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J.L. Arranz



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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-035 - VEGF-A 165 family of isoforms as predictive biomarkers in patients with non-squamous non-small cell lung cancer (NSCLC) treated with bevacizumab. (ID 2450)

      09:30 - 09:30  |  Author(s): J.L. Arranz

      • Abstract

      Background
      Bevacizumab is a recombinant monoclonal humanized antibody targeted against vascular endothelial growth factor (VEGF) that improves Time to Progression (TTP) in patients with advanced non-squamous NSCLC in combination with a doublet of platins, but currently no proven predictive markers exist. The VEGF-A 165 splice variant has been described as the most abundant and active isoform in cancer. Exon 8 distal splice site modifications of VEGF 165 generates the VEGF-A 165a family of isoforms, which has a pro-angiogenic effect, and the VEGF-A 165b family, with an anti-angiogenic activity in in vivo models. This study is aimed to explore the role of VEGF165a and VEGF165b isoform expression in tumors as predictive biomarkers of efficacy in patients with non-squamous NSCLC treated with a doublet of platin plus bevacizumab.

      Methods
      22 patients were included (20 adenocarcinomas and 2 large cell carcinomas): 5 received carboplatin-taxol-bevacizumab, 14 carboplatin-taxotere-bevacizumab and 3 cisplatin-gemcitabine-bevacizumab. Total RNA was isolated from clinical samples by RNeasy FFPE procedure (Qiagen). VEGF~165~a and VEGF~165~b expression was analyzed by RT-qPCR using appropriate specific primers and probes in LightCycler 480II platform at 45 cycles. Individual VEGF~165~a and VEGF~165~b family of isoforms expression was calibrated to normal tissue and the ratio between both isoforms was calculated.

      Results
      From studied cases, VEGF~165~a overexpression was detected in 14 (63.6%) cases and VEGF~165~b overexpression in 15 (68.2%) tumors. Individual overexpression for each family of isoforms was not predictive of benefit to bevacizumab therapy (p=0.933 and 0.166). However, the ratio between VEGF~165~a and VEGF~165~b was associated with TTP, correlating a predominant expression of the pro-angiogenic VEGF~165~a in tumor with a significant benefit compared with cases with predominant VEGF~165~b expression (median TTP, 15 vs. 8 months respectively, p=0.005). The expression of both family isoforms did not impact on overall survival (p=0.477).

      Conclusion
      The overexpression of VEGF~165~a family of isoforms associated with a low expression of VEGF~165~b correlated with benefit to anti-angiogenic therapy in this small cohort of advanced NSCLC patients, supporting a potential use as predictive biomarkers for bevacizumab treatment in stage IV non-squamous NSCLC.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-004 - Phase II study of carboplatin-docetaxel-bevacizumab as front-line treatment in patients with stage IV non-squamous non-small-cell lung cancer. Analysis of the bevacizumab (BVZ) maintenance population (ID 3008)

      09:30 - 09:30  |  Author(s): J.L. Arranz

      • Abstract

      Background
      BVZ combined with carboplatin-paclitaxel as initial treatment followed by BVZ maintenance improves overall survival in advanced non-squamous non-small-cell lung cancer. We conducted a phase II trial in order to study the efficacy and tolerability of a regimen consisting of BVZ-carboplatin-docetaxel in these patients. The objectives were to assess the efficacy and safety of this combination and to evaluate the impact of BVZ in patients who received maintenance BVZ after initial combined treatment compared with patients who did not continue with maintenance BVZ.

      Methods
      Patients were treated with carboplatin (AUC 5), docetaxel (75 mg/m2), and BVZ (7.5 mg/kg) on day 1 every 21 days, up to 6 cycles. Patients with an objective response or stable disease continued maintenance BVZ (7.5 mg/kg) every 21 days until disease progression or unacceptable toxicity . Performance Status-2, brain metastases, tumor cavitation, central tumors and mild hemoptysis were not exclusion criteria.

      Results
      Thirty-seven patients were enrolled into the study. 26 male, 11 female. Median age was 64 years (39 – 82). ECOG 0/1/2: 3.5%/70%/27.5%. 34 patients had adenocarcinoma and 3 undifferentiated large cell carcinoma. The median number of cycles for chemotherapy + BVZ was 6 (3-6) and 9 (3 – 22) for maintenance BVZ. All patients were evaluable for efficacy and toxicity. Overall response rate was 70.3% (complete response 2.7%, partial response 67.6%). 21.6% remained in stable disease and 8.15% progressed. Median progression-free survival was 10 months and median overall survival was 19 months. Patients who continued with maintenance BVZ obtained a significant benefit in progression-free survival (10 vs 6 months, p= 0.047) and median survival (20 vs 7 months, p= 0.003). The most frequent grade 3-4 adverse events were neutropenia in 18%, febrile neutropenia in 12%,nausea/vomiting in 12%, diarrhea, hemoptysis in 6% of the patients respectively. Two toxic deaths were observed.

      Conclusion
      A regimen consisting of carboplatin, docetaxel, and BVZ followed by maintenance BVZ has shown to be feasible and very effective as front-line treatment in a non-selected population. Maintenance BVZ obtains a significant impact in progression-free survival and overall survival.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-042 - Thymidylate synthase expression as predictive biomarker of pemetrexed sensitivity in advanced thoracic cancer patients. (ID 2972)

      09:30 - 09:30  |  Author(s): J.L. Arranz

      • Abstract

      Background
      Although a high level of thymidylate synthase (TS) expression in malignant tumours has been suggested to be related to a reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in routine clinical samples from patients treated with this drug. The purpose of this study was to evaluate the impact of quantitative TS expression in tumor cells as predictor of the efficacy in patients with advanced non-small cell lung cancer, small cell lung cancer (SCLC) and mesothelioma treated with pemetrexed in our institution.

      Methods
      54 patients were included in this study: 40 stage IV NSCLC (26 adenocarcinomas, 11 large cell, and 3 squamous cell carcinoma), 3 SCLC and 11 mesothelioma. 21 patients received platins-pemetrexed as first line NSCLC, 20 pemetrexed in monotherapy as second and further lines and 3 carboplatin-pemetrexed fo extensive disease SCLC. Total RNA was isolated by RNeasy FFPE procedure (Qiagen). The expression of TS was analyzed by RT-qPCR using appropriate mRNA specific primers and probes in LightCycler 480II platform at 45 cycles. TS levels was calibrated to expression in normal tissue.

      Results
      From 54 cases, TS expression data were available in 32 cases, detecting overexpression in 23 (71.8%) and low expression in 9 (28.2%) patients. The response rate for patients with low TS expression was 0.63 compared with 0.15 in patients with overexpression (p=0.015). A significant benefit in time to progression was observed in patients with low expression (median TTP 12 vs. 2 months respectively, p= 0.002), whereas did not impact on overall survival (median OS 20 vs. 19 months respectively, p= 0.595).

      Conclusion
      TS overexpression in tumor cells correlated with a reduced response to pemetrexed-containing chemotherapy and might be used as a predictive biomarker in advanced lung and mesothelioma cancer patients.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-044 - KRAS, EGFR mutations and EGFR gene copy status as predictive markers of response and time to progression in EGFR wild-type stage IV non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine-kinase inhibitors. (ID 2991)

      09:30 - 09:30  |  Author(s): J.L. Arranz

      • Abstract

      Background
      KRAS mutations on codons 12, 13 and 61 result in the constitutive activation of protein, which may render tumor cells independent of Epidermal Growth Factor Receptor (EGFR) signalling and thereby resistant to tyrosine-kinase inhibitor (TKI) therapy in NSCLC patients. This study was aimed to evaluate the associations of KRAS and EGFR copy number alteration and mutations with response and time to progression (TTP) in EGFR TKI treated patients.

      Methods
      KRAS mutations on codons 12, 13 and 61 result in the constitutive activation of protein, which may render tumor cells independent of Epidermal Growth Factor Receptor (EGFR) signalling and thereby resistant to tyrosine-kinase inhibitor (TKI) therapy in NSCLC patients. This study was aimed to evaluate the associations of KRAS and EGFR copy number alteration and mutations with response and time to progression (TTP) in EGFR TKI treated patients.

      Results
      KRAS mutation was detected in 15 (17.8%) cases, EGFR mutation in 27 (32.1%) and EGFR amplification in 8 (9.5%). Significant differences were detected in response rates for wild-type compared with mutant KRAS ( 20 vs 0%, p=0.023), mutant compared with wild-type EGFR (59 vs 8%, p=0.007), and EGFR-amplified compared with non-amplified (71 vs 18%, p=0.005). Additionally, significant benefit from TKI therapy was observed for KRAS wild-type compared with KRAS mutated patients (median TTP 7 vs. 3 months, p=0.001), for EGFR-mutated compared with wild-type patients (14 vs. 4 months, p=0.004) and for EGFR-amplification in contrast to non-amplified cases (11 vs. 5 months, p=0.001). KRAS and EGFR mutations or EGFR amplification did not correlated with overall survival (18 vs. 19 months, p=0.406; 16 vs. 21 p=0.094; 25 vs. 17 months, p=0.103, respectively). Combined analysis of favourable status of three biomarkers strongly predicted benefit to TKI therapy (median TTP 15 vs. 3 months, p<0.001).

      Conclusion
      Combined analysis of KRAS mutation, EGFR mutation and EGFR amplification in EGFR TKI treated NSCLC might provide superior predictive information than single biomarker study in these patients