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S. Viteri



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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.01-008 - SiRe Next Generation Sequencing Panel: Effective Diagnostic Tool for Circulating Free DNA Analysis (ID 5624)

      14:30 - 14:30  |  Author(s): S. Viteri

      • Abstract

      Background:
      Tissue availability is a crucial point in NSCLC. The introduction of Liquid Biopsies allows to determine circulant biomarkers, specifically using free DNA. To simultaneously analyze multiple patients sample at high sensitivity, Next Generation Sequencing (NGS) can be narrowed to target a limited number of actionable genes. Here we prospectically applied a lab-developed narrowed gene panel (SiRe) to produce a DNA library covering 568 actionable mutations in six gene (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRα).

      Methods:
      This daily clinical practice study was performed on cfDNA obtained from Non Small Cell Lung Cancer blood samples (serum and plasma) prospectically collected either prior to treatment administration in patients without tissue availability (n = 46) or after a progressive disease (n = 19) from a first line gefitinib (n = 14) or afatinib (n = 5) therapy.

      Results:
      SiRe detected an activating EGFR mutation in 4/46 (8.9%) cases and in T790M in 9/19 (47.4%) at the time of tumor progression. Using tissue data as gold standard, the SiRe panel showed a sensibility of 90.5% and specificity of 100%.

      Conclusion:
      The SiRe panel is an effective tool enabling the implementation of NGS for cfDNA mutational profiling in molecular pathology practice.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 1
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      P2.06-010 - AZD9291 as 1st-Line Therapy for EGFR Mutant NSCLC Patients with Concomitant Pretreatment EGFR T790M Mutation. The AZENT Study (ID 4267)

      14:30 - 14:30  |  Author(s): S. Viteri

      • Abstract

      Background:
      Osimertinib (AZD9291) is a selective and irreversible pyrimidine-based inhibitor of the primary activating and the secondary EGFR mutation, T790M, which is the most common mechanism of acquired resistance to 1st and 2nd-generation EGFR tyrosine-kinase inhibitors (TKIs). Progression-free survival (PFS) with osimertinib was 9.6 and 2.8 months (m) for EGFR mutated (EGFR+) NSCLC patients progressing to prior EGFR TKI therapy with and without EGFR T790M mutation, respectively, indicating that the T790M is a predictive biomarker for osimertinib efficacy. Sixty patients from two expansion cohorts of the same study, received 1st-line osimertinib and obtained a PFS of 19.3m. T790M, arising in cis with the primary activating mutation, confers resistance to EGFR TKIs, even in the absence of drug selection. The coexistence of the pretreatment T790M mutation has been under appreciated, in spite of accumulative evidence that is present in a frequency of 35-60% using different detection methods. In our experience, pretreatment T790M mutation is frequently detected by three specific aspects of the method: tumor microdissection, examination of two separate tumor areas, and the use of a peptic nucleid acid clamp that inhibits wild-type allele amplification. Thus, we designed the first phase IIa study to evaluate the safety and efficacy of osimertinib as 1st-line therapy for patients with metastatic EGFR+ NSCLC and concomitant pretreatment T790M mutation.

      Methods:
      This is a multicenter, single-arm, open-label, non-controlled phase IIa clinical study in Spain. Eligible patients are aged ≥18 years with metastatic EGFR+ NSCLC and by central testing documented presence of pretreatment T790M mutation. Seventy-three patients will receive continuous treatment with osimertinib 80 mg daily until disease progression, intolerable adverse events, consent withdrawal or noncompliance with the study protocol. The primary endpoint is the objective response rate (ORR) assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The trial is designed to detect a ≥70% ORR in this patient population. Secondary objectives include PFS, overall survival, time to treatment failure, duration of response and disease control rate. Additional pre-specified secondary objectives of the study are the longitudinal analysis of EGFR mutations (including the T790M and the C797S mutations) in plasma and serum and the expression analysis of a panel of biomarkers with possible predictive value for osimertinib treatment.

      Results:
      Not applicable

      Conclusion:
      Not applicable

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-047 - Co-Activation of STAT3 and YAP1 Signaling Pathways Limits EGFR Inhibitor Response in Lung Cancer (ID 4168)

      14:30 - 14:30  |  Author(s): S. Viteri

      • Abstract

      Background:
      EGFR tyrosine kinase inhibitors (TKIs) induce early activation of several signaling pathways. Interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) hyper-activation occur following EGFR TKI therapy in EGFR-mutant NSCLC cells. We explored the relevance of co-targeting EGFR, STAT3 and Src-YES-associated protein 1 (YAP1) signaling in EGFR-mutant NSCLC.

      Methods:
      We combined in vitro and in vivo approaches to explore whether concomitant activation of STAT3 and Src-YAP1 can limit the effectiveness of EGFR TKIs in EGFR-mutant NSCLC cells and xenograft models. In two cohorts of EGFR-mutant NSCLC patients, we examined messenger RNA (mRNA) gene expression within signaling pathways, leading to EGFR TKI resistance.

      Results:
      Gefitinib suppressed EGFR, ERK1/2 and AKT phosphorylation but increased STAT3 phosphorylation (pSTAT3-Tyr705). In EGFR mutant cells, gefitinib plus TPCA-1 (STAT3 inhibitor) abolished pSTAT3-Tyr705 but not the YAP1 phosphorylation on tyrosine 357 by Src family kinases (SFKs). The triple combination of gefitinib, TPCA-1 and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and was highly synergistic, according to the combination index. In two EGFR mutant xenograft mouse models, the triple combination of gefitinib, TPCA-1 and AZD0530 markedly and safely suppressed tumor growth. High levels of STAT3 or YAP1 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 9.6 (95%CI, 5.9-14.1) and 18.4 months (95%CI, 8.8-30.2) for patients with high and low STAT3 mRNA, respectively (p<0.001), (HR for disease progression, 3.02; 95% CI, 1.54-5.93; p=0.0013). Median PFS was 9.6 (95%CI, 7.7-15.2) and 23.4 months (95%CI, 13.0-28.1) for patients with high and low YAP1 mRNA, respectively (p=0.005), (HR for disease progression, 2.57; 95%CI, 1.30-5.09; p=0.0067). The results were similar in the validation cohort of 55 EGFR-mutant NSCLC patients treated with first-line EGFR TKI in the Department of Oncology of Shanghai Pulmonary Hospital.

      Conclusion:
      Our study reveals that STAT3 and Src-YAP1 signaling activation occurs following single EGFR TKI in EGFR-mutant NSCLC. STAT3 and YAP1 mRNA levels were significantly predictive of progression-free survival in the original as well as in the validation cohort of EGFR-mutant NSCLC patients. Co-targeting STAT3 and Src in combination with EGFR TKI could substantially improve survival.