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Y. Takiguchi



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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)

      10:30 - 12:00  |  Author(s): Y. Takiguchi

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-023 - Feasibility study of pemetrexed (PEM) plus bevacizumab (BV) as the first-line treatment for elderly advanced or recurrent non-squamous (non-Sq) non-small cell lung cancer (NSCLC): TORG1015. (ID 1487)

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

      • Abstract

      Background
      The addition of BV to cytotoxic agent(s) prolonged survival for non-Sq NSCLC patients (pts). However, there is no definitive evidence for the cytotoxic agent(s) plus BV is superior to the cytotoxic agent(s) alone for elderly non-Sq NSCLC. We conducted the feasibility study of PEM plus BV as the first-line treatment for elderly advanced or recurrent non-Sq NSCLC.

      Methods
      Major eligibility and exclusion criteria were followings; chemotherapy-naïve; unfit for bolus combination chemotherapy; stage III/IV or relapsed non-Sq NSCLC; age≥70; PS 0-1; no evidence of brain metastasis; no history of hemoptysis and irradiation for thorax. PEM (500mg/m[2]) and BV (15mg/kg) were administrated intravenously on day 1 every 3 weeks. The primary endpoint was toxicity and the secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the percentage of pts who completed more than 3 cycles.

      Results
      From November 2010 to April 2012, total 12 pts were enrolled. Patients characteristics were following; Male/Female=6/6; Median age (range) 78 (72-81); Histology was all adenocarcinoma; Activating EGFR mutation No/Yes/unknown=9/2/1; Stage IIIB/IV/Recurrence=2/8/2; ECOG PS 0/1=6/6; Smoking History Yes/No=6/6. Severe toxicities (Grade 3≥) were leukopenia (25%), neutropenia (25%), anemia (8%), thrombocytopenia (8%), febrile neutropenia (8%), anorexia (8%), hypertension (8%), fatigue (8%), nausea (8%), and perforation (colon) (8%). No dose-limiting toxicity and treatment-related death was occurred. Three patients achieved PR and the ORR was 25%. The median PFS and OS were 5.6 months (mo) (95% C.I. 1.1-7.9 mo) and 10.3 mo (95% C.I. 6.9-15.6 mo) in 11 evaluated pts, respectively. The 1-year survival rate was 49% (95% C.I. 12-79%). Seven of 12 pts (58%) received more than 3 cycles.

      Conclusion
      PEM plus BV as first-line treatment for elderly non-Sq NSCLC was well tolerable and promising.

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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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      P3.05-021 - Targeting HDACs to overcome cisplatin resistance in malignant plural mesothelioma (ID 3207)

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

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive cancer of the mesothelial cells and is becoming a worldwide health burden. Progress in the treatment of MPM remains difficult, underscored by the fact that no single treatment option has proven particularly effective and chemo-resistance is a common problem. However, epigenetic modifiers, such as histone deacetylase inhibitors (HDi) have emerged as a novel class of anti-cancer agent and are currently undergoing clinical trials in numerous cancers. There is also evidence to suggest that HDAC expression may play a role in the development of chemo-resistance. We investigated the levels of HDACs in MPM cell lines, patient samples and determined the effect of HDi on MPM cisplatin sensitive and resistant cell lines.

      Methods
      A panel of MPM cell lines (n=16) was screened for the expression of HDAC11, Class I (HDAC1/2/3/8) and Class II (HDAC4/5/6/7/9/10) HDACs at the mRNA level (RT-PCR) and at the protein level (Western Blot). The HDAC expression profile was determined in an isogenic cell line model consisting of a cisplatin sensitive (Parent) and resistant (CisR) MPM cell line, P31. In addition, HDAC expression was examined in panel of twenty patient samples (benign/biphasic/sarcomatoid/epithelial). Also, MPM TMAs were stained by imummo-histochemistry for HDAC5 expression. Furthermore proliferation assays (BrdU ELISA) were performed to determine the effect of two HDi on the p31 cell lines. The HDi used were Vorinostat (pan HDAC inhibitor) and 19i (selective HDAC5 inhibitor).

      Results
      HDAC11, Class I and II HDACs were detected to varying degrees at the mRNA and protein level within our cell line panel. In the P31 isogenic parent/cisplatin resistant, HDAC protein expression was decreased (HDAC2/3/4/5/7) in the CisR compared with the Parent. HDAC5 was significantly reduced at both the protein and the mRNA level (p<0.05). The expression of HDACs 1/2/3/5 were increased in the MPM patient samples (n=15) compared with benign (n=5) (HDAC2/3/5, p<0.05). HDAC5 staining in a cohort of MPM samples, demonstrated no significant association between survival and a low HDAC5 score. However females had a greater median survival than their male counterparts. Vorinostat and 19i significantly reduced the proliferative capacity of the p31 Parent and CisR. SAHA was more effective in the Parent cells compared with CisR. The effect of 19i was similar in both cell lines.

      Conclusion
      Altered HDAC expression was observed in an isogenic Parent and CisR MPM cell model. Work ongoing in non-small cell lung cancer (NSCLC) has also demonstrated significantly reduced HDAC5 levels in CisR compared with Parent. This may suggest that a reduction in HDAC expression is involved in cisplatin resistance. Reduced levels of HDAC5, in an MPM TMA, were not associated with survival. It should be noted, however that patient numbers were small and biphasic and sarcomatoid sub-types had the lowest expression levels of HDAC5. We are currently increasing our patient numbers for an additional IHC study. HDi significantly reduced the proliferative capacity of CisR and Parent MPM cells. HDAC levels may represent an important biomarker in stratifying patients for future epigenetic targeted therapies in MPM.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-045 - Combination chemotherapy with bevacizumab, docetaxel and carboplatin for chemotherapy-naive patients with non-squamous cell lung carcinoma: Phase II study. (ID 2660)

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

      • Abstract

      Background
      Some clinical studies suggested a possible advantage of bevacizumab combined with taxanes. Although carboplatin is slightly inferior to cisplatin in terms of survival, addition of bevacizumab to carboplatin may overcome this disadvantage. The aim of this study was to clarify the efficacy and safety of combination chemotherapy consisting of bevacizumab, docetaxel and carboplatin in the 1st line chemotherapy for non-squamous non-small cell lung cancer.

      Methods
      Patients who are untreatable with thoracic curative radiotherapy, with stage IIIB/IV non-squamous non-small cell lung cancer, age ranging from 20 to 74 years, PS 0 or 1, adequate organ functions, measurable lesions, and written informed consents were eligible. Combination chemotherapy consisting of bevacizumab (15 mg/kg), docetaxel (60 mg/m2) and carboplatin (AUC=6) on day 1 was administered every 3 weeks up to 6 cycles (induction phase). Unless PD, bevacizumab maintenance therapy was performed until PD (maintenance phase). The primary endpoint was median PFS to prove its superiority to the previous standard combination chemotherapy consisting of docetaxel and cisplatin with its historical median PFS of 4.6 months. With =0.05 and =0.20, calculated minimum sample size was 37, and the final determined sample size was 40. This trial was registered to the clinical trial registration system with the ID of UMIN000004524.

      Results
      Forty patients enrolled and 39 patients were analyzed. They included women in 31%, patients with PS of 0 in 67%, stage IV in 92%, EGFR mutations in 13% and unknown EGFR status in 8%. The median age was 62 years. The induction phase was delivered for 4 cycles in median (range: 1-6), and 21 patients (54%) received maintenance phase with median 4 cycles (range: 2-24). Frequent toxicities ≥ grade 3 during the induction phase in completely analyzed patients (n=32) included neutropenia (50.0%), anemia (9.4%), thrombocytopenia (9.4%), febrile neutropenia (25.0%) and hypertension (37.5%). Other toxicities ≥ grade 3 were cholecystitis, increased ALP, hyperpotassemia, proteinuria, diarrhea, appetite loss, nausea, constipation, infection, stomatitis, and cancer pain in 3.1%, respectively. Interim external reviews of 35 pts revealed ORR of 74% (26/35) and median PFS of 6.4 months (95% CI: 4.8-9.9).

      Conclusion
      The primary endpoint was met because the lower end of the 95%CI exceeded the threshold of 4.6 months. This combination chemotherapy seems promising in terms of safety and effectiveness, warranting phase III studies.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-014 - Multicenter study of zoledronic acid in lung cancer patients with bone metastasis. Thoracic Oncology Research Group (TORG) 1017. (ID 1043)

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

      • Abstract

      Background
      Bone is the most frequent site of metastasis for lung cancer, and metastatic bone disease causes pain. Furthermore, bone metastasis may produce skeletal-related events (SREs) that greatly reduce quality of life and may even lead to death. Several guidelines have recommended use of bone-modifying agents (BMA) such as zoledronic acid (ZA) at the first diagnosis of bone metastases in patients with solid tumors, continued every 3-4 weeks as long as the patient is able to tolerate therapy or until evidence of a substantial decline in performance status. However, due to the risk of osteonecrosis of the jaw (ONJ) and a perceived lack of evidence for reduced SRE in lung cancer, some physicians have hesitated to administer ZA in lung cancer patients with bone metastasis. Therefore, the main objective of the present study was both to describe real world data of ZA and to compare SREs among previous reports.

      Methods
      All patients with non-small cell lung cancer (NSCLC) accompanied by metastatic bone disease (MBD) who were administered ZA at least twice from 12 hospitals in the TORG in Japan between January 2008 and December 2009 were eligible for inclusion in the study.

      Results
      A total of 198 consecutive patients (126 men, 72 women; median age, 64 years; range, 44-89 years) were identified. Histological type was as follows: adenocarcinoma (n=131, 66%); squamous cell carcinoma (n=30, 15%); and others (n=37, 19%). About two-thirds of patients experienced SRE before starting anti-cancer therapy. Median duration of ZA administration was 106 days (range, 28-1126 days), and median number of ZA administrations was four (range, 2-41). Median time to first SRE in patients who experienced SRE after treatment was 202 days (range, 156-264 days). No ONJ was reported from the 198 patients.

      Conclusion
      We found that ZA was not used sufficiently in clinical practice in Japan. Our data suggest that ONJ during the treatment of lung cancer patients is very rare, and ZA is potentially useful in lung patients with bone metastasis.