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K. Nakagawa

Moderator of

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    MO08 - NSCLC - Early Stage (ID 117)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 12
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      MO08.01 - First analysis of toxicity and treament compliance in customized postoperative chemotherapy based on BRCA1 levels after NSCLC resection: SCAT (Spanish Customized Adjuvant Therapy) trial. Spanish Lung Cancer Group/GECP (ID 2454)

      16:15 - 17:45  |  Author(s): B. Massuti, M. Cobo, M. Rodriguez-Paniagua, I. Ballesteros, T. Moran, R. Arrabal, J.L. Gonzalez Larriba, I. Barneto, Y. Wah Pun, J.D. Castro Carpeño, L. Iglesias, C. Baamonde, M.A. Muñoz, G. Lopez-Vivanco, J. Rivas De Andres, D. Isla, R. Lopez, R. De Las Peñas, D. Rodriguez, P. Lopez De Castro, A. Artal, E. Esteban Gonzalez, F. Hernando Trancho, M. Provencio, J. Valdivia, P. Diaz Agero, J.L. Martin De Nicolas, E. Pereira, J.M. Sanchez, R. Rosell

      • Abstract
      • Presentation
      • Slides

      Background
      Customization is feasible in adjuvant setting (tissue availability). SCAT trial has completed planned recruitment with 500 p. For resected NSCLC with nodal involvement adjuvant platinum-based CT improves outcomes but survival remains suboptimal. Compliance may be a key issue for efficacy in adjuvant setting. mRNA BRCA1 levels are prognostic in early NSCLC and could be a predictive marker for CT activity. In advanced disease patients with low BRCA1 benefit from cisplatin doublets meanwhile p with high levels attained longer survival with taxanes.

      Methods
      Phase III trial testing 4 cycles non-selected vs customized adjuvant CT. Entry criteria: NSCLC, R0 resection, pN1 or pN2, KI > 70, recovered from surgery, adequate hematologic, renal and liver functions, no prior CT or RT, age > 18 y, informed consent. Stratification: N1 vs N2, histology (squamous vs non-squamous), resection (lobectomy vs pneumonectomy). Central lab mRNA BRCA1 levels and quartile distribution. Primary end-point: OS. Secondary end-points: DFS, toxicity, recurrence pattern. Design: R: 1:3. Control treatment: Cis-Docetaxel (CD). Experimental arm: Q1: Cis-Gemcitabine (CG); Q2-3: Cis-Docetaxel; Q4: Docetaxel (D). PORT in pN2 patients. Compliance treatment and toxicity profile analyzed by arm and correlation with potential prognostic factors explored

      Results
      500 included p; 108 control arm, 392 experimental arm. Median follow-up 18.6 m (2-59 m). Median mRNA BRCA1 levesl 15.78 (0.73-132) Q1 212 (42.4%), Q2-3 150 (30%), Q4 138 (27.6%). Mean BRCA1: Adenocarcinoma: 8.45 vs Squamous 19.6 (p< 0.001). Overall low levels BRCA1: 43.8%. EGFR mut 5.6% 297 p evaluated for compliance planned adjuvant treatment: M/F ratio: 82.5/17.5%. Median age: 62 (range 36-80). PS 0/1/2: 55.9/43,1/1%. Histology: Adenocarcinoma 47.5%, Squamous 44.1%. Stages: IIA/IIB/IIIA: 11.1/38.4/50.2%. Surgical procedure: Lobectomy 72.1%; Pneumonectomy 27.9%.. Toxicity. G3-4 AE: Neutropenic fever: CD 10% vs D 4.4% vs CG 0%. (p=0.0056); Nausea/vomits: CG 11.1% vs CD 10.4% vs D 0%. (p=0.0198); Hypersensitivity: D 5.97% (NS). Dose-reduction: 34.24% control vs 18.30% experimental (p=0.0044). Full 4 cycles CT compliance: CD control 80.83%, CG 91.2%, CD experimental 79.2%, D 88.1% (p=0.052). No differences in dose-reductions. CT compliance lobectomy 86.4% vs 85.5% pneumonectomy (NS). CT compliante < 70 y 91.1% vs 66.6% > 70 y (p<0.01)PORT compliance 55.31% of planned cases.

      Conclusion
      Planned trial recruitment achieved with median f-u 18.6 m. Majority of resected NSCLC showed low levels expression BRCA1. Adenocarcinoma lower levels than Squamous. Safety profiles differences observed between treatment schedules: neutropenic fever (CD), nausea/vomits (CG). Customized treatment requires less dose-reductions. Trend to poor compliance with Cis-Doc. No relation between extensión of surgery and adjuvant Tx compliance . Compliance CT significantly lower for age > 70 y. Low compliance for PORT.

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      MO08.02 - Adjuvant pazopanib or placebo in resected stage I NSCLC patients: results of the NSCLC adjuvant randomized phase II trial (IFCT-0703) from the French collaborative Intergroup (ID 2274)

      16:15 - 17:45  |  Author(s): B. Besse, J. Mazieres, L. Ribassin-Majed, F. Barlesi, J. Bennouna, R. Gervais, L. Moreau, H. Berard, D. Debieuvre, O. Molinier, D. Moro-Sibilot, P. Souquet, J. Pignon, E. Amour, A. Celebic, F. Morin, B. Milleron, G. Zalcman, J. Soria

      • Abstract
      • Presentation
      • Slides

      Background
      Although UFT is approved in eastern countries, most guidelines do not recommend any adjuvant treatment in resected Stage I NSCLC. Pazopanib (P) is a potent, orally active multi-target receptor tyrosine kinase inhibitor of VEGFR-1, -2, -3, platelet derived growth factor (PDGFR) type-α and –β, approved in metastatic renal cell carcinoma and sarcoma. Neoadjuvant P demonstrated single-agent activity in patients with early stage NSCLC. We report the feasibility and tolerance of adjuvant P in stage I NSCLC.

      Methods
      In this double-blind randomized multicenter phase II/III trial, completely resected patients (pts) with stage I NSCLC (7[th] TNM edition) were randomized to receive either placebo or P 800 mg/d during 6 months. The Fleming’s two stage phase II primary endpoint was compliance (i.e. % of pts able to receive at least 3 months of P, whatever the dose). After 64 pts included (interim analysis), IDMC recommended to start with P 400 mg/d because of initial insufficient compliance. A one-step Fleming design was used with the new dose. Phase II design was not comparative.

      Results
      143 pts were randomized in 29 centers between March 2009 and August 2012, 71 and 72 in the placebo and P arms respectively. Most pts were male (61%) and smokers (91%), median age was 60. Pathological stage was IA in 111 pts (78%) and 16% were squamous cell carcinomas. Compliance for P800 was adequate in 38% (95% confidence interval [21-56]) vs. 87% [71-96] in placebo; for P400 in 69% [50-84] (p=0.01, compared to P800) vs. 93% [77-99] in placebo. Dose modifications were seen in 44% and 34% of P800 and P400 groups. The proportion of patient with at least one grade 3/4 toxicity was 53% [35-71] in P800 (13% [4-29] for placebo) and 38% [21-56] in P400 (27% [12-46] for placebo). No toxic deaths were observed. Only 2 pts has grade 4 toxicities in P800 (fatigue in P arm, GGT in the placebo arm). Most common toxicities G3 in P800 were diarrhea (9%), hypertension (9%), and increased transaminases (16% vs. 0% in P400); in P400 gastro-intestinal disorders (16%, 6% diarrhea) and hypertension (6%).

      Conclusion
      IFCT-0703 is the first feasibility study demonstrating that full dose of P is safe but not feasible in the adjuvant setting in NSCLC. Compliance and tolerance with reduced dose appeared acceptable for adjuvant settings.

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      MO08.03 - Adjuvant Chemotherapy for Non-Small Cell Lung Cancer after Thoracoscopic versus open Lobectomy. (ID 1569)

      16:15 - 17:45  |  Author(s): T. Schytte, E. Jakobsen, P. Licht

      • Abstract
      • Presentation
      • Slides

      Background
      In general thoracoscopic lobectomy (VATS) is considered being associated with advantages compared to conventional thoracotomy when it comes to postoperative outcomes such as pain, duration of hospitalization and overall complications. It is also believed that a reduction in these complications leads to better patient compliance with adjuvant chemotherapy. However, this assumption is based on single-institution case-control studies and selection bias is possible. This is a study on the differences in patient compliance with adjuvant chemotherapy following lobectomy by VATS or thoracotomy. Data are obtained from a complete national registry on lung cancer patients.

      Methods
      To investigate if the surgical approach alone had an impact on patient compliance to adjuvant chemotherapy we investigated patients who underwent lobectomy for clinical stage I non-small cell lung cancer. The patient population in this study had; however, unsuspected nodal involvement and adjuvant chemotherapy was indicated. Patients were analyzed for type of adjuvant chemotherapy as well as failure to begin or complete full treatment. A clinical oncologist who was blinded for surgery approach reviewed all patient files in order to investigate the data on chemotherapy.

      Results
      From 2007-2011 lobectomy for clinical stage 1 disease was performed in a total of 1513 patients by VATS (N=718/ 47.5%) or thoracotomy (N=795/ 52.5%). Unsuspected nodal disease was diagnosed in 278 (18.4%) patients, 11 patients were excluded. They had either distant metastasis or radiotherapy due to nonradical resection. This left 267 patients for further analyses, adjuvant chemotherapy was delivered to 155 (58.1%) and 98 (36.7%) completed 4 cycles as planned. There was no significant difference in patient compliance with chemotherapy and surgical approach (p=0.35). Survival was significantly influenced by comorbidity, histology and compliance with chemotherapy (p<0.001) in a Cox proportional hazard analysis; Survival was not influenced by sex, age or surgical approach.

      Conclusion
      In this study with complete national data we did not confirm the assumption that patient compliance with adjuvant chemotherapy was better after thoracoscopic lobectomy compared to conventional lobectomy. Survival was significantly influenced by compliance with chemotherapy but not surgical approach.

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      MO08.04 - Phase 2 study of the GI-4000 KRAS vaccine following curative therapy in patients with stage I-III lung adenocarcinoma harboring a KRAS G12C, G12D, G12V or G12R mutation (ID 2451)

      16:15 - 17:45  |  Author(s): J.E. Chaft, M. Arcila, P. Patel, D.M. Apelian, A. Mattson, C. Coeshott, M.G. Kris, C.G. Azzoli

      • Abstract
      • Presentation
      • Slides

      Background
      Most patients with early-stage lung cancer will die of recurrent disease despite multimodality therapy with curative intent. KRAS is the most commonly mutated oncogene in lung adenocarcinomas, and patients with resected disease are a unique population amenable to a personalized clinical trial approach. GI4000 is a vaccine created from whole, heat killed recombinant Saccharomyces cerevisiae yeast, overexpressing KRAS Q61L plus Q61(R or H) and either a G12C, G12D, G12V, or G12R mutation. This study aimed to assess the feasibility and immunogenicity of the GI4000 vaccine in patients with KRAS-mutant lung cancers and to compare the outcomes of patients to matched controls.

      Methods
      Patients with Stage I-III KRAS-mutant lung cancers who completed curative therapy were enrolled. Each patient was routinely administered the genotype-matched vaccine from the GI4000 series subcutaneously starting 1-4 months after standard treatment completion: weekly x 3, monthly x 6 and every 3 months for a total of 3 years (19 doses). KRAS-antigen T-cell response was assessed by interferon-γ ELISpot assay in peripheral blood mononuclear cells. The study was powered to detect an immune response rate of ≥25% (N=24 patients). A comparison group matched for age, sex, KRAS genotype and stage was used to compare recurrence and survival using the Kaplan-Meier method with a hazard ratio for survival adjusted for age, sex and stage.

      Results
      In 28 months, 33 patients were screened and 24 patients enrolled. The study met its primary endpoint with 63% of evaluable patients (50% of all patients) developing an antigen-specific immune response. 19 patients had evaluable baseline samples, 9/13 with a negative response at baseline developed a treatment emergent response and 3/6 with a pre-existing baseline response had an increased response over baseline that met pre-specified immunologic criteria. There were no treatment-related Grade 3/4 or severe AEs. The median number of vaccinations received was 15 (range 1-19). 1 patient withdrew consent due to local injection site reaction and 2 died of recurrent disease during study. The baseline characteristics and clinical outcomes of the trial patients and a group of matched controls is presented in the Table below.

      GI4000 vs. Matched controls GI4000 N=24 N(%) Matched controls N=64 N(%)
      Stage I II III _____ 12 (50) 5 (21) 7 (29) _____ 42 (66) 2 (3) 20 (31)
      Age at diagnosis (median) 63 66
      Sex Male Female _____ 7 (29) 17 (71) _____ 21 (33) 43 (67)
      Recurrence free survival per year 1 2 3 _____ 86% 68% 60% _____ 85% 71% 69%
      Overall survival per year 1 2 3 _____ 100% 100% 92% _____ 93% 88% 83%
      Hazard ratio for survival (p-value) 0.58 (0.29)

      Conclusion
      The GI4000 vaccine is safe, feasible and immunogenic after completion of curative-intent therapy in patients with KRAS-mutant lung cancers. Recurrence rates are equivalent but overall survival trends favorably when compared to matched controls. Exploratory analysis of survival in the immune responders versus matched controls is underway. A randomized study with prospective biomarker analyses is warranted.

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      MO08.05 - Research and progress of vascular targeted therapy in the postoperative adjuvant chemotherapy for lung cancer (ID 732)

      16:15 - 17:45  |  Author(s): M. Liao, Z. Chen, Z. Zhou, S. Lu, Q. Luo

      • Abstract
      • Presentation
      • Slides

      Background
      Postoperative adjuvant chemotherapy is extensively received due to its extension of the time to recurrence and enhancement of survival rate in non-small cell lung cancer (NSCLC). However, it has reached the plateau at current, the beneficial cases are few, and drug-resistance and over-treatment phenomena are present in most of patients, hence it is necessary to seek a new postoperative adjuvant chemotherapy to improve the survival rate. Angiogenesis is one premise of malignant tumors to occur, develop and metastasize, but vascular endothelial growth factor (VEGF) is one of the most important tumors in the process of neovascularization. Under normal conditions, VEGF is hardly expressed in a lot of normal tissues in vivo, while highly expressed in the tumors like osteosarcoma, bladder cancer, breast cancer and colorectal cancer. Recombinant human endostatin (endostar) can significantly intervene the angiogenesis-promoting effect to block the nutritional supply of tumors and inhibit tumor proliferation or metastasis. We compare the curative effect of endostar plus adjuvant chemotherapy and adjuvant chemotherapy alone in the treatment of patients with completely resected NSCLC at stage IB-IIIA.

      Methods
      This is an open, multicenter, randomized (1:1) study, stratified by gender, stage and histology. Completely resected pts (stage IB to IIIA) were randomized to receive adjuvant NP plus Endostar (Vinorelbine 25mg/m2 on d1 and d8 plus Cisplatin 75 mg/m2 on d1, and iv plus Endostar 7.5mg/m2 per day iv for consecutive 14 days. Every 21 days as one cycle for 4 cycles) or NP regimen alone. The primary endpoint was disease-free survival (DFS). Secondary endpoints included tumor response rate, overall survival and safety.

      Results
      250 pts (1:1) were included between 07/2007 and 06/2009. Two arms were well-balanced with regard to age, gender, histology, staging, and resection type. The follow-up time is 42 months. The two groups had no significant difference in the incidence of toxicity reaction. Endostatin plus NP can prolong the DFS of patients with complete resectable NSCLC at stage IIIA (19.33±3.73m vs 17.10±9.68m) with high security, but no statistical difference. Cases with high expression of VEGF showed a better DFS than cases with low expression in Endostatin plus NP group (48.45±3.52m vs 40.18±4.54m, P < 0.05). The level of peripheral circulating endothelial progenitor cells (EPCs) in NSCLC patients is significantly higher than that in healthy volunteers. EPCs level was associated with NSCLC stage. The EPCs levels after treatment significantly decreased than that before treatment (P=0.014) in beneficiaries of NP or NP plus with endostar. The time to progression (TTP) was longer in patients with lower levels of EPCs (<0.35%) before chemotherapy or endostatin treatment (P<0.001).

      Conclusion
      This preliminary result showed vascular targeted therapy in postoperative adjuvant therapy of lung cancer has a good application prospect. VEGF and EPCs play important roles in the development of lung cancer. Deep studies should be taken for the other related molecular targets in the future.

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      MO08.06 - DISCUSSANT (ID 3960)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO08.07 - Randomized controlled phase III trial of adjuvant chemo-immunotherapy with activated killer T cells and dendritic cells in patients with resected primary lung cancer. (ID 665)

      16:15 - 17:45  |  Author(s): H. Kimura, Y. Matui, A. Ishikawa, T. Nakajima, M. Yoshino, Y. Sakairi

      • Abstract
      • Presentation
      • Slides

      Background
      We conducted a phase III randomized controlled study to investigate the efficacy of post-surgical adjuvant chemo-immunotherapy using activated killer T cells and dendritic cells (AKT-DC) obtained from regional lymph nodes of lung cancer patients. The target of immunotherapy is the residual micrometastases after surgery and the resistant clones to chemotherapy.

      Methods
      Between April 2007 and July 2012, 103 patients with post-surgical non-small cell lung cancer were randomly assigned to receive either chemo-immunotherapy (group A) or chemotherapy (group B). Immunotherapy was consisted of adoptive transfer of autologous activated killer T cells and dendritic cells (AKT-DC) obtained from regional lymph nodes of lung cancer patients. The primary end point of this study was overall survival. Secondary end points were recurrence free survival, toxicity, and adverse effects of immunotherapy.

      Results
      Two and five years over all survival were 93.4% and 81.4% in group A and 66.0% and,48.3% in group B respectively. The difference was statistically significant (log-rank test p=0.0005, generalized Wilcoxon test p=0.0005) in favor of chemo-immunotherapy group A. Hazard ratio was 0.229 (95% CI 0.093 to 0.564).Two year recurrence free survival was 68.5%(53.2 to 79.7%: group A) and 41.4% (27.5 to 54.7: group B). The difference was statistically significant (log-rank test p=0.0020 and HR 0.423(95% CI 0.241 to 0.743) in favor of group A. [Adverse effects of immunotherapy.] Chill and shiver: Out of total 762 courses, 52 courses (6.8%) were accompanied with chill and shiver and 47 courses (6.2%) fever (>38) thereafter. Out of 50 cases treated by immunotherapy, 28 cases had no side effect and 22 cases had at least more than one side effect of chill, shiver and/or fever.

      Conclusion
      Immunotherapy using this modality is effective in recurrence control of post-surgical lung cancer patients by inhibiting the growth of disseminated micrometastases.

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      MO08.08 - A cost-effectiveness analysis of the 15-gene expression signature in guiding adjuvant chemotherapy in early stage non-small cell lung cancer based on the JBR.10 trial (ID 1962)

      16:15 - 17:45  |  Author(s): K.M. Wong, S. Li, K. Ding, P. Bradbury, M. Tsao, F.A. Shepherd, C. Chung, R. Ng, L. Seymour, N.B. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      The NCIC CTG JBR.10 trial demonstrated that adjuvant chemotherapy (ACT) improves survival in resected stage IB/II non-small cell lung cancer (NSCLC) compared to observation. A 15-gene expression signature was developed from the trial population and subsequently validated to stratify patients with resected NSCLC into low and high risk prognostic groups. The signature may also be predictive for greater benefit from ACT in high risk patients (Zhu et al. JCO 2010), but this has not yet been validated. This gene expression signature may offer a risk stratification strategy to identify patients most likely to benefit from ACT. We conducted an exploratory economic analysis to assess the impact of the use of this gene signature compared to current clinical staging to guide ACT decisions in resected early stage NSCLC.

      Methods
      We developed a decision analytic model populated by the NCIC CTG JBR.10 trial cost and outcome data, including direct medical costs and overall survival (OS). Utility for each health state was estimated from quality of life data to generate quality-adjusted survival. The analysis was performed over a lifetime horizon from the perspective of the Canadian public health care system, expressed in 2013 Canadian dollars. Survival and costs were discounted at 5% per year. We determined the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) of ACT versus observation in resected stage IB/II NSCLC in the following two scenarios: (1) gene signature-directed ACT, where patients classified as having high risk of recurrence receive ACT and those at low risk are observed; and (2) clinical stage-directed ACT, where gene signature profiling is not performed – those with stage IB tumours >4cm or stage II NSCLC receive ACT, and those with stage IB tumours <4cm are observed. Nonparametric bootstrapping to estimate 95% confidence intervals (CI) and multi-way sensitivity analyses were performed.

      Results
      The analysis included 52 patients in the gene signature-based strategy and 125 patients in the stage-based strategy with available direct medical costs and gene signature data. The mean survival gain of ACT versus observation was 2.28 years using gene signature-directed selection, and 1.59 years using stage-directed selection. The discounted ICER of ACT versus observation was $8,327/life-year gained (LYG; 95% CI, $395 to $19,590) using the gene signature-directed approach, and $5,623/LYG (95% CI, -$2,161 to $14,354) for the clinical approach. There was no significant difference in the ICER between the two strategies (p=0.52). The discounted ICUR was $11,315/quality-adjusted life-year (QALY; 95% CI, $211 to $27,314) using the gene signature-directed approach, and $7,728/QALY (95% CI, -$3,080 to $19,825) for the clinical approach. Sensitivity analyses showed that the ICER was most sensitive to changes in the survival hazard ratio (i.e. treatment benefit) and utility, but less sensitive to the cost of the gene signature (range $0 to $10,000 per case, with corresponding ICER $15,794 to $28,194/LYG, respectively).

      Conclusion
      This exploratory analysis suggests that use of the 15-gene expression signature to guide decisions for ACT in resected stage IB/II NSCLC patients could be highly cost-effective. Further validation of the signature’s impact on ACT outcomes is needed.

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      MO08.09 - PET-CT scanning derived Artificial Neural Network can<br /> predict mediastinal lymph nodes metastases in NSCLC<br /> patients. Preliminary report. (ID 1198)

      16:15 - 17:45  |  Author(s): P. Wnuk, M. Kowalewski, B. Małkowski, M. Bella, M. Dancewicz, T. Szczęsny, P. Bławat, J. Kowalewski

      • Abstract
      • Presentation
      • Slides

      Background
      Mediastinal lymph nodes staging in NSCLC is of paramount importance. Although relatively precise, diagnostic modalities still employ certain level of invasiveness. Artificial Neural Network (ANN) is a well established predictor tool which, due to underlying distribution and relationship among the given variables, allow for construction of multidimensional models trained in prognosis of given outcome. Their performance in mediastinal staging based on radiological data only, currently remains unknown.

      Methods
      Samples from 467 lymph nodes were obtained from 160 patients with primary NSCLC by means of endobronchial ultrasound guided-transbronchial needle aspiration (EBUS-TBNA), mediastinoscopy or lymphadenectomy during thoracotomy and microscopically analyzed. ANN models were created and prospectively validated on unmatched cohort of 50 consecutive patients (158 groups of lymph nodes). To identify factors correlated with nodal involvement single factor tests and logistic regression analysis were performed.Figure 1 Figure 1. The multilayer perceptron (MLP). Artificial Neural Network (ANN) structure for predicting metastatic involvement of mediastinal lymph nodes in NSCLC patients.

      Results
      Size and standard uptake value (SUV) of the node along with primary tumour T characteristics were identified as the most sensitive variables regardless of the analysis conducted. Two ANN models predicted metastatic involvement with 89% and 92% accuracy. Single factor tests maintained high accuracy only for 2 out of 4 most sensitive variables (SUV >2.8 and length >15mm) in prospective validation. Additionally, logistic regression analysis allowed for construction of scoring model with certain parameters corresponding to risk thresholds of metastatic disease.Figure 1 Figure 2. Artificial Neural Network (ANN) characteristics. ROC curves for 2 manually designed ANNs (A); Sensitivity analyses of coefficients (B) and overall characteristics of ANNs performance (C).

      Conclusion
      ANN is a repeatable and accurate diagnostic tool in mediastinal staging in NSCLC patients. Before its role in clinical practice will be established in large multi-centre study, findings of this preliminary report should be considered as exploratory only.

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      MO08.10 - Efficacy of adjuvant chemotherapy for lung adenocarcinoma patients with pleural lavage cytology positive findings. (ID 174)

      16:15 - 17:45  |  Author(s): H. Ogawa, K. Uchino, N. Shimizu, K. Tane, W. Nishio, M. Yoshimura

      • Abstract
      • Presentation
      • Slides

      Background
      Pleural lavage cytology (PLC) is considered to be a prognostic factor for non-small cell lung cancer (NSCLC) patients. There has been no report describing the relationship between adjuvant chemotherapy and the presence of PLC.Backgroud: Pleural lavage cytology (PLC) is considered to be a prognostic factor for non-small cell lung cancer (NSCLC) patients. There has been no report describing the relationship between adjuvant chemotherapy and the presence of PLC.

      Methods
      From January 2000 to December 2009, we retrospectively reviewed the medical record of lung adenocarcinoma patients who underwent tumor resection and were positive for PLC immediately after thoracotomy.

      Results
      There were 53 patients (4.8%) out of 1114 lung adenocarcinoma patients had PLC positive findings, including 31 male and 22 female patients, with a mean age of 66.6 years. Median follow up period was 33.6 months. Adjuvant chemotherapy was administered intravenously to 24 patients and they were classified as adjuvant chemotherapy group. The rest of 29 patients were classified as surgery alone group. Pathological stage of I / II / III was 12 (41%) / 8 (28%) / 9 (31%) in surgery alone group and 7 (36%) / 8 (30%) / 9 (38%) in adjuvant chemotherapy group. The regimen of chemotherapy was as follows; 8 patients received cisplatin plus gemcitabine, 7 patients received carboplatin plus paclitaxel, 7 patients received gemcitabine, and 2 patients received others. 5-year survival rate was 50.3% and 29.7% (p=0.09) and 5-year recurrence free survival rate was 34.6% and 15.7% (p<0.01) in adjuvant chemotherapy group and surgery alone group. Even in stage I cases, there was a tendency that adjuvant chemotherapy group had better 5-year recurrence free survival than surgery alone group (60.1% and 29% p=0.11). In the COX proportional hazard multivariate analysis for recurrence free survival revealed that adjuvant chemotherapy (hazard ratio (HR) 0.45, p=0.03), tumor size >30mm (HR 2.23, p=0.02), and lymph node metastasis (HR 2.67, p<0.01) were significant independent prognostic factors.Figure 1

      Conclusion
      Adjuvant chemotherapy was considered to be effective for PLC positive lung adenocarcinoma patients. Even in stage I cases, our results implicated that adjuvant chemotherapy was beneficial.

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      MO08.11 - The role of aggressive local therapy and prognostic factors in postoperative recurrent non-small cell lung cancer: Is oligorecurrence state potential curable disease? (ID 925)

      16:15 - 17:45  |  Author(s): Y. Shimada, M. Kakihana, K. Yoshida, Y. Kato, M. Hagiwara, N. Kajiwara, T. Ohira, N. Ikeda

      • Abstract
      • Presentation
      • Slides

      Background
      Non-small cell lung cancer (NSCLC) with postoperative recurrence (POR) is generally believed to have an incurable disease. However, several studies have indicated that only a limited number of distant recurrences (oligorecurrence) may benefit from local therapy to the distant site of disease. We investigated factors associated with postrecurrence survival (PRS) in recurrent NSCLC, and particularly the role of local therapy to the metastatic site.

      Methods
      From 2000 through 2009, a total of 1542 patients with NSCLC underwent complete surgical resection. Of those, we reviewed the records of 356 patients with POR.

      Results
      Type of POR included locoregional only in 114 (32%), distant in 242 (68%). Of the 242, there were 65 oligorecurrences. Initial recurrence therapy found local treatment for 68 (surgery 5, radiation 12, surgery with chemotherapy and/or radiation 12, chemoradiotherapy 39). Multivariate analysis demonstrated that older age (HR1.522), advanced stage (HR1.371), shorter disease-free interval (DFI; HR1.733), non-adenocarcinoma (HR1.442), systemic treatment (-) (HR1.481), EGFR-TKIs (-) (HR1.563), local treatment (-) (HR1.705) and bone metastases (HR2.140) had a significant association with poor PRS, and oligorecurrences state appeared as an independent PRS factor in patient with distant recurrence (HR1.836). Median PRS times were 36.3 months for 37 patients with DFI > 16 months and receiving local treatment, and 16.0 months for other (p<0.001) in all patients (Fig.1), and 36.5 months for 29 patients with DFI > 16 months and oligorecurrence, and 14.6 months for other (p<0.001) in patient with distant recurrence (Fig.2). There was no significant difference in survival for the patients with oligorecurrence according to whether or not receiving local treatment. Figure 1Figure 2

      Conclusion
      This study showed that local therapy improved PRS in patients with POR. Optimization of personalized systemic treatment depends on patient selection, and therapeutic strategy for adding an aggressive local treatment options based on a careful follow-up is important.

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      MO08.12 - DISCUSSANT (ID 3961)

      16:15 - 17:45  |  Author(s): R. Kelly

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MO03 - Thymic Malignancies (ID 123)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO03.10 - A multicenter prospective study of carboplatin and paclitaxel for advanced thymic carcinoma: West Japan Oncology Group 4207L (ID 987)

      10:30 - 12:00  |  Author(s): K. Nakagawa

      • Abstract
      • Presentation
      • Slides

      Background
      Thymic carcinoma (TC) is a rare malignant tumor originated within the thymus gland and is associated with a poor prognosis, differing from thymoma which is the most common type of thymic malignant neoplasm. No results of clinical trials focusing on TC have been reported. This single-arm study evaluated carboplatin and paclitaxel (CbP) in previously untreated patients (pts) with advanced TC.

      Methods
      Pts with Masaoka’s stage III to IVb TC, ECOG PS 0 to 1, and more than 20 years old were eligible. The study treatment consisted of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks for a maximum of 6 cycles. The primary endpoint was objective response rate (ORR) by extramural assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. All pts were followed-up until 24 months (mo) after last enrollment. Based on the SWOG 2-stage design, the planned sample size of 40 pts was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05.

      Results
      From May 2008 to November 2010, 40 pts were enrolled from 21 centers. Of 39 evaluable for analysis, the median age was 62 years (range, 36–84); 23/16 males/females; 3/10/26 with Masaoka’s stage III/IVa/IVb; 9/11/19 with squamous cell carcinoma/poorly differentiated neuroendocrine carcinoma/other types. The median number of cycles was 6. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval [CI], 21-53%; P = 0.031). The median PFS was 7.5 mo (6.2-12.3 mo) while OS did not reach the median value. The 1-year and 2-year survival rates were 85% (95% CI, 69-93%) and 71% (95% CI, 54-83%), respectively. Major adverse event was grade 3-4 neutropenia in 34 pts (87%). Two cases (5%) of grade 3 febrile neutropenia, neuropathy, and arthralgia were observed, respectively. There was no treatment-related death.

      Conclusion
      CbP showed high efficacy in advanced TC. Our results established that CbP, one of the standard treatments for non-small cell lung cancer, also serves as a key chemotherapy regimen for TC.

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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.02 - Thoracic Radiotherapy With or Without Concurrent Daily Low-Dose Carboplatin in Elderly Patients With Locally Advanced Non-small Cell Lung Cancer: Updated Results of the JCOG0301 and Pooled Analysis With the JCOG9812 Trial. (ID 734)

      10:30 - 12:00  |  Author(s): K. Nakagawa

      • Abstract
      • Presentation
      • Slides

      Background
      The Japan Clinical Oncology Group (JCOG) undertook 2 randomized phase III trials (JCOG9812 and JCOG0301) to assess whether daily low-dose carboplatin plus radiotherapy could improve survival in elderly patients with stage III non-small cell lung cancer (NSCLC) when compared to radiotherapy alone. Although JCOG9812 was prematurely terminated because of a high incidence of treatment-related deaths (TRDs) and instances of protocol violation, especially with regard to radiotherapy planning, the trial regimen was assumed promising. Therefore, JCOG0301 was conducted for the same subjects using the same protocol regimen with modified inclusion criteria regarding pulmonary function and radiotherapy quality control (RTQC) measures. We then carried out a preplanned pooled analysis of these 2 studies.

      Methods
      The eligibility criteria for both trials were age of ≥71 years and unresectable stage III NSCLC. Patients were randomized to receive radiotherapy alone (60 Gy, RT arm) or chemoradiotherapy (radiotherapy, 60 Gy plus concurrent carboplatin, 30 mg/m[2] per fraction up to the first 20 fractions, CRT arm). The primary endpoint for both studies was overall survival (OS). The pooled analysis included OS, progression-free survival (PFS), response rate, and toxicities.

      Results
      In JCOG9812, 46 patients (RT arm, n=23; CRT arm, n=23) were enrolled from November 1999 to August 2001. In JCOG0301, 200 patients (RT arm, n=100; CRT arm, n=100) were enrolled from September 2003 to May 2010, and in total, 246 patients were included in the pooled analysis. Patient characteristics for the RT (n=123) and CRT (n=123) arms were as follows: median age, 77 years (range, 71–93) and 77 years (range, 71–89); stage IIIA/IIIB, 65/58 patients and 63/60 patients; performance status (PS) 0/1/2, 44/74/5 patients and 50/69/4 patients; men/women, 103/20 patients and 96/27 patients, respectively. The median OS for the RT (n=121) and CRT (n=122) arms were 16.3 months (95% CI, 13.4–18.6) and 20.7 months (95% CI, 16.3–26.9), respectively (HR, 0.672; 95%CI, 0.502–0.898, stratified log-rank test one-sided p=0.0034). The pooled HR for PFS was 0.671 (95%CI, 0.514–0.875, stratified log-rank test one-sided p=0.0015). Response rates for the RT and CRT arms were 46.3% and 53.3%, respectively. The number of patients with grade 3/4 hematological toxicities was higher in the CRT arm than in the RT arm: leucopenia (62.2% vs 1.7%), neutropenia (54.6% vs none), and thrombocytopenia (30.3% vs 3.3%). The incidence of grade 3/4 pneumonitis decreased from 4.4% (JCOG9812; RT, 4.5% and CRT, 4.3%) to 2.1% (JCOG0301; RT, 3.1% and CRT, 1.0%), and that of late lung toxicity, from 14.0% (JCOG9812; RT, 10.0% and CRT, 17.4%) to 5.9% (JCOG0301; RT, 5.3% and CRT, 6.5%). The incidence of TRD also decreased from 8.9% (JCOG9812; RT, 1 patient and CRT, 3 patients) to 3.6% (JCOG0301; RT, 4 patients and CRT, 3 patients). As per subgroup analyses, ≤75 years, stage IIIA, male, PS 0, and smoking history were associated with statistically significant improvement in OS in the CRT arm.

      Conclusion
      This combination chemoradiotherapy for elderly patients with locally advanced NSCLC provides clinically significant benefits and RTQC measures are imperative to improve treatment outcome.

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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.07 - Investigation of risk factors for developing interstitial lung disease (ILD) and poor prognostic factors for ILD death in Japanese patients with non-small-cell lung cancer (NSCLC): a final analysis of a large-scale erlotinib surveillance study (POLARSTAR) (ID 2208)

      10:30 - 12:00  |  Author(s): K. Nakagawa

      • Abstract
      • Presentation
      • Slides

      Background
      A large-scale surveillance study (POLARSTAR) was implemented to investigate erlotinib safety and efficacy in Japanese patients, focusing on the pattern of occurrence of interstitial lung disease (ILD) and specific factors that may contribute to the onset of ILD in patients receiving erlotinib. The following risk factors for erlotinib-induced ILD have been previously reported: concurrent/previous ILD (adjusted hazard ratio [HR] =3.2), existing emphysema/chronic obstructive pulmonary disease (COPD) (HR=1.9) or lung infection (HR=1.6), smoking status (HR=2.2) and ECOG performance status 2–4 (HR=1.4). These were identified as the primary risk factors for ILD by multivariate analysis. The current analysis was carried out to identify factors linked with poor prognosis in terms of ILD-related death within the POLARSTAR surveillance study.

      Methods
      Enrolment of all patients in Japan receiving erlotinib for NSCLC took place between December 2007 and October 2009; the observation period was 12 months. All ILD-like events were assessed by an independent ILD review committee. ILD was defined as all ILD-like events excluding those events deemed non-ILD by the independent ILD review committee. Risk factors for poor prognosis concerning ILD death were analyzed by multivariate analysis using a logistic regression model.

      Results
      A total of 10,708 patients were enrolled by the data cut-off of 12 October 2009, with data available for 9,909 patients. The majority of ILD cases were reported within 4 weeks of receiving erlotinib. Among the 491 patients who experienced ‘ILD-like’ events, 93 could not be evaluated by the independent ILD review committee due to lack of imaging data; the remaining 398 patients were referred to the committee for evaluation. A total of 310 patients had confirmed ILD by the ILD review committee, based on image evaluation or clinical investigation; 125 had died as a result of ILD. These patients were assessed by multivariate analysis. Sixty-two events were deemed non-ILD and 26 events could not be evaluated due to a lack of clear clinical evidence (e.g. ILD could not be distinguished from progression or pneumonitis, or insufficient imaging data were available). The multivariate analysis identified ECOG performance status 2–4 (adjusted odds ratio [OR] =2.45 [95% CI 1.41–4.27]; p=0.0016), <50% remaining normal lung area (OR=3.12 [1.48–6.58]; p=0.0029) and interstitial pneumonia with concomitant honeycomb lung (OR=6.67 [1.35–32.94]; p=0.02) as poor prognostic factors for ILD death. However, pre-existing interstitial pneumonia by grade of severity was not identified as one of these factors. This result could be attributed to practical bias in this surveillance study, such as selection or treatment bias for patients with pre-existing interstitial pneumonia within the condition of careful dosage specified in the erlotinib label.

      Conclusion
      These final data from this large surveillance study in Japanese patients with recurrent and advanced NSCLC provide further information on the risk factors for poor prognosis with ILD, identifying those patients at greatest risk of ILD-related death. Improved awareness of these prognostic factors will help clinicians in monitoring those patients at highest risk.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.10-010 - Survival outcome assessed by response and tumor shrinkage pattern in non-small cell lung cancer patients with activating mutations of the epidermal growth factor receptor (ID 752)

      09:30 - 16:30  |  Author(s): K. Nakagawa

      • Abstract

      Background
      Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the dramatic therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non–small cell lung cancer (NSCLC); however, there are no studies investigating clinical indicators that affect the likelihood of survival benefit from EGFR-TKI in selected patients with EGFR mutations. We evaluated the progression-free survival (PFS) and overall survival (OS) according to response and tumor shrinkage pattern among EGFR-mutated NSCLC.

      Methods
      Among 145 EGFR-mutation positive patients treated with EGFR-TKI, 68 patients were selected for the present analysis.

      Results
      Of those 68 patients, six patients achieved complete response (CR), 42 patients partial response (PR), and 14 patients stable disease (SD). The PFS and OS of CR/PR group was significantly longer than that of the SD group. A multivariate analysis demonstrated that response (CR/PR) to EGFR-TKI significantly correlated with both PFS and OS. Among CR/PR group, the median maximum tumor change from baseline was -56%, and the median time to response (TTR) was 4.2 weeks. No trend toward more favorable PFS and OS benefit was seen in the subset of patients who had experienced rapid tumor regression (TTR < 4.2 weeks) as well as high degree of tumor shrinkage (< -56%) compared with those who showed slow tumor regression (TTR > 4.2 weeks), or low degree of tumor shrinkage (> -56%) among CR/PR patients.

      Conclusion
      Response (CR/PR) may represent the optimal surrogate for efficacy among EGFR mutation-positive patients treated with EGFR-TKI patients.

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      P1.10-020 - Dose adjustment of single agent amrubicin in lung cancer patients with impaired hepatic function (ID 1348)

      09:30 - 16:30  |  Author(s): K. Nakagawa

      • Abstract

      Background
      The pharmacokinetics (PK) of amrubicin (AMR) in lung cancer patients with impaired hepatic function have not been reported. The objectives of this study were to evaluate the PK of AMR and its major metabolite, amrubicinol (AMR-OH), in lung cancer patients with or without impaired hepatic function, and to assess the validity of dose adjustment of AMR based on hepatic function.

      Methods
      Eligibility criteria included the presence of histologically or cytologically proven lung cancer, an ECOG PS of 0 to 2, age 20 to 70 years old, and no evidence of hepatitis B virus infection. The dose was adjusted from 25 to 45 mg/m[2]/day (iv, days 1-3, q3w) based on the history of prior treatment and baseline values of total bilirubin (T-bil), AST and ALT (Table 1). Figure 1

      Results
      Five patients with impaired hepatic function (arm I) and 10 patients with normal hepatic function (arm N) were enrolled. Terminal half-life (t~1/2~) and clearance of AMR in plasma, and t~1/2~ of AMR-OH in blood did not differ between the two arms. Area under the curve (AUC~0-24~) of AMR in plasma and AUC~0-120~ of AMR-OH in blood in arm I were similar or lower compared to those in arm N (Table 2). The dose-adjusted AUCs of AMR and AMR-OH did not show a tendency to increase with increases in baseline T-bil, AST and ALT. Two deaths occurred in arm I (one due to disease progression, and the other due to an unspecified reason), but the toxicities in arm I were not severe compared with those in arm N. Figure 1

      Conclusion
      These data show the validity of dose adjustment of AMR in patients with impaired hepatic function.

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-003 - Phase I and pharmacokinetic study of amatuximab, a novel chimeric antibody to mesothelin, in patients with advanced solid tumors (ID 1209)

      09:30 - 16:30  |  Author(s): K. Nakagawa

      • Abstract

      Background
      Amatuximab is a chimeric monoclonal antibody to mesothelin. Mesothelin, a membrane protein, is a potential target for molecular targeted therapy due to its high expressions in virtually all pancreatic cancers and mesotheliomas as well as several cancers, while showing little expression in normal tissues, except for normal mesothelium. Amatuximab inhibits the growth of mesothelin-expressing human tumors in vitro and in vivo xenograft model.

      Methods
      To investigate dose-limiting toxicities (DLTs) and estimate the maximum tolerated dose (MTD) of amatuximab in Japanese patients with advanced solid tumors. In addition, pharmacokinetics of amatuximab, human anti-chimeric antibody (HACA) and mesothelin expression by immunohistochemistry (IHC) were investigated. Patients with pancreatic cancers, mesotheliomas, or mesothelin-positive solid tumors as assessed by the IHC test, who have no other appropriate treatment were eligible in the study. Amatuximab was administered weekly until disease progression or occurrence of a DLT, and administered to 3 cohorts at 50, 100 and 200 mg/m[2] in a step-wise dose escalation manner. The pharmacokinetic parameters were calculated by model independent analysis and the dose proportionality was investigated on Cmax and AUC (0-t) values.

      Results
      58 patients were screened and a total of 17 patients were enrolled consisting of seven colorectal cancer, six pancreatic adenocarcinoma, two mesothelioma and two head and neck cancer (seven patients in 50 mg/m[2], three in 100 mg/m[2] and seven in 200 mg/m[2], respectively). Two DLTs were observed (grade 3 cytokine release syndrome in 50 mg/m[2] and grade 5 interstitial lung disease in 200 mg/m[2]). Treatment related adverse events were observed in 13 of 17 patients, and the most common events were grade 1 fatigue (five patients) and pyrexia (four patients). Amatuximab was eliminated from serum biphasically after reached Cmax. Estimated mean T1/2 on Cycle 1 Day 1 was 92.3 to 108 h and CL was 11.7 to 15.2 mL/h/m[2]. It was found that the Cmax and AUC (0-t) values on Cycle 1 Day 1 increased in an almost dose proportional manner and these were similar to those in US patients. HACA was detected in eight of 17 patients. Of 53 patients whose tissue samples were evaluated by IHC, 24 patients (45.3%) were mesothelin-positive (10 of 19 patients in colorectal cancer, four of eight in biliary cancer, four of five in pancreatic adenocarcinoma and six of 21 in other cancers).

      Conclusion
      Amatuximab was well tolerated in patients with advanced solid tumors, and MTD was not reached up to 200 mg/m[2]. Pharmacokinetic profile of amatuximab in Japanese patients was similar to that in US patients. Amatuximab is currently being investigated for its potential treatment of mesothelioma.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 2
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      P3.09-003 - Phase II study of nimotuzumab in combination with concurrent chemoradiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC). (ID 707)

      09:30 - 16:30  |  Author(s): K. Nakagawa

      • Abstract

      Background
      Nimotuzumab, a humanized IgG~1~ monoclonal anti-EGFR antibody, is approved and widely used in patients (pts) with head and neck cancer or malignant glioma in combination with radiotherapy (RT) in several countries. In previous clinical studies, nimotuzumab has demonstrated a very mild and low incidence of skin toxicity compared to other anti-EGFR antibodies. On in-vitro and in-vivo experiments using NSCLC cell lines, nimotuzumab showed a radio-sensitizing effect.

      Methods
      This open-label, multicenter phase II study evaluated the tolerability and efficacy of nimotuzumab in combination with concurrent CRT in pts with unresectable locally advanced NSCLC. All eligible pts received concurrent thoracic RT (60 Gy, 2 Gy/day, 6 weeks from day 1) and 4 cycles of chemotherapy (cisplatin 80 mg/m[2] on day 1, vinorelbine 20 mg/m[2] on days 1 and 8) once every 4 weeks as scheduled. Nimotuzumab (200 mg) was administrated once a week from cycle 1 to 4. The primary endpoint was tolerability in combination with concurrent CRT, which was measured by the percentage of pts who completed 60 Gy of RT within 8 weeks, completed 2 cycles of chemotherapy and received more than 75% of nimotuzumab.

      Results
      Between June 2009 and May 2010, 40 pts were enrolled from 7 institutions in Japan, and 39 eligible pts received the study treatment. The pts characteristics (n = 39) were as follows: 62 years (median); male/female, 34/5; stage IIIA/B, 21/18; PS0/1, 25/14. Thirty-four pts (87%) met the criteria for treatment tolerability, and 38 pts (97%) completed 60 Gy of RT within 8 weeks. Infusion reaction, >grade 3 skin rash, >grade 3 radiation pneumonitis, or >grade 4 nonhematological toxicity were not observed. The 2-year overall survival rate for the 39 pts was 76% (95% CI; 59-87%). The median PFS was 16.7 months; and 30 pts were alive at the cutoff date (Nov 2011). The 1-year PFS rate for pts with squamous cell carcinoma (Sq; n = 16) was 75%, while that for pts with non-squamous cell carcinoma (non-Sq; n = 23) was 41%. In terms of the first relapse site, in-field relapse rates were low for both Sq (3/16; 19%) and non-Sq (3/23; 13%). However, the distant relapse rate was significantly higher for non-Sq (15/23; 65%) than that for Sq (2/16; 13%) (p<0.01, chi-square test with Yates correction).

      Conclusion
      Addition of nimotuzumab to the concurrent CRT in this setting was well tolerated with clinical benefit to the patients. The low in field relapse rates may be attributed to the radio-sensitizing effect of nimotuzumab. These findings warrant further clinical evaluation of nimotuzumab/cisplatin/vinorelbine/RT in a phase III trial.

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      P3.09-007 - Update data of biomarker analysis of WJOG4107 (A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC)) (ID 1504)

      09:30 - 16:30  |  Author(s): K. Nakagawa

      • Abstract

      Background
      We conducted a randomized phase II trial for patients with resected stage II-IIIA NSCLC comparing postoperative oral S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year) (S) (N=100) or cisplatin (CDDP) (60 mg/m2 day1) plus oral S-1, (80 mg/m2/day for 2 weeks) q3w for 4 cycles (PS)(N=100). We reported that disease free survival rate at 2 years ([email protected]) (95% confidence interval: CI), a primary endpoint, was 66 (55-74) % for S and 58 (48-67)% for PS. Here, we report the preliminary results of preplanned biomarker analysis, a co-primary endpoint, to identify molecules whose expression is significantly associated with patient outcome.

      Methods
       cDNA extracted from macro-dissected formalin-fixed paraffin-embedded specimens were available for 197/200 patients. Thirty-one genes including those whose expressions have been potentially associated with CDDP (e.g. ERCC1, XRCC1, BRCA1, GSTpi, HMG1, TBP) or fluorouracil (FU) sensitivity (TS, DHFR, DPD, UMPS, UPP1) were measured by QGE analysis (MassArray, Sequenom, CA). Additional analysis are being performed to assess ERCC1 isoform expression with an isoform-specific TaqMan probe (Applied Biosystems, CA). The expression of each gene was dichotomized according to its median value.

      Results
      Molecules such as ERCC1 and GSTpi whose expression have been previously associated with CDDP sensitivity did not emerge as predictive markers (P=0.7908, 0.6406, respectively). We quantitated ERCC1 by isotype (202 and 204 cannot be distinguished). There was a trend in patients with high 201 or 202/204, CDDP/S-1 was worse than S-1.

      Conclusion
      Quantitation of ERCC1 by isotype may define a patient subset that would benefit from postoperative platinum therapy.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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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): K. Nakagawa

      • 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).

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      P3.11-034 - One-year follow-up of a Phase I/II study of a highly selective ALK inhibitor CH5424802/RO5424802 in ALK-rearranged advanced non-small cell lung cancer (NSCLC) (ID 2591)

      09:30 - 16:30  |  Author(s): K. Nakagawa

      • Abstract

      Background
      CH5424802 is a novel tyrosine-kinase inhibitor that selectively inhibits ALK as well as secondary ALK mutations including L1196M. The preliminary results of the Phase I/II study (Lancet Oncol. 2013; 14: 590–8) showed that CH5424802 was active in the CNS and achieved a 93.5% objective response rate by RECIST in crizotinib-naïve NSCLC patients with a median follow-up of 7.6 months (range, 3.4–11.3). Here we report the 1-year follow-up results after the last patient enrolled in the Phase II analysis.

      Methods
      Patients with ALK-rearranged advanced NSCLC, who progressed after ≥1 prior chemotherapy regimens and who were naïve to any ALK inhibitors, received CH5424802 300 mg orally twice daily in the Phase II portion of the study. ALK fusion gene expression was confirmed by IHC and FISH or by RT-PCR at central laboratories. Tumor assessment was performed every cycle (21 days) until Cycle 4 and every 2 cycles thereafter with RECIST ver. 1.1.

      Results
      As of April 18, 2013, 46 patients had been treated with CH5424802 in the Phase II portion: median age, 48 years (range, 26–75); male/female, 22/24; ECOG PS 0/1, 20/26; never-smoker, 59%; ≥2 prior chemotherapy regimens, 52%. The objective response rate remains the same as previously reported, 93.5% (95% CI: 82.1% to 98.6%). At 1-year follow-up, a total of 7 patients (15%) had achieved a complete response. The median progression-free survival had not been achieved, and the 1-year progression-free rate (PFR) was 83% (95% CI: 68% to 92%). 34/46 patients were still on study treatment, and the median treatment duration had passed 14.8 months. CH5424802 also shows promising efficacy in the CNS: of 14 patients with baseline brain metastasis, 9 remained in the study without CNS or systemic progression for >12 months, with 6 of them exceeding 16 months. The other 5 patients with baseline CNS metastasis had no CNS progression during CH5424802 treatment. One of these patients discontinued the study due to AE, and the remaining 4 patients had systemic progression. The safety profile remains similar to that previously reported, with no patient requiring dose reduction.

      Conclusion
      CH5424802 demonstrated a high 1-year PFR of 83% and promising CNS activity. CH5424802 could be a novel therapeutic option for the treatment of ALK-rearranged NSCLC.

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    PC02 - EGFR as a Target in Early Stage Disease (ID 71)

    • Event: WCLC 2013
    • Type: Pro/Con Session
    • Track: Medical Oncology
    • Presentations: 1
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      PC02.2 - Pro: Patients with EGFR Mutations Should Receive Adjuvant EGFR TKIs (ID 629)

      14:00 - 15:30  |  Author(s): K. Nakagawa

      • Abstract
      • Presentation
      • Slides

      Abstract
      In lung cancer field, the direction of treatment strategy is in the midst of great change since molecular-targeted-drug was introduced. One of the revolutionary drugs is EGFR-TKI for EGFR positive lung cancer. It contributes to the treatment not only of advanced lung cancer, but also resectable early lung cancer in stage II and III. Although it is common to conduct surgery as the standard of care for early-stage lung cancer treatment, Stage II and III cases show poor prognosis even though complete resection is done. According to Asamura et al, 5-year survival of stage IIA, IIB and IIIA Japanese patients are 61%, 47% and 32% respectively. In response to these results, many investigators have been trying neoadjuvant and adjuvant chemotherapy in combination with surgery. In many cases, relapse after standard resection is distant metastasis, thus it is suspected that in order to achieve better prognosis, possible micrometastasis in whole body needs to be eradicated. Currently combination therapy with platinum-doublet is commonly chosen as the strong treatment regimen for controlling the micrometastasis in advanced cancer cases. Gefitinib is an EGFR-TKI (tyrosine kinase inhibitor) approved for the treatment of unresectable or recurrent NSCLC. Since its approval in Japan in July 2002, it has been approved in about 70 countries and used as the therapeutic medication for advanced recurrent NSCLC (at the point of August 2010). When Gefitinib was initially released, 3 to 5% of drug-related ILD (Interstitial Lung Disease) and deaths were reported in Japan. After cohort study, it has been reported that those who are male, smoker, have the past illness of ILD and have low PS showed the higher ILD incidence rate than other cohorts. In 2004, it has been reported that Gefitinib shows the remarkably high response rate for EGFR positive patients, and subsequent studies demonstrated that EGFR mutation is an efficacy predictive biomarker.It is commonly known that Gefitinib induces apoptosis in EGFR positive patients. In fact, some clear anti-tumor effect have been observed in many clinical studies targeting on EGFR positive advanced NSCLC patients. The result of post-marketing Phase III clinical trial targeting on Asian patients untreated with chemotherapy (IPASS trial)was reported in September 2008. According to pre-planned subgroup analysis based on biomarker, in EGFR positive patient group Gefitinib cohort showed the significant prolongation of PFS (Progression Free Survival) compared to Carboplatin plus Paclitaxel cohort (HR 0.48, 95% CI 0.36~0.64, p<0.0001). In addition, Gefitinib cohort showed better efficacy, QOL, safety and tolerability. However, in terms of OS (Overall Survival), the difference was not observed in two cohorts (HR 1.00, 95% CI 0.76~1.33, p=0.990). On the other hand, in EGFR negative patient group, Carboplatin plus Paclitaxel cohort significantly prolonged PFS compared to Gefitinib cohort (HR 2.85, 95% CI 2.05~3.98, p<0.0001). It was reported from Japan that in the two Phase III controlled study targeting on EGFR positive advanced lung cancer patients untreated with chemotherapy, Gefitinibcohort showed better PFS (Hazard Ratio of less than 0.5) than standard chemotherapy cohort of Cisplatin plus Docetaxel (HR 0.489, 95% CI 0.336~0.710, p<0.0001) or Carboplatin plus Paclitaxel (HR 0.357, 95% CI 0.252~0.507, p<0.001) in both studies. However, the comparison of 2-year survival in the controlled study of Carboplatin plus Paclitaxel, there was no statistically significant difference (Gefitinib: 61.4%, Standard Chemotherapy of CBDCA plus PTX: 46.7%) (P=0.31). In addition, in two cohorts (Gefitinibvs CDDP plus DOC) there was no statistically significant difference in OS among them (HR 1.638, 95%CI 0.749~3.582, p=0.21), thus the superiority of Gefitinib was not demonstrated in terms of OS. In the above-mentioned three prospective controlled trial, it was demonstrated that Gefitinib dramatically prolongs PFS in EGFR positive NSCLC patients compared to standard chemotherapy, and shows high anti-tumor effect and improvement of QOL, but not in terms of OS. It is suspected this is partially because of the fact that in chemotherapy cohort many patients received Gefitinib after relapse. To sum up, Gefitinib shows higher anti-tumor effect than standard chemotherapy if the target patients are EGFR positive, and thus is an appropriate option as the adjuvant treatment regimen after complete resection. It was impliedfrom Phase I trial that Gefitinib shows anti-tumor effect for the solid tumor patients who did not benefit from standard of care or have no other treatment options and thus effective for various types of cancer. In Phase II monotherapy trial, Gefitinib showed clinically significant and continuous anti-tumor effect in locally-advanced or metastatic NSCLC patients previously treated with chemotherapy. Additionally, it improved the cancer symptoms in these patients. Orally administering 250mg or 500mg once per day showed the same level of efficacy. Although in Phase III monotherapy trial targeting on advanced NSCLC patients the efficacy of Gefitinib was demonstrated, there was no statistically significant difference in terms of OS, which is the primary endpoint. However, the response rate of Gefitinib cohort was higher than that of placebo cohort. In Phase III combination chemotherapy trial, standard chemotherapy (Gemcitabine/Cisplatin, Paclitaxel/Carboplatin) and Gefitinib 250mg per day or 500mg per day were evaluated. In this study however, statistically or clinically significant data superior to combination of standard chemotherapy with placebo was not observed. In conclusion, there are three reasons why patients with EGFR mutations should receive adjuvant EGFR-TKIs. Firstly, EGFR-TKI induces apoptosis and its exposition to EGFR positive patients potentially induces eradication of micrometastasis remaining after surgery. Secondly, for the EGFR positive patients, EGFR-TKI is superior to standard platinum-doublet in terms of safety and tolerability. Lastly, EGFR-TKI is the most potent anti-cancer drug for EGFR positive patients at the moment, which shows remarkable anti-tumor effect, prolongs PFS and improves QOL compared to platinum-doublet. Therefore, despite the issue of ILD remains, EGFR-TKI is to be considered as an appropriate treatment option in adjuvant setting for the EGFR positive patients. In order to prove this point, West Japan Oncology Group (WJOG) is currently conducting IMPACT trial, which is a prospective Phase III study.

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