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S. Morita



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.10 - Phase II study of bevacizumab, cisplatin and docetaxel plus maintenance bevacizumab as first line treatment for patients with advanced non-small cell lung cancer (n-Sq NSCLC) combined with exploratory analysis of circulating cells (CEC): Thoracic Oncology Research Group (TORG)1016 (ID 1211)

      17:10 - 17:15  |  Author(s): S. Morita

      • Abstract
      • Presentation
      • Slides

      Background
      Bevacizumab has been shown to amplify efficacy against n-Sq NSCLC in combination with platinum doublet, especially taxane including regimens. Docetaxel is one of best taxane composition combined with cisplatin for first line treatment for NSCLC, and known to have anti-angiogenic effect and may act synergistically with VEGF inhibiting agent. The object of this study was to assess the efficacy and safety of bevacizumab, cisplatin and docetaxel combination treatment in patients with chemonaive n-Sq NSCLC patients. (Trial Registry: UMIN 000004368)

      Methods
      Eligible patients had advanced or recurrent n-Sq NSCLC with no prior chemotherapy. Patients having brain metastasis or history of hemoptysis were ineligible. Patients received 4 cycles of docetaxel (60mg/m[2]), cisplatin (80mg/m[2]) and bevacizumab (15mg/kg) on day1 every 3 weeks followed by Bev alone as maintenance every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was response rate (RR) and planned sample size of this phase II study was 47 patients (Simon's two-stage minimax design). We measured circulating endothelial cells (CEC) count day1 and 8 of first cycle for exploratory analysis of efficacy and safety prediction.

      Results
      From Oct 2010 to Apr 2012, 47 patients (28 males/ 19 females, median age, 61 years, 39-73) were enrolled. Stage IIIB/IV/recurrent: 5/39/3, ECOG PS 0/1: 31/16. All patients were adenocarcinoma, EGFR status: mutated/wild/unknown: 13/31/3. Bevacizumab maintenance were administered in 87% (41/47) of the patients and 9 was median number of delivered course, 4 course of induction and 5 course of maintenance. Dose reduction was required in 28% (13/47) of the patients. Thirty-five partial responses and 11 stable diseases were observed among 47 patients, yielding a RR of 74.5% (95% confidence interval: 59.7-86.1%) and disease control rate of 97.9% (88.7-99.9%), respectively. The median progression free survival duration in the patients was 9.0 (7.0-11.3) months. Grade 3/4 leukopenia, neutropenia, hypertension, nausea and febrile neutropenia were observed in 60, 96, 47, 13 and 9% of the patients, respectively. Alveolar hemorrhage (Grade 5) after 4 cycle occurred in one patient.

      Conclusion
      Bevacizumab, cisplatin and docetaxel combination followed by bevacizumab maintenance treatment was highly effective in patients with n-Sq NSCLC, with acceptable toxicity. Exploratory analysis of CEC is ongoing and will be presented.

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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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      P1.11-016 - A Prospective, Multi-center Phase II Trial on the Efficacy and Safety of Low-dose Erlotinib Monotherapy for Patients with EGFR Mutation-positive, Previously Treated Non-small Cell Lung Cancer: Results of Thoracic Oncology Research Group (TORG) Trial 0911. (ID 1385)

      09:30 - 09:30  |  Author(s): S. Morita

      • Abstract

      Background
      Several studies of erlotinib and gefitinib have shown similar benefit in terms of response and progression-free survival (PFS) for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). However, the steady-state plasma trough concentration of erlotinib was approximately 3.5 times higher than that of gefitinib when administered at the respective approved dose. Hence, low-dose treatment of erlotinib may be as effective as gefitinib or erlotinib given at full dose, with reduced toxicity and treatment cost.

      Methods
      Eligible patients were adults (over 20 years), with advanced or recurrent EGFRm+ NSCLC who had received one to three prior chemotherapy regimens, ECOG PS of 0-2, measurable lesion, and adequate organ function. Erlotinib 50 mg was administered daily until disease progression or unacceptable toxicities. Dose was escalated to 150 mg/day in case of not achieving CR or PR classified by RECIST criteria (i.e., not responded, NR) at the first 4 weeks. The primary endpoint was objective response rate (ORR); SWOG two-stage design with an early stopping rule based on response rate was used. Response was initially judged by the investigators and confirmed by the independent review committee (IRC). Finally, 26 or more responses among 40 eligible patients were to be considered as evidence of sufficient efficacy of this treatment.

      Results
      Thirty-four patients were enrolled between April 2010 and November 2012: males/females 20/14; median age 67 (range 31-81); PS 0/1/2 16/18/0; Ad/Sq 33/1. EGFR mutation types were: exon 18 and 19/19/21/other 1/21/11/1. One patient was excluded for evaluation because of not having a measurable lesion, therefore, efficacy and safety were evaluated among 33 patients. The study was closed early according to the protocol definition at the time that NR was confirmed in 15 of 33 patients, because it was determined impossible to meet the primary endpoint even if the study was continued. The IRC-judged best responses to the 50 mg/day erlotinib were: PR 18 (54.5%), SD 10 (30.3%) and PD 5 (15.2%). ORR and disease control rate were 54.5% (95%CI: 36.4-71.9%) and 84.8 % (95%CI 68.1-94.9%), respectively. In addition, 4 out of the 10 patients with SD to the initial dose yielded PR after dose escalation to 150 mg/day. At data cut-off (April, 2013), median PFS was 8.6 months (95%CI: 6.7-15.0 months). Toxicities were generally mild, with a few grade 3 or more toxicities. The only grade 3 toxicities were 2 cases with neutropenia and 1 with AST/ALT elevation. No grade 4 toxicity or treatment-related death was observed. There was no treatment-related interstitial lung disease.

      Conclusion
      Although low-dose erlotinib appeared to have a certain efficacy in this population, this study could not meet the primary endpoint. Because of its relatively lower toxicity and cost, it may be worth further evaluation for elderly or frail patients.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P2.10-014 - A phase II study of bevacizumab in combination with carboplatin and paclitaxel in patients with non-squamous (Non-Sq) non-small-cell lung cancer (NSCLC) harboring Mutations of Epidermal Growth Factor Receptor (EGFR) gene after failing First-line EGFR-Tyrosine Kinase Inhibitors (TKIs) Hanshin Oncology Group 0109 (ID 1054)

      09:30 - 09:30  |  Author(s): S. Morita

      • Abstract

      Background
      EGFR-TKIs’ mono-therapy is one of the standard 1[st] line therapy for NSCLC harboring EGFR gene mutations. Although platinum doublet ± bevacizumab recommended for 2nd line therapy after failing EGFR-TKIs in National Comprehensive Cancer Network guideline, there is little information of these setting. Therefore, we planned prospective phaseⅡ study to evaluate the efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel(PCB) for EGFR-TKIs resistant Non-Sq NSCLC.

      Methods
      In multicenter phase II trial, we recruited non-squamous NSCLC harboring EGFR gene mutation after failing EGFR-TKIs. Key eligibility criteria were as follows: Non-Sq NSCLC with EGFR mutation, failure of 1[st] line EGFR-TKIs, stageIIIB or IV or recurrence after surgery, measurable lesion, age 20 or over, ECOG Performance status (PS) 0 or 1, adequate organ function. Clinically significant hemoptysis, symptomatic brain metastasis, uncontrollable hypertension, interstitial pneumonia were excluded. Patients received carboplatin (AUC=6/5), paclitaxel (200mg/m2), bevacizumab (15mg/kg) intravenously on day1 every 3 weeks for three to six cycles, and bevacizumab was administered every 3 weeks until disease progression or intolerable toxic effects. Primary endpoint was response rate (RR) and secondary endpoints were progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety.

      Results
      A total of 31 patients were assigned between March 2010 and February 2013. One patient was excluded because of unfitted eligibility criteria. Therefore, we analyzed thirty patients’ data. Median age was 60 years (45~74), male/female : 11/19, PS 0/1 : 9/21, non-smoker/smoker : 18/12, EGFR mutation status exon19 del/exon21 L858R : 20/11, 1[st] line EGFR-TKIs gefitinib/erlotinib/other : 22/7/1. RR : 40% (95%CI:22%-58%), DCR : 83% (95%CI:70%-97%), PFS : 6.0 month (95%CI:4.8-12.2). Major severe adverse event (Grade 3,4) were one patient with dyspnea (G4), 6 with fever neutropenia (G3) and 3 patients with hyper tension (G3). There was no grade 5 adverse event.

      Conclusion
      In patients with Non-Sq NSCLC harboring EGFR gene mutation failed 1[st] line EGFR-TKIs, RR of 2[nd] line PCB therapy was lower than it was in 1[st ]line phase II study of PCB in Japan, but same RR of E4599 study. Safety was similar to previous reports. We considered PCB therapy is one of the treatment option in 2[nd]-line for patient with EGFR-TKIs resistant Non-Sq NSCLC.

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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 - 09:30  |  Author(s): S. Morita

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P3.10-012 - Feasibility study of docetaxel and bevacizumab in elderly patients with advanced nonsquamous non-small cell lung cancer: Thoracic Oncology Research Group (TORG) 1014. (ID 1148)

      09:30 - 09:30  |  Author(s): S. Morita

      • Abstract

      Background
      A series of Japanese trials indicate docetaxel (DTX) monotherapy is a standard of care in elderly patients with advanced non-small cell lung cancer (NSCLC), and that the addition of platinum does not significantly improve the outcomes. Bevacizumab (BEV) has been shown to be beneficial when added to standard platinum-doublet chemotherapy in good-risk NSCLC patients. BEV toxicity is a major concern for elderly patients.

      Methods
      Patients with chemotherapy-naïve advanced non-squamous NSCLC who were >70 year old with performance status (PS) 0/1 and adequate organ function were enrolled. Eligible patients received DTX 60 (Level 0) or 50 (Level -1) mg/m2 and BEV 15 mg/kg on day 1, every 3 weeks. Toxicity was the primary endpoint and secondary endpoints were response rate, progression free survival (PFS), overall survival (OS), and completion rate of the 3 cycles of treatment. The planned sample size was 12 to 24, with at least 6 subjects treated at each level.

      Results
      Between December 2010 and September 2012, 21 elderly patients (9 in level 0 and 12 in level -1) were enrolled in the study (median age, 75 years; 43% male; 90% adenocarcinoma; 67% PS 1). Two of the 9 patients in level 0 had a dose limiting toxicities (DLTs). After 9 patients enrolled on level 0, two severe adverse events were reported. One patient had grade 4 sepsis in cycle 4 and another patient had grade 4 sepsis in cycle 5. We decided to stop enrollment to level 0 and reduce dose to level -1. Two of 12 patients in dose level -1 experienced DLTs. Grade 3 or 4 of toxicities among all patients were neutropenia (86%), anemia (5%), hypertension (19%), anorexia (10%), and increased aminotransferase levels (10%). Three out of 9 patients in level 0 achieved partial response (PR) and 3 out of 11 assessable patients in level -1 obtained PR. Completion rates of the 3 cycles of treatment were 78% (7/9) in level 0 and 67 % (8/12) in level -1. The median PFS and OS were 5.4 and 11.1 months, respectively.

      Conclusion
      The recommended dose for this combination in future study is docetaxel 50 mg/m2 and bevacizumab 15mg/kg.

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      P3.10-016 - A phase I/II study of combination chemotherapy with erlotinib and S-1 in pretreated Non-Small Cell Lung Cancer (NSCLC): Thoracic Oncology Research Group (TORG) 0808/0913 (ID 1351)

      09:30 - 09:30  |  Author(s): S. Morita

      • Abstract

      Background
      In BR.21 Study, erlotinib was shown to significantly prolong OS, PFS and the time to progression of NSCLC-associated symptoms. The study reported that the RR was 7% for EGFR-wt cases but the MST was longer than placebo. S-1 is a fourth-generation oral fluoropyrimidine that contains tegafur, a prodrug of 5-fluorouracil (5-FU). The consecutive administration of S-1 at 80 mg/m[2]/day was well tolerated. The objective RR and MST were 22.0% and 10.2 months. Regarding the EGFR-TKI and 5-FU-based chemotherapy, EGFR-TKI has been shown in basic studies to reduce the expression of thymidilate synthase, the target enzyme for the 5-FU-based chemotherapy, at the protein and mRNA levels, and synergistic effects of gefitinib used in combination with S-1 have been reported in basic study. Thus, we conducted a phase I study to find the maximum tolerated doses of erlotinib/ S-1 combination therapy, and a phase II study to evaluate the efficacy and toxicity of this combination strategy as a 2nd/3rd-line therapy for recurrent/advanced NSCLC in the absence of EGFR gene mutations.

      Methods
      Eligibility criterias were as follows: 1) patients with histologically or cytologically diagnosed NSCLC, 2) patients at clinical stage IIIB or IV not indicated for radical radiotherapy/radical surgery or those with postoperative recurrence, 3) patients having received 2 or fewer prior regimens of chemotherapy (at least one regimen being platinum-based), 4) patients with no history of treatment with EGFR-TKI and drugs of the fluoropyridimine family. This combination chemotherapy consisted of two 3-week cycles of S-1 treatment and once daily erlotinib at a dose of 150 mg/body. In phase I study, the initial dose of S-1 was 60 mg/m[2]/day, and 3 patients were registered for each level of S-1 treatment. In phase II study, S-1 at recommended dose and erlotinib were administered similarly to the phase I study.

      Results
      In phase I study, seven patients (one man and 6 women) with a median age of 66 years (range: 52-70 years) were enrolled. All patients had ECOG PS of 0-1, six patients had adenocarcinomas, and one had large cell carcinoma. All patients were at clinical stage IV. No patient had grade 2 or more neutropenia, and each 1 had grade 2 leukocytepenia, anemia, mucositis, general fatigue, skin rash, and diarrhea; however, none experienced DLT. The RD for the phase II study was determined as 80 mg/m[2] S-1 and 150 mg/m[2] erlotinib. The phase II study was conducted in 10 patients, 9 men and 1 woman, with a median age of 60.5 years (range 42–75). PS was 0 in 2, 1 in 6, and 2 in 2 patients. The histological subtype was adenocarcinoma in 5 patients, squamous-cell carcinoma in 4, and others in 1. One patient had grade 3 diarrhea, grade 4 colitis, and grade 4 septic shock, and the other had grade 4 dehydration and acute respiratory failure which resulted in two treatment-related deaths. With these findings, the trial was closed to additional enrollment.

      Conclusion
      Erlotinib(150mg) and S-1(80 mg/m[2] for 14 days every 21 days) therapy seemed to be toxic for pretreated patients with EGFR-wt NSCLC patients.