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K. Kobayashi



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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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      O15.05 - Randomized Phase III Trial of S-1 plus Cisplatin versus Docetaxel plus Cisplatin for Advanced Non-Small-Cell Lung Cancer (TCOG0701): Subgroup Analysis. (ID 1895)

      11:15 - 11:25  |  Author(s): K. Kobayashi

      • Abstract
      • Presentation
      • Slides

      Background
      Docetaxel plus cisplatin (DP) is the only third-generation regimen that has demonstrated statistically significant improvements in overall survival and QOL by head-to-head comparison with a second-generation regimen (vindesine plus cisplatin) in patients with advanced non-small cell lung cancer (NSCLC). S-1 plus cisplatin (SP) has shown activity and good tolerability in phase II settings. Molecularly targeted agents including bevacizumab (BEV) have shown activity and safety in non-squamous (non-Sq) NSCLC.

      Methods
      Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions were randomly assigned to receive either oral S-1 80 mg/m[2]/day (40 mg/m[2] b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m[2] on day 8 every 5 weeks or docetaxel 60 mg/m[2 ]on day 1 plus cisplatin 80 mg/m[2] on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint was overall survival (OS). A non-inferiority study design was employed; the upper confidence interval (CI) limit of the hazard ratio (HR) was <1.322. Secondary endpoints included progression-free survival (PFS), response, safety, and QOL. Subgroup analysis by histology (non-Sq vs Sq) was conducted.

      Results
      From April 2007 through December 2008, 608 patients were randomly assigned to SP (n=303) or DP (n=305) at 66 sites in Japan. Patient demographics were well balanced between the two groups. Non-Sq and Sq patients in SP/DP arm was 251/247 and 50/48 respectively. Two interim analyses were preplanned. At the final analysis, a total of 480 deaths had occurred. The primary endpoint was met. OS in the SP arm was non-inferior to that in the DP arm (median survival, 16.1 vs. 17.1 months, respectively; HR=1.013; 96.4% confidence interval, 0.837-1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. The rates of febrile neutropenia (7.4% vs. 1.0%), grade 3/4 neutropenia (73.4% vs. 22.9%), grade 3/4 infection (14.5% vs. 5.3%), and grade 1/2 alopecia (59.3% vs. 12.3%) were significantly lower in the SP arm than in the DP arm. In terms of physical functioning and global functioning on the EORTC QLQ-C30 and lung cancer module (LC-13), QOL was better in the SP arm (repeated measures ANOVA: p<0.01). Subgroup analysis by histology revealed that the median OS of non-Sq and Sq patients in SP/DP group was 17.4/19.1 months and 12.3/11.7 months respectively, of which hazard ratio was 0.973 (95% CI, 0.797-1.187) and 1.239 (95% CI, 0.819-1.874). Interaction P value was 0.3004.

      Conclusion
      S-1 plus cisplatin is a standard first-line chemotherapeutic regimen for advanced NSCLC both non-Sq and Sq histology. Favorable toxicity profile of the SP regimen and encouraging outcome in patients with non-Sq prompted us to conduct a prospective study of SP plus BEV and maintenance S-1 BEV for non-SQ currently underway.

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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): K. Kobayashi

      • 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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    P1.15 - 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): K. Kobayashi

      • 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.