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T. Kato



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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)

      16:15 - 17:45  |  Author(s): T. Kato

      • 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 - 16:30  |  Author(s): T. Kato

      • 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: 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): T. Kato

      • 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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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-007 - Preliminary safety results of MONET-A: A Prospective, Asian Phase 3, Randomized, Placebo-controlled, Double-blind Trial of the Investigational agent Motesanib in Combination with Paclitaxel and Carboplatin for Asian patients of Advanced Non-squamous Non-small Cell Lung Cancer (ID 889)

      09:30 - 16:30  |  Author(s): T. Kato

      • Abstract

      Background
      Inhibition of the vascular endothelial growth factor receptor (VEGFR) pathway appears to be an effective treatment strategy for frontline non-small cell lung cancer (NSCLC), but small molecule VEGFR kinase inhibitors have failed to show survival benefit. Motesanib is an orally administrated small molecule antagonist of VEGFR 1, 2, and 3, platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor (c-kit). In a subgroup analysis of Asian patients (n = 227) from the global phase 3 study (MONET-1), treatment of motesanib in combination with paclitaxel and carboplatin demonstrated significant improvements in overall survival (HR, 0.65; 95% CI, 0.46-0.91), progression free survival (HR, 0.59; 95% CI, 0.44-0.79), and overall response rate compared to placebo. To prospectively evaluate efficacy and safety of motesanib in Asian patients with NSCLC, this phase 3 study has initiated.

      Methods
      Stage IV/recurrent non-squamous NSCLC patients without prior chemotherapy receive oral motesanib (125 mg) or placebo once daily in combination with paclitaxel (200 mg/m[2]) and carboplatin (AUC = 6) every 3 weeks up to 6 cycles and continue motesanib or placebo until disease progression, consent withdrawal, or unmanageable adverse event. ECOG performance status 0 or 1 are eligible for this study regardless of epidermal growth factor receptor (EGFR) mutation status. Patients with untreated or symptomatic central nervous system metastases are excluded. Approximately 400 patients will be randomized in a double-blind 1:1 ratio to motesanib or placebo. Stratification factors include EGFR mutation status, weight loss of ≥ 5% in the previous 6 months, and region. This MONET-A trial will be assessed twice by the Independent Data Monitoring Committee (IDMC), at the time 50 and 150 patients complete their first cycle for unblinded safety data.

      Results
      This study initiated in July 2012 and is being conducted in Japan, Korea, Taiwan, and Hong Kong. The enrollment is ongoing. First evaluation by IDMC was performed using the data as of 26 December 2012. A total of 64 patients were enrolled and 63 patients (63 Japanese; median age, 64.5 years) received study treatment. All the blinded patients who received study treatment experienced adverse events (AEs); Grade 3 to 5 AEs were reported in 38 patients (60.3%). Common AEs included alopecia (63.5%), peripheral sensory neuropathy (57.1%), and decreased appetite (50.8%). 7 patients had 8 serious AEs (SAEs). SAEs considered to be related to blinded study drug were cholecystitis in 2 patients, gastric ulcer haemorrhage, nausea, and upper gastrointestinal haemorrhage in 1 patient. A treatment-related fatal AE (interstitial lung disease) was reported in one patient (blinded). AEs leading to permanent discontinuation of unblindedunblinded study drug (motesanib or placeco) were cholecystitis (Grade 2), liver injury (Grade 3), purpura (Grade 2), rash (Grade 3), eye haemorrhage (Grade 2), upper gastrointestinal haemorrhage (Grade 3), and gamma-glutamyltransferase increased (Grade 4).

      Conclusion
      The first IDMC recommended continuation of the study after the review of unblinded data of 63 patients. Updated safety data will be presented after the second IDMC (JapicCTI-121887).