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A. Inoue



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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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      P1.10-021 - Phase II study of S-1 plus irinotecan for EGFR-mutated non-small cell lung cancer (NSCLC) resistant to both platinum-based chemotherapy and EGFR-TKI: NJLCG0804 (ID 1373)

      09:30 - 09:30  |  Author(s): A. Inoue

      • Abstract

      Background
      From the results of recent trials, both EGFR-TKI and platinum doublet are believed to be important for patients with EGFR-mutated NSCLC. However, standard subsequent regimen after the failure of those treatments remains unclear. Some reports suggested high synergistic effect between S-1 (a novel oral fluorouracil derivative) and irinotecan against TKI-resistant cell lines. We therefore conducted this phase II trial of the combination of S-1 plus irinotecan to evaluate the efficacy and safety in EGFR-mutated NSCLC patients resistant to both platinum-based chemotherapy and EGFR-TKI.

      Methods
      Eligible patients were required advanced or recurrent NSCLC with an EGFR activating mutation, disease progression (PD) during or after second- or third-line EGFR-TKI, and previous chemotherapy including platinum doublet prior to EGFR-TKI. All patients received S-1 (80 mg/m2, day 1 to 14) orally and irinotecan (70 mg/m2, day 1 and 15) intravenously every 3 weeks. The primary endpoint was disease control rate (DCR) at 8 weeks after enrollment. The estimated accrual was 23 patients to confirm a DCR of 60% as a desirable target level and a DCR of 30 % as a lower limit of interest with alpha = 0.05 and beta = 0.10.

      Results
      From February 2009 to April 2012, 25 patients were enrolled from 6 institutions. The patients comprised 5 males and 20 females with a median age of 62 years (range, 53 to 78 years). ECOG performance status was PS 0 in 4 patients and PS1 in 21 patients. The histological subtypes were: adenocarcinoma 23 patients (92%), squamous cell carcinoma 1 patient, adenosquamous carcinoma 1 patient. EGFR activating mutations were, exon 19 deletion in 17 patients and exon 21 point mutation termed L858R in 8 patients. The current line of treatment in this study was the 3rd in 22 patients and the 4th in 3 patients. The median cycles of treatment was 4 (range 1-12). The objective responses were CR 0, PR 13, SD 8, and PD 4, giving a DCR at 8 weeks of 84.0% (95% CI, 63.9-95.5%). The overall response rate was 52.0% (95% CI, 31.3-72.2%). The median PFS was 5.0 months, whereas the median overall survival was 17.1 months. There was no significant difference in efficacy between the two types of EGFR mutations. Major grade 3 or worse toxicities included neutropenia (52%), anemia (20%), febrile neutropenia (16%), diarrhea (16%), thrombocytopenia (4%), and pulmonary thromboembolism (4%). No treatment-related death was observed.

      Conclusion
      This combination therapy with S-1 and irinotecan in EGFR-mutated NSCLC that was resistant to both platinum-based chemotherapy and EGFR-TKI showed promising efficacy with manageable toxicities. Further evaluation of this regimen in comparison with other cytotoxic agents or with irreversible EGFR-TKI is warranted.

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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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      P1.11-003 - Exon 19 deletions, smoking history and gender as additional predictive factors for treatment benefit with EGFR Tyrosine Kinase Inhibitors in patients harbouring activating EGFR mutations: A Meta-analysis of 1432 patients in six randomised trials. (ID 1789)

      09:30 - 09:30  |  Author(s): A. Inoue

      • Abstract

      Background
      Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are now recognised as the standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations. Many studies consistently demonstrated superior tumour response and progression-free survival (PFS) over chemotherapy. However, there are still ongoing questions whether there are any significant differences in treatment outcomes between patients of different ethnicity, gender, age, performance status, smoking history, tumour histology and different subtypes of EGFR mutation. We performed a meta-analysis to assess the impact of these factors on the PFS benefit of EGFR-TKIs in advanced NSCLC patients harbouring activating EGFR mutations.

      Methods
      An electronic search of all randomised controlled trials comparing efficacy of first-line therapy of EGFR-TKI vs chemotherapy in advanced NSCLC patients harbouring EGFR mutation was performed. We extracted the published hazard ratio (HR) and the 95% confidence interval (CI) for PFS, if available, or obtained unpublished data, for subgroups defined by each factor. For each subgroup, pooled estimates of treatment efficacy of EGFR-TKI vs chemotherapy were calculated with the fixed-effects inverse variance weighted method. The predictive effect of each factor was analysed by a test for interaction between the factor and treatment effect; P<0.05 was considered statistically significant. All statistical tests were two-sided.

      Results
      We included 6 eligible studies, with two trials for each of these different EGFR-TKIs - Gefitinib, Erlotinib, and Afatinib – with a total of 1432 patients. As expected, overall the use of EGFR-TKIs in this mutated population significantly prolonged PFS as compared with chemotherapy (HR 0.37, 95% CI 0.32 to 0.43, P<0.001). While mutations at both Exon 19 (deletions) and at Exon 21 (L858R point mutations) were associated with significantly prolonged PFS, the benefit with Exon 19 mutations was greater: HR 0.26, 95% CI 0.21 to 0.31, P<0.001; as contrasted to Exon 21: HR 0.42, 95% CI 0.34 to 0.52, P<0.001 (treatment-EGFR mutation interaction P=0.001). Smoking status also showed differential benefit in this mutated population: never smokers: HR 0.30, 95% CI 0.26 to 0.36, P<0.001; contrasted to current or ex-smokers: HR 0.48, 95% CI 0.37 to 0.61, P<0.001; treatment-smoking history interaction P=0.003). There was also a trend for greater benefit for females with EGFR-TKI therapy as contrasted to males (HR [females] 0.32, 95% CI 0.27 to 0.38, P<0.001; HR [males] 0.42, 95% CI 0.33 to 0.53, P<0.001; treatment-gender interaction P=0.06). Interestingly, several parameters were not significant predictors of PFS benefit with EGFR-TKI treatment in this mutated population: performance status (ECOG 0 and 1 vs 2; interaction P=0.86); age (<65 vs ≥65 years; interaction P=0.58); ethnicity (Asian vs others; interaction P=0.18); and tumour histology (adenocarcinoma vs others; interaction P=0.52).

      Conclusion
      While EGFR-TKIs significantly prolong PFS in all advanced NSCLC patients harbouring classic activating EGFR mutations when compared with chemotherapy, other molecular and demographic factors have a further influence on benefit. Exon 19 deletions, never-smoking history, and possibly female gender were all associated with longer PFS in these patients when treated with EGFR-TKIs as compared with chemotherapy. These findings should enhance better trial design in future clinical trials.

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    P1.15 - Poster Session 1 - Thymoma (ID 189)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      P1.15-003 - Phase II study of amrubicin (AMR) and carboplatin (CBDCA) for invasive thymoma (IT) and thymic carcinoma (TC) : North Japan Lung Cancer Group 0803 (ID 951)

      09:30 - 09:30  |  Author(s): A. Inoue

      • Abstract

      Background
      There has been no standard chemotherapy for advanced thymic malignancies including invasive thymoma(IT) and thymic carcinoma(TC) although anthracycline or platinum agents have been commonly used for them. AMR, a new anthracycline agent, was approved for lung cancer in Japan and we had previously conducted some prospective studies of AMR combined with CBDCA for patients with small-cell lung cancer, which revealed this regimen was active with acceptable toxicity. The objective of this study is to evaluate the efficacy and safety of this combination for patients with advanced thymic malignancies.

      Methods
      Patients with histologically confirmed thymic malignancies received AMR (35 mg/m2, day1-3) and CBDCA (AUC 4.0, day1) every 3 weeks. Patients who underwent previous chemotherapy received reduced dose of AMR (30 mg/m2). The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival and toxicity profile. Assuming that ORR of 75% and 45% would indicate the potential usefulness while ORR of 50% and 20% would be the lower limit of interest, with alpha = 0.10 and beta = 0.20, for IT patients and TC patients, respectively, 18 IT patients and 16 TC patients were at least required.

      Results
      From December 2008 to October 2012, 51 patients (18 IT and 33 TC) were enrolled from 20 institutions in Japan. The ORR and disease control rate were 17% and 89% in IT, and 30% and 85% in TC. Median PFS was 7.6 months in both groups. Toxicity was generally moderate and no treatment related death was observed.

      Conclusion
      This is the largest prospective study of chemotherapy for advanced thymic malignancies. AMR combined with CBDCA was effective for TC patients with acceptable toxicities.