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L. Zhang



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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.03 - Biomarker analysis of a randomized, controlled, multicenter clinical trial comparing pemetrexed/cisplatin and gmcitabine/cisplatin as first-line treatment for advanced nonsquamous non-small cell lung cancer (ID 3483)

      10:40 - 10:45  |  Author(s): L. Zhang

      • Abstract
      • Presentation
      • Slides

      Background
      The platinum-based doublet regimen was standard of care in advanced non-small cell lung cancer (NSCLC), but the biomarkers to predict the efficacy of first-line chemotherapy is still controversial.

      Methods
      We collected 239 tumor samples (83.0%) from a a randomized, controlled, multicenter clinical trial, which enrolled 288 treatment naïve nonsquamous NSCLC patients who were randomly assigned (1:1) to experimental group to receive cisplatin plus pemetrexed (PC) or the control group to receive gemcitabine plus cisplatin (GC) every 3 weeks for up to 6 cycles. We evaluated the EGFR mutation by Amplification Refractory Mutation System(ARMS) method and EML4-ALK fusion by real-time PCR. Meanwhile, the mRNA expression of excision repair cross complementation 1 (ERCC-1), thymidylate synthase (TS), ribonucleotide reductase M1(RRM-1), and folatereceptor 1(FR-1) was tested by real-time PCR. All of the EGFR mutation, ALK fusion and mRNA expression were analyzed for the correlation with progression free survival, the primary endpoint in the tiral.

      Results
      The EGFR mutation rate was 46.6%(110/236) in the overall population and the ALK fusion rate was 12.0%(29/233). The median PFS was similar between the EGFR mutated patients and wild-type patients(6.0m vs 5.7m,p=0.85), however, the patients of EGFR wild-type had better PFS in the PC group compared with GC group (5.7m vs 3.5m, p=0.03). There are no significant difference between groups in EGFR mutated patients(5.6m vs 6.1m, p=0.59). The patients with ALK fusion seem to have better PFS compared with fusion negative patients (7.7m vs 5.7m), but the difference is not significant(p=0.48). The mRNA expression level was available in 225 patients(94.1%) and we determined the median expression as the cutoff value. The TS expression is significantly correlated with ERCC-1(r=0.67,p<0.001) and negatively correlated with FR-1 expression(r=-0.21,p=0.002). EGFR mutation correlated with lower TS expression(p=0.034) and ALK fusion correlated with higher FR-1 expression(p=0.017). The differences of PFS between the high and low expression of ERCC-1, TS, RRM-1and FR-1 was not significant, in both PC group and GC group.

      Conclusion
      The expression level of ERCC-1, TS, RRM-1and FR-1 could not effectively predict the progression free survival of NSCLC patients receiving platinum-based doublet regimen. The pemetrexed plus cisplatin regimen should be the priority choice for EGFR wild type patients compared with gemcitabine plus cisplatin regimen.

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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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      P3.10-013 - Open-label, randomized multicentre, phase II trial of Oral vinorelbine (NVBo) or intravenous vinorelbine (NVBiv) with cisplatin (CDDP) in patients (pts) with advanced Non Small Cell Lung Cancer (NSCLC): A Chinese experience (CA225 study) (ID 1188)

      09:30 - 09:30  |  Author(s): L. Zhang

      • Abstract

      Background
      Aim of the study: to evaluate efficacy (CR, PR) of the two formulations with CDDP in advanced NSCLC. Secondary objectives were progression-free survival (PFS), overall survival (OS) and safety.

      Methods
      NVBo, 60 mg/m² (Arm A) and NVBiv, 25 mg/m² (Arm B) were delivered on D1, D8, repeated every 3 weeks. Doses were increased at cycle 2 (NVBo 80 mg/m[2], NVBiv 30 mg/m[2]) according to hematological tolerance. CDDP doses were 80 mg/m[2] D1 every 3 weeks in both arms. Pts received a maximum of 4 cycles in absence of progression.

      Results
      Between 1/2008 and 6/2009, 132 pts were randomized at 6 investigational centres (cut-off date for final analysis: August, 31[st] 2012 - Arm A 67 pts, Arm B 65 pts). One patient in Arm A was not treated. Among the 131 pts analyzed by an independent panel review, PR was 25.8% (95% CI [15.8-38.0]) in Arm A and 23.1% (95% CI [13.5-35.2]) in Arm B, and disease control (PR+SD) 72.7% (95% CI [60.4-83.0]) in Arm A and 72.3% (95% CI [59.8-82.8]) in Arm B. PFS (months) was 6.2 [3.8-7.7] for Arm A and 6.2 [4.9-7.8] for Arm B. One Year Survival was 59% and 61.6 in Arm A and Arm B, respectively, Two Years Survival: 39% Arm A, 38.7% Arm B, and 30 months Survival 29.2% Arm A, 26.9% Arm B. Median dose intensity (DI): NVBo 44.7 mg/m²/week, NVBiv 15.6 mg/m²/week. Relative dose intensity (RDI): NVBo 89.3%, NVBiv 81.5%. The CDDP median DI was 24.6 mg/m[2]/week in Arm A and 24.5 mg/m[2]/week in Arm B, with a RDI of 92.1% and 91.6% respectively. Grade 3/4 neutropenia: 29 pts and 43 cycles Arm A, 56 pts and 106 cycles Arm B. Febrile neutropenia : 4 (6.1%) pts Arm A, 6 (9.2%) pts Arm B. Grade 3 anaemia : 6 (9.1%) pts and 10 cycles Arm A, 13 pts (20%) and 18 cycles Arm B, with grade 4 anaemia in 3 (4.6%) pts and 5 cycles only in arm B. The most frequent non hematological disorders were nausea (8 pts Grade 3 - 12.1% Arm A; 6 pts Grade 3 - 9.2% Arm B) and vomiting (10 pts Grade 3 - 15.2%, 1 pt Grade 4 - 1.5% Arm A; 9 pts Grade 3 - 13.8%, 1 pt Grade 4 - 1.5% Arm B). Diarrhea was reported in 15 (22.7%) and 9 (13.8%) pts in Arm A and Arm B, respectively.

      Conclusion
      Both arms testing NVBo and NVBiv with CDDP reported similar efficacy results in term of Response Rate, PFS and OS, coupled with an optimal safety profile. NVBo is a step forward in the treatment of NSCLC since it optimises treatment convenience thanks to its oral formulation while maintaining a high level of efficacy.

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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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      P3.11-005 - Randomized, open-label, multi-center study of Gefitinib dose-escalation (500mg/d versus 250mg/d) in advanced NSCLC patient achieved Stable Disease (SD) after one-month Gefitinib treatment (ID 784)

      09:30 - 09:30  |  Author(s): L. Zhang

      • Abstract

      Background
      Some retrospective studies revealed that higher drug exposure of EGFR-TKIs was associated with better clinical outcome, especially in EGFR mutation-negative patients (pts). This randomized, open-label, multi-center study try to confirm whether dose-escalation of gefitinib would improve effect and survivals.

      Methods
      Key eligibility criteria of this study include: ECOG PS 0-2, stage IIIB/IV NSCLC all histologies, progression after previous platinum-based chemotherapy, SD after one-month treatment of standard dose gefitinib (250mg/d). Patients were randomized (1:1) to received either higher dose (500mg/d, H group) or continue standard dose (250mg/d, S group) of gefitinib untill progression or toxicities. The primary end-point was objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The sample size was determined based on the assumption that H group was superior to S group in ORR (15% vs 5%, a one-sided alpha of 0.1, 1 - beta = 0.8) and 50 pts per arm was needed. Paired plasma was collected for detection of gefitinib concentration with high-performance liquid chromatographic method with tandem mass spectrometric (LC–MS/MS) method in consented patients at baseline (randomization, D1) and first evaluation (D60). (NCT01017679)

      Results
      From May 2009 to Jan 2012, 466 pts treated with gefitinib were included in this study. Among these pts, 155 achieved SD after one-month gefitinib treatment and 96 pts were randomly assigned to H group (48 pts) or S group (48 pts), respectively. Baseline factors including age (55.5 vs 57.5 years), gender (M/F: 24/24 vs 19/29), histology (adenocarcinoma/others: 44/4 vs 41/7), smoking status (Y/N: 18/30 vs 15/33) and EGFR mutantion rate (20% vs 31%) were balanced between two arms. ORR were same (12.5%) in two groups (p=1.000); median PFS were 159 days (H group) vs 187 days (S group, p=0.077); and median OS were 411 days (H group) vs 743 days (S group, p=0.098), respectivedly. Significantly more grade 3/4 acne-like rash was seen in H group (14.6% vs 0%, p=0.012). PFS was significantly longer in EGFR mutation pts than wild type pts (344 d vs 135 d, p =0.001 ). Plasma gefitinib concentration increased significantly in the H group (n=12, D1 vs D60: 217.02 ng/ml vs 397.25 ng/ml, p=0.017) while it remained stable in S group (n=7, 312.59 ng/ml vs 310.33 ng/ml, p=0.972). However the gefitinib concentration increase did not translate to survival improvement.

      Conclusion
      Gefitinib 500mg/d did not confer a response or survival advantage over gefitinib 250mg/d in patients achieved SD with one-month gefitinib treatment. EGFR mutation remained predictive for PFS with gefitinib.