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R. Rosell



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    MO08 - NSCLC - Early Stage (ID 117)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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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 - 16:20  |  Author(s): 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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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.02 - Update genotyping non-small cell lung cancer (NSCLC) in Latin America: Latin-American Consortium for the Investigation of Lung Cancer (CLICaP) (ID 3462)

      16:20 - 16:25  |  Author(s): R. Rosell

      • Abstract
      • Presentation
      • Slides

      Background
      Previously we reported that the frequency of mutations in EGFR and KRAS in non-small cell lung cancer (NSCLC) is Latinoamerica,finding the frequency of EGFR mutations in Latin-America between Asian (40%) and European (15%) populations. We report the update frequency of mutations in Latin America.

      Methods
      3606 biopsies of NSCLC patients from Latin-America (Argentina, Colombia, México and Peru) were used by extracted genomic DNA which was used to perform direct sequencing of EGFR gene (exons 18 and 21) and KRAS gene in 2385 samples.

      Results
      Of all patients the median age was 62.2 ±12.3, 52.6% were women, and 51% had smoking history. Frequency of EGFR mutations in NSCLC was 24.4% [CI 95% 22.7-24.1] (Argentina 14.4%, Colombia 24.9%, Mexico 34.4%, Peru 67.0%). The frequency of KRAS mutations was 7.1%. EGFR mutations were independently associated with gender (29.8% vs 16.3%; p< 0.001), older age (<60 vs >60; p= 0.001), non-smokers 25.9% vs 15.7%; p= 0.001), ethnicity (Hispanic 37.7%, Caucasic 13%, Afro-American 0%, non-determinate 22.9%; p< 0.001), histology (adenocarcinoma 23.8%, squamous 4.4%, large cells 33.3% and non differenced 22.2%) and absence of KRAS mutation. Overall response rate to tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutated patients (n=56) was 62.5% [95% CI 50-75] with a median overall survival of 16.5 months [95% CI 12.4-20.6].

      Conclusion
      Our findings confirm the high frequency of EGFR Mutation in Latino-america and low frequency of K-RAS mutation, particularly in patients of Hispanic ethnicity. Differences in risk factors associated with lung cancer in our population and ethnic variability could explain these findings.

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    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO16.08 - Cytology samples (s) for EGFR, KRAS and ALK testing in Non-Small-Cell Lung Cancer (NSCLC) (ID 2439)

      17:00 - 17:05  |  Author(s): R. Rosell

      • Abstract
      • Presentation
      • Slides

      Background
      Recent advances in targeted therapy in NSCLC have achieved impressive results in advanced disease. For molecular testing,cytology samples are not commonly used since is less likely to be adequate. At ICO Badalona- Germans Trias i Pujol Hospital we have used cytology specimens when biopsy was not available. We describe the general results when using cytology specimens in NSCLC to detect EGFR mutation, KRAS mutations and ALK translocations.

      Methods
      From February 2007 to May 2012, 227 cytology samples from patients with NSCLC were collected at the Department of Pathology as cell block or fresh specimen over an apropiate slide. After that, tumor cells were(8-150) captured by laser microdissection. DNA sequencing for EGFR exons 18, 19, 20, 21, KRAS codons 12 and 13 was performed at Molecular Biology Laboratory( ICO-Badalona) and ALK translocation were analyzed at Pathology Department by FISH

      Results
      EGFR mutations were tested in 227 samples.The overall output was 86.3% (not evaluable in 15 , insufficient tissue in 8, no tumor cells in 4, not done in 4). EGFR mutation was detected in 8.81% (20/227). KRAS mutation were tested in 41 samples with results in 33, 80.5% (2 not evaluable, insufficient tumor cells 3, no tumor 1 and not done 2 samples). KRAS mutation was positive 6 (14.6%). ALk translocation were tested in 9 p with results in 6 p ( 1 not evaluable and 2 insufficient tumor cells) Both cell-block and fresh specimen over an apropiate slide were used to perform molecular testing. The output for cell-block was 83.3%(124/148) and testing was not possible in 23(11 not evaluable, 6 insufficient tumor cells, 4 not tumor and 3 not done). The output for membrane was 91.1% (72/79) and was not possible in 7(4 were not evaluable, 2 insufficient tumor cells and not done in 1). 54.7% of samples were obtained from endobronquial ultrasound guided transbronquial needle aspiration of mediastinal adenopathies, 11.3% lung mass needle aspiration and 11.7% from pleural effusion.

      Conclusion
      Our results support the potential use of cytology samples for molecular testing in NSCLC when biopsy specimens are not available. Both membrane preparations and cytology blocks have been used and are equally suitable for molecular testing.

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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.05 - Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients with acquired resistance to erlotinib. (ID 1426)

      10:50 - 10:55  |  Author(s): R. Rosell

      • Abstract
      • Presentation
      • Slides

      Background
      NSCLC patients with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs) but ultimately relapse. Sub-genomic molecular studies indicate that the EGFR T790M mutation and the activation of MET, PI3K, AXL, HER2 and MAPK can lead to acquired resistance to EGFR TKIs. To date, no integrated comprehensive genomic investigation of EGFR TKI resistance has been reported.

      Methods
      FFPE biopsies of erlotinib-sensitive and erlotinib-resistant tumors were obtained from 13 EGFR mutant NSCLC patients. The samples were analyzed by whole exome sequencing and whole transcriptome sequencing utilizing the Illumina HiSeq2500 platform. In addition, targeted gene sequencing was performed with the Illumina TruSeq Amplicon-Cancer Panel and run on the MiSeq system.

      Results
      Erlotinib resistant NSCLC specimens harbored known resistance drivers, including EGFR T790M mutations (9/13; 69%), MET amplification (3/13; 23%), HER2 amplification (3/13; 23%), and AXL upregulation (3/13; 23%). Differential expression analysis between resistant and pre-treatment states revealed enrichment in the pre-treatment tumors of immune signaling pathways, and in the resistant tumors upregulation of ERBB2, mTOR, PI3 kinase and ribosomal signaling pathways. PI3K/AKT pathway upregulation also occurred through somatic mutations in AKT and LKB1 in the resistant tumors. Copy number analysis demonstrated both large scale and focal amplifications and deletions in the resistant tumors, including the focal loss of EGFR and gain of c-Myc and NKX2-1. There was strong correlation between the copy number changes observed and the expression mRNA levels of the involved cancer-associated genes. Of note, each resistant tumor exhibited greater copy number similarity to the corresponding matched pre-treatment sample compared to other tumors within the resistance cohort.

      Conclusion
      We conducted the first ever comprehensive integrated genomic analysis of EGFR TKI resistant NSCLC patients, and identified both known and potentially novel drivers of EGFR TKI resistance. This study demonstrated the feasibility and utility of comprehensive genomic analysis in the clinical management of NSCLC receiving targeted therapy. Together, our data provide unprecedented insight into the molecular pathogenesis of escape from EGFR oncogene inhibition in NSCLC. We are now conducting a prospective observational study in additional NSCLC patients on targeted therapy.

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    MO26 - Anatomical Pathology II (ID 129)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO26.08 - The concomitant presence of echinoderm microtubule associated protein like 4 - anaplastic lymphoma kinase (EML4-ALK) EML4-ALK fusion gene in EGFR-mutant non-small-cell lung cancer (NSCLC) patients treated with erlotinib or chemotherapy in the EURTAC trial</b> (ID 1109)

      11:10 - 11:15  |  Author(s): R. Rosell

      • Abstract
      • Presentation
      • Slides

      Background
      Activating mutations in the epidermal growth factor receptor (EGFR) confer sensitivity to gefitinib and erlotinib in patients with NSCLC. However, response is often short-lived, and patients ultimately relapse, indicating that other concomitant actionable mutations could influence outcome in these patients. The EML4-ALK fusion gene has recently been identified in a subset of NSCLCs, but its specific role remains unclear. We have evaluated the frequency and impact of the concomitant presence of EML4-ALK in patients included in the randomized phase III EURTAC trial.

      Methods
      The EURTAC study enrolled 173 EGFR-mutant NSCLC patients who were randomized to receive erlotinib or standard chemotherapy with cisplatin or carboplatin plus docetaxel or gemcitabine. Tumor specimens were available from 95 of these patients for the analysis of EML4-ALK. EML4-ALK variants 1 and 3 (v1, v3) were analyzed by an independent single round of PCR followed by sequencing, using cDNA as a sample.

      Results
      EML4-ALK was detected in 15 samples (15.79%). Nine tumors contained v1 (E13;A20) and six v3 (E6;A20). No significant differences were found in baseline characteristics between patients with and without EML4-ALK. Progression-free survival was 10.4 months (m) for patients harboring the EML4-ALK fusion gene compared to 7.1 m for those without EML4-ALK. Overall survival (OS) was not reached in patients with EML4-ALK, compared to 22.9 m in those without. Complete data on outcome according to treatment arm will be presented.

      Conclusion
      Our findings indicate that the EML4-ALK rearrangement is concomitant with EGFR mutations in a considerable number of NSCLC patients and may affect 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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      O03.01 - GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients. (ID 1715)

      10:30 - 10:40  |  Author(s): R. Rosell

      • Abstract
      • Presentation
      • Slides

      Background
      Ganetespib (G) is a highly potent 2[nd]-generation Hsp90 inhibitor showing synergistic activity with docetaxel (D) in NSCLC xenografts. G has a favorable clinical safety profile and has shown single-agent clinical activity in NSCLC patients with tumors harboring EML4-ALK translocations and KRAS mutations (mKRAS).

      Methods
      We conducted a randomized, international open-label Phase 2 study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m[2] on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m[2] on Days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutation. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma patients, including 120 eLDH and 80 mKRAS patients. The study was initiated in all NSCLC patients and amended to include only those with adenocarcinoma histology.

      Results
      Enrollment of 252 adenocarcinoma patients completed in November 2012; enrollment of eLDH (total N=112) and mKRAS (total N= 86) patients completed in May 2013. In all adenocarcinoma patients (N=252), baseline characteristics were balanced between the two arms (median age 60 years, males 56%, PS 0 41% and never-smokers 25%). Median numbers of cycles delivered were 6 and 4 for D+G and D, respectively. Grade 3/4 adverse events for the D+G and D alone arms were: neutropenia 37% vs. 38%; fatigue 6% vs. 3%; anemia 8% vs. 2%; diarrhea 3% vs. 0; fever with neutropenia 11% vs. 2%. A pre-specified analysis was conducted in May 2013. PFS HR for eLDH population (N=76) was 0.88 (90% CI: 0.57, 1.36, p=0.310); OS HR was 0.63 (90% CI: 0.40, 0.99, p=0.046). PFS HR for mKRAS population (N=63) was 0.83 (90% CI: 0.51, 1.37, p=0.271); and OS HR was 0.85 (90% CI: 0.48, 1.50, p=0.313). OS HR in the all adenocarcinoma population was 0.82 (90% CI: 0.62, 1.09, p=0.082), and the PFS HR was 0.84 (90% CI: 0.65, 1.07, p=0.038). For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=176), a pre-specified stratification factor, the OS HR was 0.61 (90% CI: 0.43, 0.87, p=0.0093), and the PFS HR was 0.61 (90% CI: 0.45, 0.83, p=0.0041). Final data analysis is expected by end of September 2013. Updated PFS and OS results for all populations will be presented at the meeting.

      Conclusion
      Survival improvement was noted in all adenocarcinoma patients with the addition of ganetespib to docetaxel. The maximal benefit was achieved in patients with eLDH and those diagnosed with advanced NSCLC >6 months prior to study entry.

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    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      O15.02 - The Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized phase III trial of customized chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) (NCT00617656/GECP-BREC) (ID 1157)

      10:40 - 10:50  |  Author(s): R. Rosell

      • Abstract
      • Presentation
      • Slides

      Background
      RAP80, a component of the BRCA1 complex, influenced outcome both in p with low BRCA1 expression treated with cisplatin (cis)/gemcitabine (gem) and in p with intermediate/high BRCA1 levels treated with cis/docetaxel (doc) or with doc alone in the SLCG phase II customized chemotherapy trial (NCT00883480). Based on these findings, the SLCG and the French Lung Cancer Group performed a prospective, randomized phase III trial in metastatic NSCLC patients to compare non-customized cis/doc with customized therapy customized according to BRCA1 and RAP80 mRNA expression levels.

      Methods
      From 2008 to 2013, patients with wild-type EGFR were randomized 1:1 to the control or experimental arm. Planned accrual was 391 patients. Treatment in the control arm was cis/doc, while patients in the experimental arm received treatment according to their BRCA1 and RAP80 levels: 1) those with low RAP80, regardless of BRCA1 levels, received cis/gem; 2) those with intermediate/high RAP80 and low/intermediate BRCA1 received cis/doc; and 3) those with intermediate/high RAP80 and high BRCA1 received doc alone. The primary endpoint was progression-free survival (PFS).

      Results
      At 15 October 2012, 279 patients had been included and the planned interim analysis was performed. PFS was 5.49 months (m) in the control and 4.38 m in the experimental arm (P=0.07). Overall survival (OS) was 12.66 m in the control and 8.52 m in the experimental arm (P=0.006). Response rate (RR) was 37.3% in the control and 27% in the experimental arm (P=0.07). In the multivariate analysis including PS, treatment arm, BRCA1, RAP80, histology, smoking status and metastatic site, only extrathoracic metastases were associated with an increased risk of progression (HR, 1.78; P=0.02). In a post hoc analysis restricted to patients with ECOG PS 0, PFS was 3.91 m in the control and 7.47 m in the experimental arm (P=0.01) for those with low RAP80 levels (experimental group 1). PFS for patients in experimental groups 1, 2 and 3 was 7.47, 7.01 and 3.22 m, respectively (P=0.02). OS for patients in experimental groups 1, 2 and 3 was 28.88, 15.86 and 11.81 m, respectively (P=0.04).

      Conclusion
      Based on the negative results for PFS at the interim analysis, accrual was closed on this study. The negative results may be due to the poor predictive capacity of RAP80 and/or to the inclusion of doc alone as a treatment in the experimental arm. In addition, doc/cis may not have been the ideal combination for the control arm. Customized chemotherapy could be further encouraged in oncogene-driven pan-negative patients with PS 0.

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      O15.06 - Randomized Phase III Trial of Gemcitabine (G)/Carboplatin (C) with or without Iniparib (I) in Patients (Pts) with Previously Untreated Stage IV Squamous Lung Cancer (ID 3322)

      11:25 - 11:35  |  Author(s): R. Rosell

      • Abstract
      • Presentation
      • Slides

      Background
      Iniparib is an agent originally thought to function as an inhibitor of the DNA repair enzyme PARP-1, which is overexpressed in squamous lung cancers. Promising phase II activity and safety were reported with iniparib in combination with GC in pts with metastatic triple-negative breast cancer (O’Shaughnessy, NEJM 2011); however, subsequent phase III data were negative. Further study of iniparib’s mechanism of action suggests that this agent induces DNA damage, cell cycle arrest in the G2/M phase, and potentiates DNA-damaging chemotherapies not through PARP inhibition. Herein we report the final results from an international Phase III trial (NCT01082549) of first-line chemotherapy and iniparib in pts with advanced squamous lung cancer.

      Methods
      Pts were randomized 1:1 to GC or GCI. All pts received G 1000 mg/m[2] IV days (D) 1 and 8, and C AUC=5 IV D1 of each 21-D cycle. Iniparib was dosed 5.6 mg/kg IV D 1, 4, 8, and 11. All pts were assessed for response per RECIST 1.1 every 6 weeks. Pts without evidence of progressive disease (PD) or other reason for discontinuation could remain on treatment beyond 6 cycles. Accrual of 780 pts provides 89% power to detect an improvement in survival from 8 months (mos) anticipated with GC to 10.7 mos with GCI (HR of 0.75). Eligibility: Pts with newly diagnosed stage IV (M1a and M1b) squamous lung cancer, ECOG PS 0-1. Exclusion criteria included: history of recent cardiac disease, untreated brain metastases, and treatment for early-stage lung cancer within 12 months of study entry. The primary endpoint was overall survival (OS). Interim analyses for safety and futility were performed by an independent data safety monitoring board.

      Results
      780 pts were enrolled and randomized (GC, 390), (GCI, 390) from March 2010 to May 2012. Baseline characteristics were well balanced between groups (GC/GCI): median age 66 years (21-86); 74%/73% male; 30%/33% ECOG 0; 28%/33% current smokers; 66%/62% past smokers. The median number of cycles for GC/GCI were 4 (1-26)/5 (1-32). Dose reductions, dose intensity, and discontinuations due to tumor progression or adverse events were similar in both arms. The median OS for GC/GCI was 8.9 v. 8.9 months, HR 1.08 (0.92-1.28), p=.348. 1-year OS was 41 v. 40%. The median progression-free survival (PFS) for GC vs GCI was 4.9 v. 4.8 months, HR 0.99 (0.83-1.19), p=.92. The objective response rate (ORR) for GC v GCI was 34 v. 32%, p=.648. The safety profile was similar in both arms; anemia (28/26%), neutropenia (31/35%), thrombocytopenia (27/28%), and fatigue (6/9%).

      Conclusion
      The addition of iniparib did not improve the efficacy of GC in the treatment of pts with advanced squamous lung cancer. Further development of iniparib in squamous lung cancer is not recommended.

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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O16.03 - Cost-utility analysis of first-line treatment with erlotinib versus chemotherapy in EGFR-mutant advanced non-small-cell lung cancer (NSCLC): economic analysis of EURTAC trial (ID 1100)

      10:50 - 11:00  |  Author(s): R. Rosell

      • Abstract
      • Presentation
      • Slides

      Background
      The impact of tyrosine kinase inhibitors (TKIs) in EGFR-mutant advanced NSCLC is poorly documented. Two studies (Jacob et al, ISPOR2010, Brown et al, Health Technol Assess, 2010) are based on modelisation and indirect comparisons. The present study reports a cost-utility analysis of a phase III randomized trial (EURTAC).

      Methods
      A three state Markov model (first line PFS, second line PD and death) was built. Clinical data and resource assessment (drugs, drug administration, adverse events, second-line treatment) were collected from the trial. Utility values were derived from Nafees et al, as previously published (Vergnenegre et al. JTO 2011). Incremental cost-utility ratios (ICUR) were calculated for the first-line treatment and the overall strategy until death from the perspective of different countries (2013 actualized euros). Sensitivity analyses researched the main cost drivers.

      Results
      The quality-adjusted life-years gained was 0.124 with erlotinib, which showed an improvement in the quality of life for these patients. Despite the extra treatment costs of second-line erlotinib in the chemotherapy arm, there was a cost benefit for erlotinib first, resulting in fewer patients receiving second-line pemetrexed along with other therapy. Cost gain in favor of first-line erlotinib was 8,918 Euros. The main results are depicted in Table1.

      First-line erlotinib First-line chemotherapy
      Average cost of first-line (euros 2013)
      Drugs 21,679 1030
      Administration 329 4,455
      Adverse events 546 2,686
      Cost of post-first progression care 40,467 67,281
      ICUR (erlotinib versus chemotherapy)
      ICUR France negative
      ICUR Spain negative
      ICUR Italy negative
      Sensitivity analyses will be presented at the meeting.

      Conclusion
      ICUR favored first-line erlotinib in EGFR-mutant patients with advanced NSCLC, which is the widely accepted treatment compared to chemotherapy. The cost-utility of the overall strategy remained beneficial in three different European countries. On behalf GFCP,GEPC and AIOT groups

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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.01 - Prognostic and predictive value of a new IASLC/ATS/ERS lung adenocarcinoma classification in a pooled analysis of four adjuvant chemotherapy trials: a LACE-Bio study (ID 3255)

      10:30 - 10:40  |  Author(s): R. Rosell

      • Abstract
      • Presentation
      • Slides

      Background
      A new IASLC/ATS/ERS classification for lung adenocarcinoma has been proposed to classify invasive lung adenocarcinoma patients according to the predominant growth pattern present in the tumor: lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MPP) and solid (SOL). Several studies have reported consistently that early stage resectable lung adenocarcinoma patients with LEP predominant pattern have a better prognosis, while MPP and SOL predominant patterns have a significantly poorer prognosis. However, the prognostic significance of these histological patterns has not been tested in clinical trials. Furthermore, the clinical utility of this new classification for predicting benefit from adjuvant chemotherapy is unknown.

      Methods
      The representative single H&E slide of 1766 non-small cell lung cancer patients from IALT, JBR.10, CALGB 9633 and ANITA adjuvant chemotherapy trials who participated in the LACE-Bio study were reviewed to confirm the histological diagnosis. These cases were independently assessed by two pathologists involved in the development of this new IASLC/ATS/ERS classification for subtyping. Discordant cases were resolved by consensus. Clinical outcomes were overall survival (OS, main outcome), disease-free survival (DFS) and specific disease-free survival (SDFS) (DFS with censoring deaths not related to cancer). Multivariable Cox models stratified by trial were used for prognostic analyses and the interaction between treatment (chemotherapy / control) and histology subtypes added for predictive analyses. The five histology subtypes were first analysed separately and 3 groups (LEP, PAP+ACN and MPP+SOL) were considered.

      Results
      573 patients were classified as 23 (4%) as LEP, 148 (26%) as ACN, 99 (17%) as PAP, 39 (7%) as MPP and 264 (46%) as SOL. The distribution of histology subtypes was different across trials (p=0.02) but not related with standard prognostic variables. The number of deaths, events and cancer-related events were 269, 320 and 292 respectively. No significant difference was observed between the survival curves of 5 subtypes whatever the endpoint. No prognostic value of 3 histological subtypes was observed for OS (p=0.21 in the control arm) contrary to DFS (p=0.04) and SDFS (p=0.03). These last 2 results were explained by the difference between PAP+ACN and MPP+SOL with hazard ratio (HR)~ACN+PAP vs. MPP+SOL~=0.66 95% confidence interval (CI)=[0.47-0.91] and HR~ACN+PAP vs. MPP+SOL~=0.67 [0.44-0.89] for DFS and SDFS, respectively. Due to the small number of patients with LEP predominant pattern, the predictive value was assessed after excluding this subtype. MPP+SOL patients reported significant DFS benefit from adjuvant chemotherapy (HR=0.58 [0.43-0.80], p<0.001) compared to ACN+PAP patients (HR=1.12 [0.79-1.59], p=0.53; p interaction < 0.01). A similar result was observed for SDFS with HR=0.58 [0.42-0.80], p<0.005 in MPP+SOL compared to HR=1.13 [0.78-1.63], p=0.52 in ACN+PAP (p interaction <0.01) while no predictive effect for OS.

      Conclusion
      Resectable lung adenocarcinoma patients with micropapillary and solid predominant patterns showed a trend for poorer DFS and SDFS compared to patients with the other subtypes, and they show a significantly higher benefit from adjuvant chemotherapy on these outcomes. Histological subtypes according to the IASLC/ATS/ERS classification may be proposed as a stratification factor in design of future adjuvant chemotherapy trials.

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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-005 - EGFR and KRAS mutations in patients having lung adenocarcinoma associated with human papilloma virus infection (ID 2626)

      10:26 - 10:40  |  Author(s): R. Rosell

      • Abstract

      Background
      Many studies have reported the presence of human papilloma virus (HPV) primary oncoproteins in lung cancer patients. Their detection depends on histological and geographical patterns and seems to be associated with the response obtained to EGFR inhibitors.

      Methods
      Information regarding 84 patients suffering lung adenocarcinomas and EGFR mutations and another 48 patients lacking them (including 7 KRAS carriers) was explored for the presence of HPV16 in paraffin-embedded tumour tissue using INNO-LiPA PCR-based assays. The results were correlated with clinical characteristics and multiple outcomes, including response rate, progression-free survival (PFS) and overall survival (OS).

      Results
      Mean age was 59.9 years (+/- 12.2) and HPV16 infection positivity was 39% (N=52). HPV was predominant in females (N=42; p=0.032), no differences being found regarding histological pattern (p=0.72) or having a background of smoking (p=0.54). 62% of the patients had EGFR exon 19 deletions and 22.6% the L858R mutation. Changes in exon 19 were positively related to the presence of HPV16 (p=0.043), differently to the exon 21 mutation (p=0.3). Overall response rate to tyrosine -kinase inhibitors in EGFR mutation carriers’ was 65%, stable disease was 31% and clinical benefit 86.5%. Positive differences were found for response according to HPV virus status (p=0.03). PFS rate was greater in patients who were EGFR+/HPV+ compared to the EGFR+/HPV- population (p=0.014). Likewise, OS was longer for the EGFR+/HPV+ population compared to the EGFR+/HPV- population (34 months versus 24 months; p=0.0001). OS was also longer for HPV+ patients in the absence of EGFR mutations (p=0.001). The presence of HPV also discriminated OS in the small cohort of KRAS+ patients.

      Conclusion
      The present study has documented a high HPV positivity rate in Hispanic patients suffering lung adenocarcinoma. The presence of viral DNA can thus be presumed to be a positive prognostic factor for EGFR and KRAS mutated patients, thereby leading to considering infection as a dominant part of carcinogenesis amongst non-smokers in Latin America.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P1.06-019 - Common and uncommon EGFR mutations and their impact on response to EGFR tyrosine-kinase inhibitors and platinum-based chemotherapy in non-small cell lung cancer (NSCLC): Latin-American Consortium for the Investigation of Lung Cancer (CLICaP) (ID 1728)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      An association has been well-established between common EGFR mutations and response to reversible and irreversible direct EGFR tyrosine-kinase inhibitors (EGFR-TKIs); however, there is a significant lack of information about the impact of uncommon mutations on outcomes such as overall response (OR), progression-free survival (PFS) and overall survival (OS) rates after being exposed to EGFR-TKIs or platinum-based chemotherapy (CT).

      Methods
      Information regarding 186 NSCLC patients from three Latin-American countries was analysed. Tests were made for EGFR and KRAS mutations; the clinical and pathological characteristics and the presence of common and uncommon EGFR mutations were considered according to OR, PFS and OS rates concerning EGFR-TKIs and CT.

      Results
      79.5% of the patients had common EGFR mutations and 20.5% uncommon mutations, including complex alterations. Lepidic and acinar histological subtypes were associated with higher common EGFR mutation frequency (p= 0.010). Patients having an OR to EGFR-TKIs treatment also had an OR to CT (p< 0.001). Patients harbouring common EGFR mutations had greater sensitivity to EGFR-TKIs than those having uncommon mutations (63.8% [IC 95% 51.1-76.5] vs 32.4% [20.0-44.7] p< 0.0001). Median PFS regarding EGFR-TKIs (16.4 [12-21.1] vs 4.1 months [1.9-5.9]) and CT (16 [10.9-21] vs 4.3 months [0.9-12.9]) was better in patients having common EGFR mutations compared to patients carrying uncommon mutations. The median OS of patients treated with EGFR-TKIs that harbored common EGFR mutations (37.3 months [33.2-41]) was longer compared to those patients who harbored uncommon mutations (17.4 months [12.9-21.8]).

      Conclusion
      Our findings suggest that patients with EGFR uncommon mutations, could receive platinum-based chemotherapy as first line of treatment and EGFR-TKIs can be reserved as second or third line treatment options.

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      P1.06-042 - Klotho expression in patients having EGFR mutations (CLICaP study) (ID 2666)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      Klotho is a type I transmembrane protein which is encoded by the KL gene; it is associated with many metabolic processes in differing neoplasias, including lung adenocarcinoma. Its abnormal expression conditions irregular endothelial growth and hyperactivation of proliferation via the PI3K/Akt signalling pathway.

      Methods
      Information concerning 84 patients with epidermal growth factor receptor (EGFR) mutations was taken to explore Klotho’s cytoplasmic positivity using an anti-Klotho antibody (Calbiochem, BD Biosciences, San Jose, CA, USA; 1:100 dilution). The results were correlated with multiple outcomes, including differing clinical characteristics, response rate, progression-free survival (PFS) and overall survival (OS).

      Results
      Mean age was 60.7 years (SD±13.1) and Klotho expression in the population of patients having EGFR mutations was considered positive in 35.7% of them (n=30), negative in 31.0% (n=26) and unknown in the remaining 33.3% (n=28). Positive Klotho expression was not influenced by gender (p=0.51), histological pattern (p=0.063), base functional state (p=0.49) or a history of smoking (p=0.19); nevertheless, Klotho overexpression was greater amongst exon 19 deletion carriers (p=0.030) and in patients having the L858R mutation (p=0.009) compared to the group of subjects having infrequent mutations. EGFR mutation patients’ overall response was greater in those having increased Klotho expression compared to the population of subjects lacking reactivity or in those where evolution following the administration of any type of reversible tyrosine-kinase inhibitor remained unknown (p=0.011). Overall population PFS was 16.7 months (12-21 95%CI) after directed therapy was started; PFS lasted longer in the Klotho positive group (positive expression 21.1 months vs. negative 13.7 months; p=0.032). Median OS was 28.5 months (25.8-31.2 95%CI), longer for patients having increased Klotho expression (31.9 versus 22.0 months; p=0.039).

      Conclusion
      Klotho expression revealed by immunohistochemistry in lung adenocarcinoma patients having EGFR mutations facilitated stratifying prognosis.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.11-037 - Phase II activity of the HSP90 inhibitor AUY922 in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) (ID 2730)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. HSP90 is a molecular chaperone of oncogenic client proteins relevant in NSCLC pathogenesis, including epidermal growth factor receptor (EGFR), which is mutated in 10% of NSCLC cases in the Western population, and in 30% of NSCLC cases in the Asian population. We report here a subgroup analysis of data from the 2 EGFR mutation strata of a Phase II study of AUY922 in patients with previously treated, advanced NSCLC stratified by molecular status.

      Methods
      Patients with advanced NSCLC who progressed following ≥1 prior line of therapy, received AUY922 (70 mg/m[2]) as a once-weekly, 1-hour infusion. Patients with EGFR-mutant NSCLC were divided into 2 strata: pretreated EGFR-mutant (>2 prior regimens), or less-heavily treated EGFR-mutant (≤2 prior regimens and documented response to an EGFR tyrosine kinase inhibitor [TKI]). The primary endpoint was confirmed response, stable disease at 18 weeks, or no clinical benefit. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety/tolerability.

      Results
      At the cut-off date of 14 March 2013, 66 patients with EGFR-mutant NSCLC had been treated (median age 58 years; 67% female; 94% adenocarcinoma; EGFR-initial stratum n=35; less-heavily pretreated EGFR-mutant stratum n=31); all patients had been pretreated with an EGFR TKI. Clinical activity of AUY922 was seen, with any responses (investigator assessed), in 12/66 (18.2%) patients. A total of 34/66 (51.5%) patients had a best overall response of stable disease or non-confirmed partial response; of these patients, 11 (32%) had stable disease for ≥18 weeks. The 18-week PFS rate was 39% in all patients with ≤2 prior lines of therapy (n=43), and 28% in all patients (n=21) who had received >2 lines of therapy. The most frequent adverse events (AEs; any grade, regardless of study drug relationship) were diarrhea (73%), nausea (47%), decreased appetite (38%), fatigue (35%), and headache and night blindness (both 29%). Most AEs were Grade 1 or 2; Grade 3 or 4 AEs included diarrhea (9%), and fatigue, decreased appetite, and hyponatremia (all 6%).

      Conclusion
      AUY922 had an acceptable safety profile. Strong evidence of clinical activity was demonstrated in EGFR TKI-pretreated patients with EGFR-mutant NSCLC. Median PFS, OS and biomarker data for the EGFR-mutant stratum will be presented.

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      P1.11-040 - Treatment strategies after failure to reversible Tyrosine Kinase Inhibitors (rTKI) in EGFR mutant (mut) Non-Small Cell Lung Cancer (NSCLC) patients (p). A retrospective analysis of 59 Spanish Patients (ID 2853)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      Different therapeutic approaches have been used in the clinical setting in NSCLC p harbouring EGFR mutations progressing to rTKI, although the standard of care in this situation is still not well established.

      Methods
      A multinstitutional database from five different centers in Spain was review to identify EGFR mut p with acquired resistance to rTKI in order to evaluate the therapeutic strategies after rTKI failure and the effect on the post-progression survival (PPS) of these treatments.

      Results
      59 p with acquired resistance to rTKI were identified: 61% female; median (m) age 63 ±11 yrs; 96.6% Caucasian; del19 73.7%, never or light former smokers 98.3%; 93.2% adenocarcinomas; 59.4 % received TKI as first line therapy; 87% were initial stage IV. mPFS for the rTKI was 9,9 months (mo) and mOS was 32.8 mo for the entire population. P were treated with a median of 2 therapeutic strategies after the rTKI failure. 6 therapeutic strategies have been identified. As immediate approach, 31p were switched to chemotherapy (CT) with a mPPS of 5,6 mo. 10 p were switched to an irreversible TKI obtaining a mPPS of 4 mo. rTKI plus other drug was maintained in 12 p: rTKI plus CT in 9 p with a mPPS of 5,8 mo and rTKI plus other drug different to CT in 3 with a mPPS of 2 mo. Despite the progression, rTKI was maintained in 3 p, considered slow progressors obtaining a mPPS of 1,4 mo with an OS of 9mo. Furthermore, 3p with oligometastatic progressive disease local therapy was added to rTKI, obtaining mPPS of 1,4mo, but an OS of 17 mo. 4 p were treated sequentially with ≥5 strategies. These p attained a mOS of 45mo.

      Conclusion
      The combination of different strategies when treating EGFR mut p after rTKI failure may impact the survival especially when p are candidates to receive some of this treatments sequentially. These strategies may reflect different subsets of EGFR mut disease.

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    P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.02-001 - MED12, a component of the transcriptional MEDIATOR complex, and STAT3 influence outcome to platinum-based chemotherapy in patients (p) with advanced non-small-cell lung cancer (NSCLC) (ID 323)

      09:30 - 09:47  |  Author(s): R. Rosell

      • Abstract

      Background
      MED12 negatively regulates TGF-b receptor signaling. Loss of MED12 induces an EMT-like phenotype associated with chemotherapy resistance. IDO and IL6 activate the JAK2/STAT3 signaling pathway, which – together with NFkB (RelA) signaling – is often altered in lung cancer. BIM could influence response to chemotherapy. We have examined these components and KRAS mutations in NSCLC tumor samples and correlated results with progression-free survival (PFS).

      Methods
      The mRNA expression of MED12, IDO, JAK2, STAT3, RelA and BIM was examined in microdissected tumor samples from p with stage IV NSCLC. mRNA levels were assessed by RT-PCR and categorized by terciles (high vs low/intermediate). KRAS mutations were assessed by high resolution melting.

      Results
      A total of 55 p with performance status (PS) 0-1, treated with platinum plus either gemcitabine or pemetrexed: median age, 62 years; 27.6% females; 84.2% smokers; 66% adenocarcinoma; 16% with KRAS mutations. There was no correlation between gene expression levels and KRAS mutation status. In the multivariate analysis, including gene expression levels, histology and PS, only MED12 and STAT3 were associated with PFS (low MED12: HR=11.6, P=0.005; high STAT3: HR=6.5, P=0.01). HR for low BIM expression was 2.4 (P=0.16). None of the markers were associated with overall survival.

      Conclusion
      To the best of our knowledge, this is the first time that low expression of MED12 with significantly shorter PFS in NSCLC p receiving platinum-based chemotherapy. MED12 could be a new biomarker of chemoresistance and inhibition of TGF-bR signaling can restore chemotherapy response in patients with low MED12.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P2.06-012 - Impact of EGFR T790M mutations and BIM mRNA expression on progression-free survival (PFS) and overall survival (OS) in patients with EGFR-mutant non-small-cell lung cancer (NSCLC) treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial (ID 1167)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      Activating EGFR mutations confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs) in patients with NSCLC, but responses are transient, with delay in disease progression but no impact on survival. Concomitant genetic alterations could account for these incomplete clinical responses. Erlotinib-treated EGFR-mutant NSCLC patients harboring the EGFR T790M mutation had shorter PFS than those without the mutation (12 vs 18 months [m]). Low BIM levels were associated with gefitinib resistance in EGFR-mutant NSCLC.

      Methods
      The efficacy results of the EURTAC trial were updated at January 24, 2013. We have evaluated the frequency and potential impact of pretreatment EGFR T790M mutations and BIM mRNA expression in 95 patients with EGFR-mutant NSCLC included in the EURTAC trial.

      Results
      T790M mutations were detected in 65.26% of patients. PFS to erlotinib was 9.7 m for those with T790M mutations and 15.8 m for those without, while among patients receiving chemotherapy, it was 6 and 5.1 m, respectively (P<0.0001). BIM expression was successfully analyzed in 83 patients. PFS to erlotinib was 12.9 m for those with high BIM levels and 7.2 m for those with low/intermediate BIM levels, while among chemotherapy-treated patients, it was 5.8 and 5.5 m, respectively (P=0.0003). OS was 28.6 m for patients with high BIM expression and 22.1 m for those with low/intermediate BIM expression (P=0.0364). The multivariate analyses showed that erlotinib was a marker of longer PFS (HR, 0.35; P=0.0003), while high BIM expression was a marker of longer PFS (HR, 0.49; P=0.0122) and OS (HR, 0.53; P=0.0323).

      Conclusion
      BIM mRNA expression is a biomarker of PFS and OS in EGFR-mutant NSCLC. T790M mutations and BIM mRNA expression can potentially be used for designing combination therapeutic strategies for use in lieu of EGFR TKI monotherapy.

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      P2.06-046 - EML4-ALK monitoring of crizotinib response in blood platelets and plasma of NSCLC patients (ID 3267)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      The discovery of various genetic alterations that underlie lung cancer has opened-up a new era in the development of specifically targeted therapies employing specific alteration-dependent inhibitors. In the vast majority of NSCLC patients genetic alterations occur in EGFR (20-25%), BRAF (3%), and ALK (3-10%), seemingly in a predominant mutual exclusive manner. Hence, patient stratification for EGFR, KRAS, BRAF, and ALK alterations is becoming common practice among oncologists. The mutational status of NSCLC patients is considered dynamic and can change in due course of the disease and selection in response to therapy. Longitudinal monitoring of the mutational status of NSCLC patients is of crucial importance to tailor targeted therapy by adapting treatment regimens according to mutational status. However, technical challenges associated with serial tumor biopsy constitute a major challenge in longitudinal molecular monitoring and targeted treatment of NSCLC patients. Blood-based assays may overcome such limitations and allow for frequent assessment of the mutational status.

      Methods
      Here, tumor tissue, platelets, and/or plasma of NSCLC patients were collected and analyzed for the presence of translocated ALK using FISH, IHC, and/or RT-PCR. Monitoring of EML4-ALK in platelets and plasma was performed by RT-PCR on EML4-ALK positive patients treated with crizotinib and correlated to the clinical response as measured by serial radiographic CT.

      Results
      From a multicenter cohort of NSCLC patients we identified EML4-ALK positive patients by FISH, IHC, and RT-PCR, for blood platelet and/or plasma isolation. In blood platelets of ALK positive NSCLC patients (n=24) and ALK negative control subjects (n=54) we demonstrated an EML4-ALK test sensitivity of 70-80% and specificity of 100%. We detected EML4-ALK in plasma of ALK positive NSCLC patients (n=22), however with inferior sensitivity of 20-30%. In addition, longitudinal EML4-ALK monitoring in blood platelets of an ALK positive NSCLC patient correlated with the crizotinib response.

      Conclusion
      We demonstrate here that blood platelets of NSCLC patients are a biosource for the detection of the EML4-ALK translocation and may proof useful for longitudinal monitoring of ALK inhibitors in NSCLC patients, with superior outcome over plasma.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 3
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      P2.10-031 - Chinese randomized phase II trial of customized chemotherapy based on BRCA1-RAP80 mRNA expression in advanced non-small-cell lung cancer (NSCLC) patients (p) (ChiCTR-TRC-12001860/BREC-CHINA) (ID 1883)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      BRCA1 serves as a differential modulator of chemosensitivity to docetaxel (doc) and cisplatin (cis). RAP80 targets the BRCA1-BARD1 E3 ligase at double-strand breaks. A Spanish Lung Cancer Group (SLCG) phase II customized chemotherapy trial (NCT00883480) indicated that RAP80 and BRCA1 jointly influenced outcome in NSCLC p treated with cis- or doc-based chemotherapy. Based on these findings, the SLCG initiated a randomized phase III trial (NCT00617656/GECP-BREC), and we have performed a parallel phase II trial comparing non-customized cis/doc with customized therapy in metastatic NSCLC p in China.

      Methods
      Since October 2010, 104 p have been randomized 1:3 to control and three experimental arms. p in the control arm receive cis/doc; p in the experimental arm receive treatment according to their BRCA1 and RAP80 levels: p with low RAP80, regardless of BRCA1 levels, cis/gemcitabine (gem); p with intermediate/high RAP80 and low/intermediate BRCA1, cis/doc; p with intermediate/high RAP80 and high BRCA1, doc alone. The primary endpoint is progression-free survival (PFS).

      Results
      PFS was 4.15 months (m) in the control and 3.59 m in the experimental arm (P=0.68). Overall survival (OS) was 10.82 m in the control and 11.74 m in the experimental arm (P=0.68). Response rate (RR) was 23.3% in the control and 32.4% in the experimental arm (P=0.48). In ancillary analyses of p with low, intermediate and high BRCA1 levels, PFS in the control arm was 2.66, 4.15 m and 7.5 m, respectively, while PFS in the experimental arm was 10.66 m, 3.45 m and 3.06 m, respectively. In the multivariate analysis including PS, treatment arm, BRCA1, RAP80, histology and smoking status, only ex-smokers were associated with an increased risk of progression (HR, 1.906; P=0.029).

      Conclusion
      Customized chemotherapy based on BRCA1/RAP80 expression does not improve PFS. The predictive value of BRCA1 alone seems to be stronger than that of BRCA1/RAP80 combined.

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      P2.10-035 - EGFR mutation (m) status in serum only to treat Non Small Cell Lung Cancer (NSCLC) patients (p) (ID 2412)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      Treatment of EGFR mutated NSCLC p with EGFR TKIs in phase III trials has shown improved efficacy to standard chemotherapy.However, it can be difficult to obtain sufficient tumor tissue for analysis of EGFR m status in a large proportion of p. Nevertheless,so far,no data exists for NSCLC p treated according to EGFR m status in serum alone.

      Methods
      We reviewed our database to identify EGFR mutated p, excluding those for whom status was available in both serum and tissue.We analyzed p treated with an EGFR TKI for whom EGFR mutation status was known in serum only(status in tissue unknown due to insufficient material).At the same time, we reviewed p in whom EGFR m status in tissue was available over the same period in order to compare clinical characteristics and efficacy parameters,PFS,ORR and Overall Survival(OS). EGFR m analysis was performed in cell free circulating DNA(cfDNA)isolated from serum and plasma using the QIAmp DNA blood mini kit.

      Results
      9 p with EGFR m detected in serum and 33 p with EGFR m in tissue were included. In EGFR mutated p in serum, median age 63; male 55.6%; non-smokers 33.3%; former smokers 44.4%; ECOG PS 0-1 66.7%; adenocarcinoma 77.8%; deletion19 33.3%, L858R 66.7%; EGFR TKI treatment in 1st line 44.4%; 2nd or 3rd line 55.6%. ORR: complete response (CR) 22.2%; partial response (PR) 22.2%; stable disease (SD) 22.2%; progressive disease (PD) 11.1%. 2p had poor PS and died prior to evaluation. mPFS 4.7 months (mo). mOS 18 mo. In p with EGFR m in tissue, median age 61; male 36.4%; non-smokers 75.8%; former smokers 24.2%; adenocarcinoma 87.9%; deletion19 75.8%; L858R 24.2%; 1st line 54.5%; 2nd or 3rd line 45.5%. ORR: CR 15.2%; PR 57.6%; SD 12.1%; PD 15.2%. mPFS 8.9 mo. mOS 32.7 mo. The multivariate analysis for OS considering EGFR m in serum differed according to PS (PS 0-1 16.6 mo vs PS > 2 5.2 mo)

      Conclusion
      Obtaining sufficient tissue from NSCLC p for analysis of EGFR m status and other molecular alterations can be difficult. Determination of EGFR m in serum alone is feasible, yields similar results to mutation status in tissue, and could permit us to take treatment decisions.

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      P2.10-043 - Phase II study of biweekly irinotecan plus bevacizumab in heavily treated advanced non-small cell lung cancer (NSCLC) (ID 2605)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      Irinotecan and bevacizumab are effective against non-small cell lung cancer (NSCLC) and synergism with non-cross-resistance has been demonstrated in preclinical studies.

      Methods
      Twenty-four patients having heavily treated metastatic NSCLC were enrolled from March 2011 to November 2012. Sixteen of these subjects had never been exposed to bevacizumab and 8 had received antiangiogenic therapy as part of their first-line (all had achieved a previous response for more than 6 months). Treatment consisted of a 90-min intravenous infusion of 125 mg/m[2] irinotecan on day 1 and 8 plus 7.5 mg/kg bevacizumab on day 1. The treatment was repeated every 3 weeks and all patients underwent genotype evaluation (including EGFR and KRAS mutation screening).

      Results
      One patient (4.2%) achieved a complete response and six (25%) had a partial response. Objective response rate (ORR) was 29.2% (4.6 months median response duration). Seven patients had stable disease, and disease control rate (DCR) was 58.3%. After a median follow-up of 12.8 months, median progression-free survival (PFS) rate was 4.8 months (95%CI 1.8-9.2) and median overall survival (OS) rate was 19.8 months (95%CI 9.2-30.2). Major toxicity was myelosuppression (grade 3-4 neutropenia occurred in 43% of patients and thrombocytopenia in 8.3%). Two patients experienced febrile neutropenia and non-haematological toxicity was usually mild. One patient suffered grade 4 diarrhoea, and four patients harbouring EGFR mutations had a long-lasting, partial response (>7 months after at least 4 prior lines).

      Conclusion
      The irinotecan pus bevacizumab combination resulted in favourable activity and manageable toxicity profiles as third or fourth line for patients suffering advanced NSCLC. Our results suggested that such regimen can represent a reasonable chemotherapeutic option, especially for subjects having EGFR mutations. This hypothesis can be partly supported because of topo I activity resulting from increased topo I mRNA and protein expression caused by MET signalling.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-044 - Phase IB study to evaluate the efficacy and tolerability of Olaparib (AZD2281) plus Gefitinib in patients (P) with Epidermal Growth Factor Receptor (EGFR) mutation positive advanced Non-Small Cell Lung Cancer (NSCLC) patients (P). (NCT=1513174/GECP-GOAL) (ID 3051)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      Progression-free survival (PFS) and response rate (RR) to EGFR tyrosine kinase inhibitors (TKIs) vary in P with NSCLC driven by EGFR mutations, suggesting that other genetic alterations may influence oncogene addiction. In our experience, high BRCA1 mRNA expression negatively influenced PFS among EGFR mutant P treated with erlotinib. We hypothesiszed that since olaparib can attenuate and/or prevent BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these P.

      Methods
      This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK), and clinical activity of orally administered olaparib in combination with gefitinib in EGFR mutant advanced NSCLC. In a standard 3+3 design based on toxicity, P were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Steady state Cmax and AUC (AUC0-12) were determined following dosing on Day 7 and 14 of the study and the Day 14:Day 7 treatment ratio calculated to assess the impact on olaparib steady state exposure of dosing in combination with gefitinib

      Results
      22P have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (6) and 250mg TDS (7). Median age, 65 (range 39-84); male, 6P; PS 0-1, 20P; EGFR TKI treatment-naïve, 13P; Most toxicities were G1-2, including anemia, leucopenia, nausea, diarrhea, asthenia, rash and anorexia; G3 drug-related events included lymphopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 3 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions for both drugs were needed. 1P died due to pulmonary embolism unrelated to study treatment. 19P were evaluated for response: For those not previously treated P, partial responses (PR) were observed in 8P (72,2%), stable disease (SD) in 3P (27,27%) and no progressive disease (PD) (0%). In previously TKI treated P, 3 (37,5%) PR were observed, 3 (37,5%) SD, and 2 (25,5%) PD. Durable PR and SD were observed in both EGFR TKI-naïve and previously treated P.10P are still on treatment. The derived PK parameters were the following: 100mg bid: Olaparib Cmaxss(ug/ml): Day 7:4.60; Day 14:3.53; TR(range) 0.77. AUCss(ug.h/ml) Day 7:24.4; Day 14:18.9; TR:0.79. 200mg bid: Cmaxss(ug/ml): Day 7:7.68; Day 14:6.60; TR:0.89. AUCss(ug.h/ml) Day 7:48.6; Day 14:40.0; TR:0.85; 200mg tds: Cmaxss(ug/ml): Day 7:8.35; Day 14:8.01; TR:0.96. AUCss(ug.h/ml) Day 7: 34.9*; Day 14: 32.7*; TR: 0.94; 250mg tds: Cmaxss(ug/ml): Day 7:9.85; Day 14:9.46; TR:0.97. AUCss(ug.h/ml) Day 7: 44.2*; Day 14: 43.3*; TR: 0.99. *AUC quoted is AUC0-6 not AUCss.

      Conclusion
      This phase IB trial of gefitinib plus olaparib, confirms the tolerability of the combination and the anti-tumor activity seen warrants further exploration in treatment-naïve patients. MTD of olaparib was 200mg TDS. Co-administration of gefitinib does not appear to have altered steady state exposure to olaparib. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC is planned to start in 2013. The final recommended dose of olaparib will be 200 mg TDS

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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-015 - <b>Outcome in pemetrexed/cisplatin-treated non-small-cell lung cancer (NSCLC) patients according to mRNA expression levels of BRCA1, TS, AEG1 and REV3 </b> (ID 1170)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase x, can continue replication past DNA adducts. Depletion of REV3 sensitizes A549 lung cancer cells to cisplatin. REV3 expression is part of a gene signature that predicted pemetrexed sensitivity in 17 NSCLC cell lines. BRCA1, TS, AEG1 and RAP80 are involved in DNA damage repair through homologous recombination. The homologous recombination and TLS pathways have non-redundant functions in response to cisplatin. We hypothesized that low mRNA expression of these genes – either alone or in combination – could confer improved outcome to cisplatin/pemetrexed in NSCLC patients.

      Methods
      REV3, BRCA1, RAP80, TS and AEG1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles. Expression of each gene was correlated with outcome in 47 cisplatin/pemetrexed-treated NSCLC patients.

      Results
      63.8% male; 47% smokers; 80.9% ECOG PS 1; 80.8% adenocarcinoma. Overall response rate was 51%, with no differences according to expression levels of any of the genes. Progression-free survival (PFS) for patients with low, intermediate and high BRCA1 levels was 13.4, 5.5 and 3.9 months (m), respectively (P=0.005). Similar differences in PFS were observed according to TS (P=0.003) and AEG1 (P<0.001) expression. The hazard ratio (HR) for PFS for patients with high BRCA1 levels was 4 (P=0.002). Overall survival (OS) for patients with low, intermediate and high BRCA1 levels was 29.7, 7.4 and 6.3 m, respectively (P=0.05). Similar differences in OS were observed according to TS (P=0.005) and AEG1 (P=0.001) expression. HR for OS for patients with high BRCA1 levels was 3.6 (P=0.004). There were no differences in PFS or OS according to REV3 or RAP80 levels. However, the joint effect of BRCA1 and REV3 was significant for predictive modeling. PFS for patients with low, intermediate and high levels of both genes was 14.9, 7.2 and 2.8 m, respectively (P=0.001). OS for patients with low, intermediate and high levels of both genes was 29.7, 7.8 and 6.3 m, respectively (P=0.04).

      Conclusion
      Low BRCA1 expression predicts longer PFS and OS in pemetrexed/cisplatin-treated NSCLC p. Low TS and AEG1 levels have similar predictive value. The combination of low BRCA1 and REV3 expression confers longer PFS and OS. Analysis of these genes could be useful for customizing pemetrexed/platinum chemotherapy.

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-009 - <b>ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer (NSCLC) patients with the EGFR T790M mutation</b> (ID 1395)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      Molecular cross-talk between EGFR and other signaling pathways creates alternative means of tumor cell proliferation and promotes resistance to single-agent erlotinib therapy in NSCLC driven by EGFR mutations. ROR1 knockdown inhibited the growth of NCI-H1975 cells (harboring EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling in cooperation with AKT has been demonstrated. We have assessed ROR1 expression in 45 patients from the EURTAC trial (clinicaltrials.gov NCT00446225), 27 of whom harbored pretreatment concomitant EGFR T790M mutations, and correlated results with outcome.

      Methods
      ROR1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles; patients were classified as having low/intermediate or high ROR1 expression. The T790M mutation was determined by Taqman with a PNA to inhibit amplification of the wild-type (wt) allele. Tumor samples were run in octuplicates; this method can detect 1 mutated allele among 10,000 wt alleles.

      Results
      Median age 65; 68.9% female; 57.8% never-smokers; 95.6% ECOG PS <2; 91.1% adenocarcinoma; 68.9% exon 19 deletion. No differences in baseline characteristics were observed according to ROR1 expression levels. 24 patients (53.3%) were treated with erlotinib and 21 (46.7%) with chemotherapy. 10 (41.7%) erlotinib-treated patients and 6 (28.6%) chemotherapy-treated patients had high ROR1 mRNA levels. Among erlotinib-treated patients, response rate (RR) was 40% for the 10 patients with high ROR1 levels vs 71.4% for the 14 with low/intermediate levels (P=0.058). Among chemotherapy-treated patients, RR for the 15 patients with low/intermediate ROR1 levels was 6.7%; the 6 patients with high ROR1 levels did not respond. Progression-free survival (PFS) was 11.8 months (m) for erlotinib-treated patients with low/intermediate ROR1 levels vs 5.8 m for those with high levels. PFS for chemotherapy-treated patients was 5.6 and 9 m, respectively (P=0.0165). 15 erlotinib-treated patients harbored concomitant T790M mutations; for these patients, PFS was10.8 m for those with low/intermediate ROR1 levels vs 2.7 m for those with high levels (P=0.0138).

      Conclusion
      ROR1 expression has a differential effect on outcome to erlotinib and chemotherapy in EGFR-mutant NSCLC patients. High ROR1 expression significantly limits PFS in erlotinib-treated patients with T790M mutations and ROR1-directed therapies can enhance the efficacy of treatment. In contrast, high ROR1 expression confers longer PFS to chemotherapy in the same group of patients. The role of chemotherapy and erlotinib in EGFR-mutant NSCLC patients with high ROR1 expression warrants further investigation.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 3
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      P3.06-006 - Integrated genomic analysis of EGFR-mutant non-small cell lung cancer immediately following erlotinib initiation in patients (ID 1003)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      Major obstacles limiting the clinical success of EGFR TKI therapy in EGFR mutant non-small cell lung cancer (NSCLC) patients are heterogeneity and variability in the initial anti-tumor response to treatment. The underlying molecular basis for this heterogeneity has not been explored in patients immediately after initiation of therapy.

      Methods
      We conducted CT-guided core needle biopsies immediately prior to erlotinib treatment initiation and at 6 days and 60 days post erlotinib initiation in a patient with histologically confirmed NSCLC harboring an established activating mutation in EGFR. DNA and RNA from each of the frozen biopsies were analyzed by whole exome sequencing and whole transcriptome sequencing, respectively. High-resolution CT images were also obtained at the time of each biopsy to assess the degree of molecular and radiographic responses observed.

      Results
      Two established activating somatic mutations were identified in EGFR (p.G719A and p. R776H). Gene expression analysis revealed that several proapoptotic genes including BID, CASP3 and several growth inhibitory genes including GADD45B, GADD45G were upregulated at 6 days post erlotinib treatment, while at 60 days their expression levels decreased to below pretreatment levels. Other proapoptotic genes such as BAD and BAX and were noted to be upregulated most significantly 60 days, as was growth inhibitory gene CDKN1A. In contrast, the growth-promoting genes CCNB1 and CCND3 exhibited a progressive decrease in expression across time points. Whole exome sequencing demonstrated the progressive evolution of global copy number abnormalities. High-resolution CT scans revealed no interval radiographic change in tumor size after 6 days of erlotinib treatment, and a decrease in tumor size 60 days into therapy. No clinical complications were encountered.

      Conclusion
      This study is the first reported longitudinal integrated genomic analysis of EGFR-mutant NSCLC in a patient treated with an EGFR TKI. We documented the feasibility, safety and utility of this strategy to establish initial drug efficacy at the molecular level prior to any radiographic evidence of response (6 days), as well as evidence that acquired resistance can emerge early in the course of TKI therapy. Serial integrated genomic analysis is ongoing in other TKI treated patients to enhance the management of NSCLC patients on targeted therapy.

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      P3.06-035 - Study of the correlations between SNPs in angiogenic genes and treatment response/ outcome in patients with advanced NSCLC (non-squamous histology) treated in first line with carboplatin, paclitaxel and bevacizumab (CPB). The ANGIOMET study. (ID 2664)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      It has been demonstrated that the addition of bevacizumab to paclitaxel plus carboplatin (CPB) in the treatment of advanced NSCLC improves survival. Even though, there is a high variability in drug efficacy between patients, leading to different response rates. ANGIOMET is an exploratory study promoted by the SLCG in advanced NSCLC, non-squamous histologies (NS-NSCLC) treated in first line with a combination scheme based in CPB, designed to investigate the relationship between angiogenic mediators and the outcome and response to treatment. The primary end-point was progression-free survival (PFS), and the secondary end-points are the follows: OS, response-rates and toxicity profiles.

      Methods
      In this multicentric study, patients with stage IIIB/IV NS-NSCLC (ECOG status 0–2) were included and treated in first line with CPB. Peripheral blood samples were collected before treatment administration and DNA was purified from the leukocyte fraction. Ten SNPs of VEGF-pathway genes were genotyped in 186 samples by RT-PCR in duplicate. SNPs were related to PFS and OS (Kaplan-Meir method, log-rank test) and to response rate.

      Results
      10 SNPs were determined in 186 DNA samples. In this preliminary analysis there were data from 108 patients valid for PFS and OS analysis. Baseline characteristics of the patients were: median age, 63 years [37-80]; 74.5% male; 94.1% ECOG PS 0-1; 14% never-smokers, 100% caucasian; 89.7% adenocarcinomas, 2.8% large cell carcinomas; median number of CPB cycles was 4. There was no response assessment in 27 patients (25%), 30.6% PR, 31.5% SD and 13.0% PD. The SNP rs833061 (CC) in VEGFA correlated with lower response rates to CPB than the other genotypes (p=0.07). SNPs in KRAS and VEGFR2 were associated with PFS and/or OS in our cohort. The KRAS SNP rs10842513 (TT+CT) was associated with shorter PFS compared with the CC genotype (median: 5.39 vs 6.81 months; p=0.04, respectively). The VEGFR2 SNP rs2071559 (AA) was significantly associated with longer PFS and OS (Table 1). No significant differences in PFS or OS were observed according to other SNPs analyzed. Table 1: PFS and OS for VEGFR2 SNPrs2071559.

      PFS
      % Median (months) 95%CI p
      VEGFR2 (rs2071559)
      AA 25.6 9,408 5,084 - 13,732 0.01
      GG+AG 74.0 5,724 4,902 - 6,546
      OS
      % Median (months) 95%CI p
      VEGFR2 (rs2071559)
      AA 25.6 NR ---- 0.001
      GG+AG 74.0 12,270 8,760 – 15.780

      Conclusion
      These preliminary data indicate that genetic variation in VEGFR2, SNP rs2071559 variant AA, is associated with prognosis in advanced NS-NSCLC patients treated with CPB and may have predictive implications as biomarkers in patients treated with chemotherapy with bevacizumab. On behalf of the Spanish Lung Cancer Group (SLCG)

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      P3.06-045 - E-Cadherin and vimentin as biomarkers of clinical outcomes among EGFR+ lung adenocarcinoma (LA) patients treated with erlotinib (CLICaP) (ID 3025)

      09:30 - 09:30  |  Author(s): R. Rosell

      • Abstract

      Background
      Epithelial-mesenchymal transition (EMT) has been known to play a key role in stromal invasion of lung adenocarcinoma. Loss of E-cadherin and acquisition of vimentin are two critical steps in EMT, that are induced by Snail-1 and TWIST upregulation associated with overexpression of epidermal growth factor receptor (EGFR). However, roles of EMT-related proteins in EGFR mutants have not been fully elucidated. We investigated the inmunoexpression of EMT-related proteins in EGFR lung adenocarcinoma to demonstrate their key roles in tumor progression.

      Methods
      E-Cadherin and vimentin expression was assessed in 84 patients with EGFR+ LA to determine if these markers had the potential to predict clinical outcomes in patients treated with Erlotinib. The percentage of tumor cells with grades 0, 1, 2, or 3 membrane staining of E-Cadherin and cytoplasmic staining of vimentin was measured. We selected previously reported cut-off points shown to provide optimal stratification: ≥40% of tumor cells with staining of +2 and +3 for E.cadherin and ≥10% of tumors cell with any staining for vimentin. Overall response rates (ORR), clinical benefit (CB), time to progression (TTP), and overall survival (OS) were estimated, as well as variables that influenced OS.

      Results
      Mean age was 59.6 years (SD +/- 13.1) and 79.8% of patients were women. Mutations of EGFR, L858R and G719X in exon 19 were present in 61%, 31% and 6% respectively. Vimentin expression was strong in 9.5% (n=8) and E-cadherine expression was weak in 51.2%, moderate in 23.8% and strong in 23.8%. Highest positivity of E-Cadherin was related to exon 19 deletion (p=0-001) but not to L858R mutations (p=0.14). Strong vimentin reactivity was associated with history of smoking (p=0.03). OS was 12.3 [10-14], 27.0 [23-31],26.1 [20-32] and 33.5 [30-36] months when E-cadherine expression was negative, weak, moderate and strong (p=0.05). OS was 33 months [31-35] in vimentin-negative and 8.2 months [6-10] in vimentin-positive (p=0.001). Similar trends were observed for progression-free survival and response rate.

      Conclusion
      E-Cadherin and vimentin are valuable predictive biomarkers for EGFR+ patients. These results warrant further research on EMT in selected populations exposed to erlotinib.