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Y. Hasegawa



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    P1.02 - Poster Session 1 - Novel Cancer Genes and Pathways (ID 144)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.02-010 - Evaluation of the oncogenic ability of EML4-ALK to transform human bronchial epithelial cells (HBECs) (ID 1503)

      09:30 - 16:30  |  Author(s): Y. Hasegawa

      • Abstract

      Background
      Lung cancer is a highly lethal disease, and is believed to develop through a multistep carcinogenic process, which involves numerous genetic and epigenetic alterations. Among these alterations, mutations in “driver genes” such as KRAS and EGFR are found in non-small cell lung cancer (NSCLC) and they are demonstrated to contribute to a phenomenon, oncogene addiction. Recently, the EML4-ALK (echinoderm microtubule-associated protein–like 4 anaplastic lymphoma kinase) fusion gene has been discovered as a novel driver gene in a subset of NSCLC. We evaluated the oncogenic transformation ability of EML4-ALK by using an hTERT/CDK4-immortalized normal human bronchial epithelial cell (HBEC) model.

      Methods
      We used two HBEC lines, HBEC3 and HBEC4. Mutant KRAS[V12]-expressing HBEC was used as a positive control for oncogenic transformation. A lentiviral vector system was used to generate HBECs stably expressing EML4-ALK. EML4-ALK protein expression was confirmed by westernblotting, and downstream pathways were analyzed by westernblotting with phospho-specific antibodies. Malignant phenotypes of EML4-ALK-expressing HBECs were examined by WST-1 proliferation assay and liquid and soft agar colony formation assays.

      Results
      Westernblotting analysis showed that EML4-ALK was expressed in HBECs. Analysis of downstream pathways did not show significant differences between EML4-ALK-expressing and control HBECs. Introduction of EML4-ALK in HBECs increased the number of soft agar colonies but its effect was not as strong as KRAS[V12].Figure 1 A. Soft agar colony formation assay showing that EML4-ALK increased the number of colonies compared to control cells to a lesser extent than did KRAS[V12]. B. Cell proliferation assay (MTS-1) showing no significant difference between EML4-ALK-expressing and control HBECs.

      Conclusion
      EML4-ALK alone did not induce dramatic oncogenic changes in HBECs. To acquire more malignant phenotype, additional genomic alterations may be required and this is now under investigation.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-041 - A phase II trial of erlotinib for previously treated Japanese patients with advanced non-small cell lung cancer harboring EGFR mutations: results of the Central Japan Lung Study Group trial (CJLSG0904). (ID 2283)

      09:30 - 16:30  |  Author(s): Y. Hasegawa

      • Abstract

      Background
      Several prospective studies have demonstrated activating mutations in the epidermal growth factor receptor (EGFR) gene are a predictor of response to EGFR tyrosine kinase inhibitor (TKI). Erlotinib is one of EGFR-TKIs available in Japan. However, there are a few prospective reports on the efficacy and safety of erlotinib therapy in Japanese patients with previously treated advanced EGFR mutation-positive non-small cell lung cancer (NSCLC).

      Methods
      We undertook a multicenter, open-label, single-arm, phase II study. Patients with performance statuses of 0 to 2 and stage IIIB/IV NSCLC with EGFR-sensitive mutations (exon19 and 21) were eligible if they were treated with one or two prior chemotherapy regimens containing at least one platinum-based doublet. They received oral erlotinib at a dose of 150mg daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), while secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) as well as toxicity. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000002716.

      Results
      Between November 2009 to July 2012, 29 patients (median age, 68 years; range, 40-77 years) were enrolled. No complete response and 17 partial responses were observed, giving the ORR was 58.6% (95% confidence interval (CI): 38.9-76.5%). Ten patients had stable disease and 2 patients had progressive disease. Thus, the DCR was 93.1% (95% CI: 77.2-99.2%). After a median follow-up of 14.7 months (range, 5.3-37.0 months), the median PFS was 9.5 months (95% CI, 5.9-13.2 months). The median OS has not yet been reached. The most common adverse events were skin rash (96.6%; 13.8% grade ≥ 3), and hepatic function disorder including increased ALT (65.5%) and increased AST (48.3%). No interstitial lung disease events or cases of toxic death were reported.

      Conclusion
      These results indicate that erlotinib monotherapy could be a potential treatment option with favorable clinical outcomes for Japanese patients with previously treated advanced NSCLC with EGFR mutations.

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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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      P1.11-017 - First-line gefitinib therapy for elderly patients with non-small cell lung cancer harboring EGFR mutation: Central Japan Lung Study Group 0901 (ID 1413)

      09:30 - 16:30  |  Author(s): Y. Hasegawa

      • Abstract

      Background
      Recently, the elderly population of lung cancer patients is increasing worldwide. Although first-line gefitinib is one of the standard treatments for advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation, few data have been reported on elderly patients. Thus, we conducted a phase II trial to evaluate the efficacy, safety, and quality of life of first-line gefitinib therapy for this specific population.

      Methods
      Chemotherapy-naïve patients aged 70 years or older with stage IIIB or IV non-small cell lung cancer harboring EGFR activating mutation were enrolled and treated with gefitinib 250 mg daily until disease progression or unacceptable toxicity occurred. Quality of life was assessed by the Lung Cancer Subscale of the Functional Assessment of Cancer Therapy-Lung (FACT-LCS) questionnaire, before and during treatment (at 4, 8, and 12 weeks). The primary endpoint was response rate.

      Results
      Twenty patients were enrolled between June 2009 and March 2011. The median age was 79.5 years (range: 72-90). All the patients had adenocarcinoma, 13 patients (65%) were female, 12 had exon 19 deletion, and 8 had L858R mutation. Overall response rate was 70% (95% CI, 46 - 88%), and the disease control rate was 90% (95% CI, 68 - 99%). The median progression-free survival was 10.0 months and the 2-year survival rate was 55%. The median follow-up time was 26.4 months and median overall survival time has not been reached yet. The most common adverse events were rash and liver dysfunction, and grade 1 interstitial lung disease developed in one patient. No treatment-related death was observed. The scores of FACT-LCS improved significantly four weeks after the initiation of gefitinib and maintained a favorable tendency during 12 weeks (p = 0.037). Among the seven items of FACT-LCS, especially shortness of breath and cough improved significantly after 4 weeks of treatment (p = 0.046, p = 0.008, respectively).

      Conclusion
      The present study reveals that first-line therapy with gefitinib is effective and feasible for elderly patients harboring EGFR mutation and improves disease-related symptoms, especially shortness of breath and cough.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-026 - Final results of EGFR mutation reanalysis and KRAS mutation screening by Scorpion ARMS method: Phase II Study of Erlotinib for EGFR wild type Non-small cell Lung Cancer Patients. Central Japan Lung Study Group (CJLSG) 0903 trial. (ID 1529)

      09:30 - 16:30  |  Author(s): Y. Hasegawa

      • Abstract

      Background
      Erlotinib might benefit non-small cell lung cancer (NSCLC) patients with EGFR wild-type (WT) genotype based on the subgroup analysis of the BR21 trial and SATURN trial. However, the sensitivity of methods for detection of EGFR mutation can influence the evaluation of erlotinib efficacy. We conducted CJLSG0903 trial, a phase II study of erlotinib for previously treated EGFR WT NSCLC patients screened by peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp method. The efficacy and safety results of CJLSG0903 were previously reported at the ESMO meeting 2012. Here we present the final results of EGFR mutation reanalysis and KRAS mutation screening by S-ARMS method.

      Methods
      Stage IIIB or IV NSCLC patients were eligible. EGFR mutation status was screened by PNA-LNA PCR clamp method, which is known to be a highly sensitive. Primary endpoint was objective response rate (ORR). Oral erlotinib 150 mg was given daily until progression or unacceptable toxicity.

      Results
      From February 2010 and April 2012, 53 evaluable patients were enrolled. ORR was 11.3% (95% confidence interval: 4.3–23.0%). We performed preplanned reanalysis of EGFR mutation status and KRAS mutation by Scorpion ARMS (S-ARMS) methods if remaining samples from participants were available. Samples from 26 patients (49%) were available for EGFR mutation reanalysis. Only one patient who achieved partial response (PR) was EGFR mutation positive (exon 19 deletion). In 25 patients, EGFR WT genotype was reconfirmed by S-ARMS method. Two of them achieved PR. ORR was 8.0 % in patient with EGFR WT genotype confirmed by both PNA-LNA PCR clamp and S-ARMS methods. Samples from 42 patients (79%) were available for KRAS mutation screening. KRAS mutations were detected in 4 of 42 patients, and progressive disease (PD) was observed in all of KRAS mutation positive patients.

      Conclusion
      Erlotinib still shows activity in patients with EGFR WT genotype confirmed by two different highly sensitive methods. Activating KRAS mutation might be negative predictive factor for erlotinib efficacy in patients with EGFR WT genotype. (UMIN Clinical Trials Registry: UMIN000002692)