0%. In multivariate analysis, poor PS(HR 1.33; p=0.027), others in histological subtypes (HR2.00; p=0.047) and K-RAS mutation(HR 2.74; p=0.021) correlated significantly with a shorter overall survival and low CYFRA(≤3.0ng/ml, HR 0.55; p=0.002) correlated significantly with a longer overall survival.

      Conclusion:
      High CYFRA, KRAS mutation and others in histological subtypes may be associated with shorter overall survival treated with pemetrexed/platinum in non-squamous NSCLC. The development of effective treatment regimens for such patients is needed to improve their outcomes.

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    PC 02 - Pro vs Con: Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? / Pro vs Con: Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) (ID 48)

    • Event: WCLC 2015
    • Type: Pro Con
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      PC02.04 - Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) - Con (ID 2033)

      14:15 - 15:45  |  Author(s): Y. Yatabe

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Great advantages of next generation sequencing have been published so far, and many new genetic alterations were found with whole genome sequencing. Targeted sequencing using next generation sequencing technique can analyze FFPE small biopsy specimens, but may be equivalent or less than the current selected testing, such as EGFR and ALK testing. Although the targeted sequencing can actually analyze multiple genes, most diagnostic panels include the genes that are frequently altered in cancer generally, thus practically useful genes are limited in terms of lung cancer, such as EGFR, ALK, ROS1, and RET. In contrast, whole exome sequencing is potentially useful, as it can comprehensively examine mRNA expression on tumor cells. In general, mRNA in clinical samples well represents tumor genetic status even with significant dilution with the normal cells, which are less active in transcription. However, it is difficult to perserve high quality RNA with clinical samples, and it is unclear that the whole exome sequencing is constantly clinically applicable for small biopsy specimens. Furthremore, there are some cases that show discrepant results between DNA and RNA based assays. As EGFR transcript is suppressed in SCLC, EGFR mutation cannot be detected with the exome sequencing in SCLC transformed as a resistant mechanism to EGFR-TKI treatment. On the other hand, current selected testing for EGFR and ALK has been confirmed with clinical trials and are adjusted to clinical demands, e.g., short turnaround time and high sensitivity.

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