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N. Yamamoto
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ORAL 01 - Chemotherapy Developments for Lung Cancer (ID 88)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G. Blumenschein, S. Lee
- Coordinates: 9/07/2015, 10:45 - 12:15, 401-404
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ORAL01.01 - Randomized Phase III Study of Nedaplatin plus Docetaxel versus Cisplatin plus Docetaxel for Advanced Squamous Cell Lung Cancer (WJOG5208L) (ID 621)
10:45 - 10:56 | Author(s): N. Yamamoto
- Abstract
- Presentation
Background:
Nedaplatin (N) is a second-generation platinum compound with lower nausea/vomiting and nephrotoxicity than cisplatin (C). Nedaplatin plus docetaxel (ND) showed a promising efficacy with acceptable toxicity for advanced squamous cell lung cancer (SqLC) in the previous phase II study.
Methods:
Eligible patients (pts) were those with pathologically proven SqLC with stage IIIB/IV or postoperative recurrence, aged 20-74 years and ECOG PS 0-1. Pts were randomized 1:1 to ND (N 100 mg/m[2] and docetaxel (D) 60mg/m[2] iv, q3w, up to 6 cycles) or C plus D (CD) (C 80 mg/m[2] and D 60mg/m[2] iv, q3w, up to 6 cycles) according to stage, gender and institution. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), response rate (RR) and adverse events (AEs). Target sample size of 350 provided 90% statistical power to detect a hazard ratio of 0.71 with one-sided type I error of 0.05.
Results:
Between July 2009 and July 2012, 355 pts were randomized. Of 349 for efficacy analysis (ND 177; CD 172), baseline characteristics were well-balanced between two arms. ND had a significantly longer OS (p=0.037, one-sided stratified log-rank test). The OS HR was 0.81 (90%CI, 0.67-0.98) with a median OS of 13.6 months [m] for ND and 11.4 for CD. ND had a longer PFS (p=0.050) with a HR of 0.83 (0.69-1.00) and a median PFS of 4.9 m in ND and 4.5 in CD. RR was 54.5% in ND vs 52.9% in CD (p=0.829). Grade 3 or higher AEs of nausea (4.0% vs 14.3%), fatigue (3.4% vs 10.9%), hyponatremia (13.6% vs 30.3%) and hypokalemia (2.3% vs 8.6%) are more frequent in CD. Grade 3 or higher AEs of neutrophils (82.5% vs 70.3%) and platelets (9.0% vs 0.0%) are more frequent in ND, but there was no difference in grade 3 or higher febrile neutropenia (13.6% vs 15.4%). Treatment related deaths occurred in 4 and 3 pts in ND and CD, respectively.
Conclusion:
ND showed a significantly longer OS as compared to CD with different toxicity profile. ND will be considered as a new standard treatment for advanced or relapsed SqLC. Clinical trial information: UMIN000002015.
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ORAL 17 - EGFR Mutant Lung Cancer (ID 116)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:P. Meldgaard, E. Felip
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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ORAL17.03 - Biomarkers for Efficacy in JO25567 Study Evaluating Erlotinib plus Bevacizumab versus Erlotinib in Advanced NSCLC with EGFR Mutation (ID 306)
11:07 - 11:18 | Author(s): N. Yamamoto
- Abstract
- Presentation
Background:
Bevacizumab (B), an anti-vascular endothelial growth factor (VEGF) monoclonal antibody has been proven to provide additional efficacy benefit in combination with platinum-based chemotherapy for 1[st] line therapy of non-squamous non-small cell lung cancer (NSCLC). In JO25567 study, we observed that bevacizumab in combination with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib (E) also provided additional 6.3 months median progression free survival (PFS) in advanced EGFR mutation-positive non-squamous NSCLC. To try to understand this additional effect of bevacizumab, we investigated the predictive biomarkers related to angiogenesis comprehensively in JO25567 study. Clnical trials registry number: JapicCTI-111390
Methods:
We evaluated the biomarkers in blood and tissue samples. All samples were collected before E+B or E treatment in JO25567 study. Angiogenesis related ligands and soluble receptors in serum were analyzed by multiplex, bead-based suspension array. Single nucleotide polymorphisms (SNPs) or variable number of tandem repeats (VNTR) of angiogenesis related genes were analyzed by direct sequencing or electrophoresis after PCR for blood sample. VEGF-A concentration in plasma were analyzed by Immunological Multi-Parametric Chip Technique (IMPACT) assay. Messenger RNA of genes related to angiogenesis in tumor tissue were quantitated by multiplex TOF-mass spectrometry (MassARRAY). Immunohistochemistry of neuropilin and exploratory proteomics analysis were planned for surgically resected tumor tissues. PFS were used as an efficacy variable of prediction. Multivariate Fractional Polynomial (MFP) and Subpopulation Treatment Effect Pattern Plot (STEPP) were used for biomarker screening.
Results:
One hundred fifty-two patients were treated with E+B or E in JO25567 study. We analyzed 26 ligands or soluble receptors in 134 serum samples. Follistatin and leptin were identified as potential biomarkers by MFP. The interaction p-value with adjustment of covariates for biomarker and efficacy was 0.0168 for follistatin and 0.0049 for leptin. STEPP suggested that high follistatin related to limited bevacizumab efficacy and low leptin related to higher bevacizumab efficacy. SNPs could be analyzed in 135 blood samples. In 12 SNPs and 1 VNTR of 8 genes, no gene related to bevacizumab efficacy. Plasma samples were collected from 105 patients. Median VEGF-A concentration of E+B group and E group were 18.0 pg/mL and 18.8 pg/mL respectively and was one sixth or more lower than previously reported breast and gastric cancers. Hazard ratio of E+B comparing with E for was 0.23 (95% CI: 0.09-0.60) for low plasma VEGF and was 0.56 (95% CI: 0.26-1.25) for high plasma VEGF. This trend was not consistent with previously reported studies. We analyzed mRNA expression from 24 surgical resected tumors and no predictive value was observed. Because of limited number of surgically resected tumors obtained, we couldn’t proceed exploratory proteomics analysis nor evaluate predictive value of neuropilin expression.
Conclusion:
In this comprehensive predictive biomarker analysis, follistatin and leptin in blood were identified as potential biomarker candidates for E+B therapy.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-080 - An Open-Label, Multicenter, Phase 1b/2 Study to Evaluate Necitumumab in Combination with Gemcitabine and Cisplatin in the First-Line Treatment of Patients with Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer (NSCLC) (ID 184)
09:30 - 09:30 | Author(s): N. Yamamoto
- Abstract
Background:
Necitumumab (N) is a human IgG1 anti-epidermal growth factor receptor (EGFR) monoclonal antibody. Squamous (SQ) histology accounts for 25-30% of non-small cell lung cancer (NSCLC) and gemcitabine combined with cisplatin (GC) is a standard of care for advanced or metastatic SQ-NSCLC. In the previous global randomized, open-label, Phase 3 trial (SQUIRE), compared with GC, the addition of N to GC (GC+N) significantly improved overall survival (OS) (HR=0.84, p=0.012; median 11.5 vs 9.9 months) and progression-free survival (PFS) (HR=0.85, p=0.020; median 5.7 vs 5.5 months). The objective response rate (ORR) was 31% vs 29% (p=0.400), and the disease control rate (DCR) was 82% vs 77% (p=0.043), respectively. The SQUIRE results were an important advance in the search for a new treatment for patients with metastatic SQ-NSCLC, where limited progress has been made over the last two decades. However, only 8% of patients in SQUIRE Trial were Asian and no Japanese institutions participated. We have therefore conducted this Phase 1b/2 trial to evaluate the efficacy and safety of GC+N in Japanese patients with advanced SQ-NSCLC.
Methods:
This trial consists of a Phase 1b and Phase 2 part. Patients with advanced (Stage IV) SQ-NSCLC are eligible for enrollment if they are aged³20 years with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1; measurable or nonmeasurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0; adequate organ function. GC+N or GC may continue for a maximum of 4 cycles; patients with at least stable disease in GC+N may continue to receive N until disease progression or emerging non-acceptable toxicity. The purpose of Phase 1b part is to determine the recommended dose of the combination of GC (G=1000 or 1250 mg/m[2] iv, Days 1 and 8; C=75 mg/m[2] iv, Day 1; 3-week cycle) and N (800 mg iv, Days 1 and 8; 3-week cycle). Patients are enrolled in 2 cohorts using a conventional 3+3 study design, with dose-escalation of gemcitabine permitted according to the incidence of dose-limiting toxicity (DLT). The Phase 2 part is an open-label, randomized trial to evaluate the efficacy and safety of addition of N to GC. Patients are randomly assigned on a 1:1 basis (Stratification factors: ECOG PS and gender) to GC+N (Arm A) or GC (Arm B). The primary endpoint is OS for which the final analysis will be performed when at least 137 events are observed. The sample size of 180 patients (137 events) has 68% power for a log-rank test at 0.2 one-sided alpha. The secondary endpoints include PFS, ORR, time to treatment failure, Pharmacokinetics, safety and patient-reported outcomes. The relationship between EGFR protein expression level by immunohistochemistry (IHC) and each of several efficacy measures will also be assessed. Translational research analyses will be performed to analyze relevant biomarkers for clinical outcomes. ClinicalTrial.gov Identifier: NCT01763788.
Results:
Not applicable
Conclusion:
Not applicable
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PC 03 - Pro vs Con: Prophylactic Cranial Irradiation (PCI) Post Chemotherapy Response / Pro vs Con: Is There a Role for Radiation in Oligometastatic Disease? (ID 49)
- Event: WCLC 2015
- Type: Pro Con
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:A. Brade, K. Rosenzweig, A. Bezjak, J.S. Lee
- Coordinates: 9/09/2015, 14:15 - 15:45, 708+710+712
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PC03.02 - Prophylactic Cranial Irradiation (PCI) Post Chemotherapy Response - Con (ID 2035)
14:40 - 15:00 | Author(s): N. Yamamoto
- Abstract
- Presentation
Abstract not provided
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