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M. Domine



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    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O15.02 - The Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized phase III trial of customized chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) (NCT00617656/GECP-BREC) (ID 1157)

      10:30 - 12:00  |  Author(s): M. Domine

      • Abstract
      • Presentation
      • Slides

      Background
      RAP80, a component of the BRCA1 complex, influenced outcome both in p with low BRCA1 expression treated with cisplatin (cis)/gemcitabine (gem) and in p with intermediate/high BRCA1 levels treated with cis/docetaxel (doc) or with doc alone in the SLCG phase II customized chemotherapy trial (NCT00883480). Based on these findings, the SLCG and the French Lung Cancer Group performed a prospective, randomized phase III trial in metastatic NSCLC patients to compare non-customized cis/doc with customized therapy customized according to BRCA1 and RAP80 mRNA expression levels.

      Methods
      From 2008 to 2013, patients with wild-type EGFR were randomized 1:1 to the control or experimental arm. Planned accrual was 391 patients. Treatment in the control arm was cis/doc, while patients in the experimental arm received treatment according to their BRCA1 and RAP80 levels: 1) those with low RAP80, regardless of BRCA1 levels, received cis/gem; 2) those with intermediate/high RAP80 and low/intermediate BRCA1 received cis/doc; and 3) those with intermediate/high RAP80 and high BRCA1 received doc alone. The primary endpoint was progression-free survival (PFS).

      Results
      At 15 October 2012, 279 patients had been included and the planned interim analysis was performed. PFS was 5.49 months (m) in the control and 4.38 m in the experimental arm (P=0.07). Overall survival (OS) was 12.66 m in the control and 8.52 m in the experimental arm (P=0.006). Response rate (RR) was 37.3% in the control and 27% in the experimental arm (P=0.07). In the multivariate analysis including PS, treatment arm, BRCA1, RAP80, histology, smoking status and metastatic site, only extrathoracic metastases were associated with an increased risk of progression (HR, 1.78; P=0.02). In a post hoc analysis restricted to patients with ECOG PS 0, PFS was 3.91 m in the control and 7.47 m in the experimental arm (P=0.01) for those with low RAP80 levels (experimental group 1). PFS for patients in experimental groups 1, 2 and 3 was 7.47, 7.01 and 3.22 m, respectively (P=0.02). OS for patients in experimental groups 1, 2 and 3 was 28.88, 15.86 and 11.81 m, respectively (P=0.04).

      Conclusion
      Based on the negative results for PFS at the interim analysis, accrual was closed on this study. The negative results may be due to the poor predictive capacity of RAP80 and/or to the inclusion of doc alone as a treatment in the experimental arm. In addition, doc/cis may not have been the ideal combination for the control arm. Customized chemotherapy could be further encouraged in oncogene-driven pan-negative patients with PS 0.

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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 - 16:30  |  Author(s): M. Domine

      • 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: 2
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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 - 16:30  |  Author(s): M. Domine

      • 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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      P1.11-005 - EVEREST Study: Evolution of disease-related symptoms of patients (p) with advanced non-small cell lung cancer (NSCLC) and its correlation with response to first-line (1L) treatment. (ID 3277)

      09:30 - 16:30  |  Author(s): M. Domine

      • Abstract

      Background
      The control of symptoms to maintain the health-related quality of life continues to be a priority in the treatment of advanced NSCLC. The aim of our study was to assess the evolution of the disease-related symptoms and, due to the lack of evidence, to evaluate its correlation with the response to 1L treatment in p with advanced NSCLC.

      Methods
      EVEREST is an observational prospective study carried out in 33 Spanish institutions. A total of 155 p with advanced NSCLC initiating standard platinum-based 1L treatment were included. Disease-related symptoms were assessed at baseline and after completing 4-6 cycles of 1L treatment (final visit) with the Lung Cancer Symptom Scale (LCSS) and an ad-hoc specific questionnaire evaluating their frequency. Response to treatment was assessed according to RECIST criteria.

      Results
      Baseline characteristics of the 155 p enrolled were: 76.1% male, 96.1% Caucasian, 70.3% adenocarcinoma, 16.8% squamous-cell carcinoma; median age was 62 years. ECOG PS 0/1/2: 26.5%/54.8%/14.8%. 65.3% and 12.9% of p maintained or improved the ECOG status during the study, respectively. 118 p completed at least 4 cycles of treatment. Best response to 1L treatment was: 1.7% complete response, 68.4% partial response and 26.5% stable disease. Most frequent disease-related symptoms were asthenia and pain. 1L treatment did not deteriorate disease-related symptoms compared to baseline (LCSS score was reduced 1.4 points) and an improvement in cough was observed (p=0.026). The frequency of cough (p<0.001), dyspnea (p=0.025), pain (p=0.009) and discomfort (p=0.034) were significantly reduced. No significant correlation with response to treatment and the evolution of symptomology between visits was found.

      Conclusion
      1L treatment was associated with a reduction of the frequency (cough, dyspnea, pain and discomfort) and intensity (cough) of disease-related symptoms in p with advanced NSCLC, irrespective of the response achieved.

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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 - 16:30  |  Author(s): M. Domine

      • 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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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-004 - Phase II study of sequential versus concurrent chemotherapy and radiotherapy in poor risk patients with inoperable stage III non-small cell lung cancer (NSCLC): final results of the Spanish Lung Cancer Group 00-05 study (ID 1102)

      09:30 - 16:30  |  Author(s): M. Domine

      • Abstract

      Background
      Inoperable stage III NSCLC is increasingly diagnosed in poor-risk patients for whom there is not yet a standard treatment. We conducted a randomized two-stage phase II study to assess whether sequential or concurrent chemoradiation was feasible, tolerable and showed efficacy.

      Methods
      Patients with inoperable stage IIIA and B NSCLC and at least one of the following conditions: age ≤ 75 years, ECOG PS=2, weight loss > 5%, creatinine clearance < 60 ml/min, a comorbid condition precluding the patient from being treated in a protocol for fit patients,were randomized to receive either carboplatin AUC 2.5 and vinorelbine 15 mg /m[2] both on days 1,8,22, and 29, and thoracic radiotherapy (TRT) total dose 60 Gy starting day 1 (CT arm) or, carboplatin AUC 5, days 1 and 22 and vinorelbine 25 mg/m[2] days 1, 8, 22, and 29, followed by TRT 60 Gy starting day 43 to 50 (ST arm). The primary end-point was response rate.

      Results
      From June 2001 to June 2006, 70 patients from 8 centers were included : 47 in CT arm and 23 in ST arm. Forty-eight of these patients were randomized during the first stage of the trial. By September 2004, due to a decrease in treatment compliance and an increase in early deaths in the ST arm, accrual was continued in the second stage of the trial only in the CT arm. Patient characteristics: median age 74 (49-84), Male 96%, Stage IIIB 65%; ECOG =2, 28%; Weight loss >5%, 29%; Creatinine clearence <60, 26%; Comorbidity, 70%. More than one poor risk inclusion criteria: 59 %. Fifty-eight patients completed treatment 93 % in CT arm, and 73% in ST arm. There were 2 CR and 25 PR (RR 60%) in CT arm, and 10 PR (RR 45.5%) in ST arm. Grade 3- 4 hematological toxicity was absent in CT arm and was 14% (neutropenia) in ST arm. Grade 3 and 4 non-hematological toxicities experienced by more than 5% of patients were asthenia (7%) and dyspnea (9%) in CT arm and anorexia (9%), asthenia(14%), and dyspnea (14%) in ST arm. Only one patient developed grade 3 esophagitis (CT arm) There were five deaths during treatment: two in CT arm and three in ST arm. Median PFS and overall survival rate were 6.7 (95% CI:4.9-8.5) and 16.8 months (95% CI 9.5-24), and 7.9 (95% CI:3.9-16.2) and 5.6 months (95% CI:2.7-8.9 ), for the CT arm and ST arm, respectively.

      Conclusion
      In poor-risk patients with inoperable stage III NSCLC, concurrent chemoradiotherapy outperformed sequential chemotherapy and radiotherapy, and was feasible, very well tolerated, and provided efficacy. The survival outcome with concurrent chemoradiotherapy was notably longer than anticipated.

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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-011 - Targeting epithelial to mesenchymal transition with Met inhibitors reverts chemoresistance in small cell lung cancer (ID 2082)

      09:30 - 16:30  |  Author(s): M. Domine

      • Abstract

      Background
      Met receptor phosphorylation is associated with poor prognosis in human SCLC. Several Met inhibitors are being tested for the treatment of different neoplasms. Met activation has been shown to be an inductor of epithelial to mesenchymal transition (EMT) in a number of tumor models. The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/Met induced EMT in SCLC, to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models and to investigate the significance of EMT in human SCLC.

      Methods
      Biological features (growth, invasiveness, tumorogenesis) and chemosensitivity of SCLC models (H69) of HGF-induced EMT (H69M) were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice). Mice with mesenchymal chemoresistant SCLC xenografts were treated with etoposide, the Met inhibitor PF-2341066 (Crizotinib) and the combination. Human SCLC samples at diagnosis and relapse were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and correlated these with patient outcome. Association between clinical-pathological characteristics were tested with Chi-Square and Fisher tests. Differences in survival according to biomarker status were evaluated by log-rank and Cox regression models, assuming a 2-sided statistical significance p< 0.05.

      Results
      We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers (Snail1, SPARC, vimentin) and downregulation of E-cadherin. This derived in increased tumorogenesis, local invasion and chemoresistance in xenograft models. The combination of etoposide and PF-2341066, but not the Met inhibitor alone significantly decreased tumor growth in this chemoresistant/mesenchymal models. Moreover, Snail1, SPARC and vimentin expression in human SCLC specimens (N:87) was significantly associated with Met activation (co-localization by immunofluorescence). Expression of mesenchymal markers predicted worse survival (all p-values <0.05) in the multivariate analysis. In 5 paired biopsies, we observed upregulation of mesenchymal markers and p-Met in chemorefractory disease.

      Conclusion
      These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and support clinical trials of Met inhibitors and chemotherapy in this fatal disease.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P3.06-035 - Study of the correlations between SNPs in angiogenic genes and treatment response/ outcome in patients with advanced NSCLC (non-squamous histology) treated in first line with carboplatin, paclitaxel and bevacizumab (CPB). The ANGIOMET study. (ID 2664)

      09:30 - 16:30  |  Author(s): M. Domine

      • Abstract

      Background
      It has been demonstrated that the addition of bevacizumab to paclitaxel plus carboplatin (CPB) in the treatment of advanced NSCLC improves survival. Even though, there is a high variability in drug efficacy between patients, leading to different response rates. ANGIOMET is an exploratory study promoted by the SLCG in advanced NSCLC, non-squamous histologies (NS-NSCLC) treated in first line with a combination scheme based in CPB, designed to investigate the relationship between angiogenic mediators and the outcome and response to treatment. The primary end-point was progression-free survival (PFS), and the secondary end-points are the follows: OS, response-rates and toxicity profiles.

      Methods
      In this multicentric study, patients with stage IIIB/IV NS-NSCLC (ECOG status 0–2) were included and treated in first line with CPB. Peripheral blood samples were collected before treatment administration and DNA was purified from the leukocyte fraction. Ten SNPs of VEGF-pathway genes were genotyped in 186 samples by RT-PCR in duplicate. SNPs were related to PFS and OS (Kaplan-Meir method, log-rank test) and to response rate.

      Results
      10 SNPs were determined in 186 DNA samples. In this preliminary analysis there were data from 108 patients valid for PFS and OS analysis. Baseline characteristics of the patients were: median age, 63 years [37-80]; 74.5% male; 94.1% ECOG PS 0-1; 14% never-smokers, 100% caucasian; 89.7% adenocarcinomas, 2.8% large cell carcinomas; median number of CPB cycles was 4. There was no response assessment in 27 patients (25%), 30.6% PR, 31.5% SD and 13.0% PD. The SNP rs833061 (CC) in VEGFA correlated with lower response rates to CPB than the other genotypes (p=0.07). SNPs in KRAS and VEGFR2 were associated with PFS and/or OS in our cohort. The KRAS SNP rs10842513 (TT+CT) was associated with shorter PFS compared with the CC genotype (median: 5.39 vs 6.81 months; p=0.04, respectively). The VEGFR2 SNP rs2071559 (AA) was significantly associated with longer PFS and OS (Table 1). No significant differences in PFS or OS were observed according to other SNPs analyzed. Table 1: PFS and OS for VEGFR2 SNPrs2071559.

      PFS
      % Median (months) 95%CI p
      VEGFR2 (rs2071559)
      AA 25.6 9,408 5,084 - 13,732 0.01
      GG+AG 74.0 5,724 4,902 - 6,546
      OS
      % Median (months) 95%CI p
      VEGFR2 (rs2071559)
      AA 25.6 NR ---- 0.001
      GG+AG 74.0 12,270 8,760 – 15.780

      Conclusion
      These preliminary data indicate that genetic variation in VEGFR2, SNP rs2071559 variant AA, is associated with prognosis in advanced NS-NSCLC patients treated with CPB and may have predictive implications as biomarkers in patients treated with chemotherapy with bevacizumab. On behalf of the Spanish Lung Cancer Group (SLCG)

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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 - 16:30  |  Author(s): M. Domine

      • 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