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S. Novello



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    Best of Posters - IASLC Selection - Part 2 (ID 263)

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
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      P2.11-024 - Efficacy Analysis for Molecular Subgroups in MARQUEE: a Randomized, Double-blind, Placebo-controlled, Phase 3 Trial of Tivantinib (ARQ 197) Plus Erlotinib versus Placebo plus Erlotinib in Previously Treated Patients with Locally Advanced or Metastatic, Non-squamous, Non- small Cell Lung Cancer (NSCLC) (ID 2909)

      10:00 - 10:05  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background
      MARQUEE, a Phase 3 study which investigated the role of tivantinib, a c-MET inhibitor, in previously treated non-squamous NSCLC, collected EGFR and KRAS genotype on >90% of randomized patients, and MET expression was determined for 42%. In the ITT population, addition of tivantinib to erlotinib significantly improved PFS and ORR but did not show benefit in OS. Additional efficacy analyses in the pre-defined molecular subgroups are presented.

      Methods
      Patients with locally advanced or metastatic non-squamous, EGFR inhibitor naive NSCLC previously treated with 1 or 2 lines of systemic therapy, including a platinum-doublet, were stratified by number of prior therapies, sex, smoking history, and EGFR and KRAS mutation status, then randomized to oral tivantinib (360 mg twice daily) + erlotinib (150 mg once daily) or placebo + erlotinib until disease progression. Primary endpoint was OS with one interim analysis for futility/superiority. MET was assessed centrally by IHC using CONFIRM (SP44) antibody. Based upon a stability study, tumor tissue must have been sectioned within 90 days prior to MET immunostaining to be considered reliable. MET High was pre-specified as ≥50% of tumor cells staining with 2+ or 3+ intensity.

      Results
      From 1/2011 to 7/2012, 1048 patients were randomized to tivantinib + erlotinib (TE, n=526) or placebo + erlotinib (PE, n=522). Baseline characteristics were median age = 62 years (range, 24-89), prior therapies = 1 (66%) or 2 (34%), ECOG performance status = 0 (32%) or 1 (68%), EGFR mutant (10.4%), and KRAS mutant (27.1%). In 9/2012, the data monitoring committee recommended trial discontinuation because the pre-planned interim analysis of OS crossed the futility boundary. At the 12/2012 data cutoff, median OS was 8.5 months and 7.8 months for TE and PE, respectively (hazard ratio [HR] = 0.98; 95% CI, 0.84-1.15; p = 0.81). Median PFS was 3.6 months and 1.9 months, respectively (HR = 0.74; 95% CI, 0.62-0.89; p < 0.0001). Overall response rate (ORR) improved to 10.3% for TE compared with 6.5% for PE (p < 0.05). MET expression was obtained for 445 patients. In the pre-specified, MET High subgroup (n = 211), median OS improved to 9.3 months for TE vs 5.9 months for PE (HR = 0.70; 95% CI, 0.49-1.01; p = 0.03). In the MET Low subgroup (n = 234), median OS was 8.5 months for TE and 7.7 months for PE (HR=.90, 95% CI, 0.64-1.26, p=.53). OS did not differ between treatments in KRAS wildtype (n=702), KRAS mutant (n=284), and EGFR wildtype (n=937) subgroups; OS was immature for the EGFR mutant (n=109) subgroup at the cut-off time. Consistent with ITT, PFS was increased with TE vs PE across all molecular subgroups. Common adverse events (TE vs PE, respectively) included rash (33.1% vs 37.3%), diarrhea (34.6% vs 41.0%), and asthenia/fatigue (43.5% vs 38.1%), which occurred at similar rates between treatments; neutropenia (Grade 3/4: 10.0% vs 1.0%) was more common with TE.

      Conclusion
      Tivantinib significantly improved PFS and OS in the prospectively defined MET High subgroup. Further investigation of tivantinib in MET High selected, non-squamous NSCLC is warranted.

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    E03 - Chemotherapy for NSCLC (ID 3)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Medical Oncology
    • Presentations: 1
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      E03.4 - Lung Cancer in Women (ID 385)

      15:05 - 15:25  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Abstract
      At the beginning of 20th century only a few hundred cases of lung cancer were diagnosed annually, but the progressive huge spread of tobacco consumption caused a dramatic increase of the incidence of this disease among men and later on among female smokers. US data shows that the prevalence of smoking in American women peaked in 1965 at 33% and remained at that level throughout the 1970s, before beginning to slowly decrease in 1980. In contrast, more than half of American men smoked before 1965, but the prevalence dramatically decreased during the subsequent 20 years. Currently, 18% of American women smoke compared with 23% of men, reflecting the earlier and more marked decline in the prevalence of tobacco use in men. Nowadays, more women in United States die from lung cancer each year than from breast, ovarian and uterine cancer combined: lung cancer is the leading cause of cancer death with more than 110,000 new cases and more than 72,000 estimated deaths in 2013. In European countries there are more than 79,000 new cases of lung cancer in female sex per year and 82,000 is the estimated death number in 2013, that means 9,024 more than what was reported in 2009. Approximately 80% - 85% of lung cancers in women are caused by cigarette smoking. Wang et al. investigated the association of both active and passive smoking on lung cancer risk in a prospective cohort of more than 90,000 post-menopausal women: the results of the Women’s Health Initiative Observational Study (WHI-OS) have been presented at 2013 ASCO annual meeting and evidenced an higher lung cancer incidence, particularly small cell lung cancers and squamous lung cancers, in current smokers (Hazard Ratio, HR 13.44, 95%, CI 10.80-16.75) and former smokers (HR 4.20, 95% CI 3.48-5.08) compared to never smokers. In the same study, among never smoking women, passive exposure, as an adult at home for > 30 years, was associated with a trend of increased risk (HR 1.61, 95% CI 1.00-2.58) for lung cancer, confirming findings of previous prospective cohort studies. In recent times, an increased proportion of non-smoking female patients, with earlier age at diagnosis and a majority of adenocarcinoma has been observed, particularly in Asian countries. Prevalence of lung cancer in females without history of tobacco smoking is estimated to represent 19% compared with 9% of male lung carcinoma in the United States. Freedman et al. reported, on a cohort of nearly 500,000 individuals, aged from 50 to 71 years, a significant increase in the rate of lung cancer for women who did not smoke, compared with male non-smokers, whereas no increased risk was described in current and former female smokers compared with matched males. Hormonal status is one of the potential explanations for gender differences. Estrogens are involved in lung tumorigenesis and progesterone receptor expression has been described in non small cell lung cancers (NSCLC). Combination of estrogen and progesterone works synergistically in vitro to promote vascular endothelial growth factor secretion increasing tumor-associated angiogenesis. Chlebowski et al. examined estrogen plus progestin (E+P) association with lung cancer incidence and outcome evaluating more than 30,000 postmenopausal women. Results have been presented at 2013 ASCO annual meeting: in non users of E+P, lung cancer incidence and deaths from lung cancer were significantly and substantially greater in current smokers versus never smokers (p< 0.0001 for both comparisons). In current smokers, lung cancer incidence and deaths from lung cancer were significantly and substantially greater in E+P users versus non-users (p=0.0021 and 0.0005, respectively), nearly doubling a smoker’s already high risk of death from lung cancer. Conversely, the role of androgens remains unclear. Harlos et al. evaluated more than 3,000 men with lung cancer evidencing that exposure to androgen deprivation therapy (ADT) is associated with significantly better survival when compared with no exposure. Patients exposed to ADT after their diagnosis were found to have a significantly better survival than those not exposed (HR 0.36 p=0.0007). This effect was also seen in those who received ADT before and after diagnosis (HR 0.53 p<0.0001). With regard to specific gene alterations there are relevant differences in men and women. The most widely recognized is the epidermal growth factor receptor (EGFR) mutation, that is found at a much higher frequency in adenocarcinomas, women, Asians and never smokers. Mutations in HER2 gene, although much rarer, target the same subpopulations. Mutations in EGFR (and HER2) are mutually exclusive of K-ras mutations: these are primarily observed in smokers and historically associated with male sex, but there are also publications demonstrating an higher frequency in women of “non-classical” type of K-ras mutations even if these data need further validations. The echinoderm microtubule associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation has been evidenced to occur more frequently in young patients, light or never smokers, while no major differences have been clearly stated between genders. B-Raf (V600) is described in 2% of patients with lung adenocarcinoma in western countries, related with worse prognosis and it is noted more frequently in women. An analysis of the p53 mutation databases indicated that the different spectra of p53 mutational patterns among smoker and never smoker cancers were almost entirely a result of differences between lung cancers in women, whereas male tumours did not show significant differences. Finally, recent studies investigated the role of telomere shortening in lung cancer. Kim et al. hypothesized that relative telomere length may be associated with recurrence in early stage NSCLC after curative resection. Longer telomeres were significantly associated with higher risk of developing recurrence in female (HR 2.25; 95% CI, 1.02-4.96, P= 0.044) and adenocarcinoma subgroups (HR 2.19; 95% CI, 1.05-4.55). All these findings provide multiple evidence for the specificities of lung cancer in women. The different expression of specific biomarkers, which could be targeted by therapy, will improve research towards personalized sex-based investigations, stimulating the development of further gender-based approaches in thoracic oncology.

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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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      MO21.01 - Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): VeriStrat analysis of longitudinal samples (ID 3122)

      10:30 - 10:35  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background
      2nd-line therapy for advanced NSCLC patients (pts) after progression on platinum-based regimens typically employs CT or E. A test for optimizing choice of treatment in these pts is of clinical value. VeriStrat (VS) is a serum protein test that assigns "good" (VSG) or "poor" (VSP) classification and has demonstrated prognostic and predictive utility. PROSE is a multicenter prospective randomized biomarker validation trial, designed to evaluate the ability of VS to predict survival in 2nd- line NSCLC pts treated with E or CT. As reported at 2013 ASCO1, PROSE met its primary endpoint of demonstrating significant treatment*VS interaction with a p value of 0.031, with VSG pts deriving similar overall survival (OS) benefit from both treatments (hazard ratio (HR) for E=1.06; p=0.71) and VSP pts benefitting more from CT than E (HR for E=1.72; p=0.02). Previous studies in EGFR-TKI-treated pts have shown that at progression around 30% of pre-treatment VSG pts have changed classification to VSP2. The present report discusses the exploratory analysis of longitudinal VS classifications generated during the PROSE study.

      Methods
      Of the 263 pts in the PROSE primary analysis population, 89 provided serum samples during treatment and 108 at progression, with 47 pts providing both. VS testing was performed on these longitudinal samples blinded to all clinical and treatment outcomes and pts and physicians remained blinded to VS results.

      Results
      VSG or VSP classifications were obtained for 89 pts from treatment samples (67 VSG / 22 VSP) and 107 pts (one sample was classified as indeterminate) from progression samples (59 VSG / 48 VSP). In pts with matched baseline and progression samples, the percentage of VSG classifications was lower at progression (55%) than at baseline (77%) (p < 0.001 ). Twenty eight pts (34%) classified at baseline as VSG changed to VSP at progression, in line with previous studies2, and this did not show any significant dependence on treatment. When treated with E, pts whose classification changed from VSG at baseline to VSP during treatment (n=6) had inferior PFS to the 25 pts who remained VSG (p=0.001, median PFS: 3.6 and 7.7 months (mos), respectively). Patients whose classification changed from VSG at baseline to VSP at progression on E (n=18) had numerically inferior OS (median 10.0 mos) compared with the 31 pts who remained VSG at progression (median 14.6 mos) and significantly superior OS (median 5.0 mos) compared with the 10 pts who were VSP at both time points (p<0.001).

      Conclusion
      The observed changes in VS classification at progression demonstrate the importance of obtaining a VS result prior to each line of therapy for which erlotinib is considered as a therapeutic option. The proportion of patients who are good candidates for erlotinib therapy (VSG) decreases from 2[nd] to 3[rd] line and the possible impact of this on treatment sequencing and monitoring for 2[nd] and higher line advanced NSCLC pts merits further studies.

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    MO24 - NSCLC - Chemotherapy III (ID 110)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO24.02 - Treatment decisions for elderly patients with advanced non-small cell lung cancer (NSCLC) in Italian clinical practice: results from the RIGHT-3 project by Italian Association of Medical Oncology (ID 3115)

      10:35 - 10:40  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background
      In 2004, the Italian Association of Medical Oncology (AIOM) created the RIGHT (Research for the identification of the most effective and highly accepted clinical guidelines for cancer treatment) program. The third step of the program, RIGHT3, aimed to evaluate the concordance between AIOM lung cancer guidelines and clinical practice in Italy. Description of treatment decisions for elderly patients with advanced non-small-cell lung cancer (NSCLC) was among the indicators. According to 2009 AIOM guidelines, single-agent chemotherapy with a third-generation agent was a reasonable choice for elderly patients with advanced NSCLC, whilst evidence about use of platinum-based treatment in the elderly population was judged potentially affected by selection bias and not conclusive.

      Methods
      RIGHT3 was a retrospective observational study conducted in a sample of 53 Italian lung cancer centers, representative of 230 AIOM centers. Patients with NSCLC diagnosis who had their first visit at the oncology center during 2010 and followed-up for at least 6 months were included. Proportion of elderly patients with stage IV disease receiving chemotherapy was among the 14 indicators evaluated.

      Results
      Overall, 306 pts with stage IV NSLSC were enrolled, and 299 were evaluable. Of these, 91 (30.4%) were older than 70. In the elderly subgroup, 81 pts (89%) were treated with first-line chemotherapy. In detail, a single-agent treatment was administered in 28 (34.6%) of cases, and a combination chemotherapy in the other 53 cases (65.4%). Among pts receiving platinum-containing doublets, carboplatin was more frequently used than cisplatin: carbo-gemcitabine (16 pts), carbo-pemetrexed (12 pts), cisplatin-pemetrexed (8 pts), cisplatin-gemcitabine (7 pts), carbo-vinorelbine (4 pts) were the 5 most frequently used regimens.Thirty pts (33%) received a second-line chemotherapy: single-agent in 23 cases, combination chemotherapy in 7 cases.

      Conclusion
      First-line platinum-based combination chemotherapy was commonly used in elderly patients with advanced NSCLC in 2010 by the Italian Lung cancer centers involved. First-line single-agent treatment, recommended by AIOM 2009 guidelines as the treatment choice with highest level of evidence, was used only in a minority of patients.

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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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      MO25.03 - Safety data from a Phase II study of pemetrexed (PEM) and cisplatin (CIS) with concurrent thoracic radiation after PEM+CIS induction in patients with unresectable locally advanced (LA) Non Squamous Non-Small Cell Lung Cancer (NS-NSCLC) (ID 226)

      10:40 - 10:45  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background
      This single-arm multicenter Phase II study investigated the efficacy and safety of PEM+CIS induction chemotherapy (CT) followed by full-dose PEM+CIS with concurrent radiotherapy (RT) in patients with LA NS-NSCLC. The 1-year progression-free survival (PFS) rate (primary endpoint) was 51.3% (ESMO 2013). Here, we report the safety data for induction CT and concurrent CT+RT.

      Methods
      Patients with unresectable Stage IIIA/IIIB NS-NSCLC (AJCC Version 6), ECOG-PS 0-1 and forced expiratory volume (FEV) >50% of predicted normal FEV received 2 cycles of PEM 500mg/m[2] + CIS 75mg/m[2] on Day 1, every 21 days. Patients who did not progress, with no residual neurological toxicity >Grade (G)2, ECOG-PS 0-1 and lung V20<35% were candidates to receive 2 cycles of the same full-dose PEM+CIS regimen with concurrent thoracic RT of 2Gy/fraction, 5d/week for 7wks (66Gy total). All patients received vitamin supplementation/dexamethasone prophylaxis as per PEM-label.

      Results
      90 patients were enrolled in 4 European countries, 75 (83.3%) completed induction CT and started concurrent CT+RT. Characteristics of 90/75 patients starting induction/concurrent therapy: median age 61/62yrs, male 57%/53%, ECOG-PS 0 66%/65%, mean(SD) FEV 2.3(0.62)/2.3(0.59)L, adenocarcinoma 90%/92%, Stage IIIA 36%/37%. 63 of 75 patients starting concurrent CT+RT (84.0%) received all 4 CT cycles and full dose RT. Median PEM+CIS dose intensities were 90-92% during induction and >97% during concurrent CT+RT, median RT dose was 66Gy (only 6 patients <60Gy). One patient died from study-drug-related toxicity (enteritis) during Cycle 4. Four patients discontinued due to non-fatal drug- or radiation-related adverse events (AEs), 1 on induction CT (renal failure), 3 on concurrent CT+RT (hypoacusis, 2 patients with radiation esophagitis). During induction/concurrent therapy, 8 of 90 patients (8.9%)/12 of 75 patients (16.0%) had ≥1 CT dose delay due to AEs, mainly neutropenia (n=5/6). 2/6 patients (2.2%/8.0%) required CT dose reductions. 13 of 75 patients (17.3%) experienced AEs requiring interruption of radiation, mainly radiation esophagitis (9.3%). Common G1-4 toxicities are presented in the table. 41.3% of patients reported ≥1 G3/4 toxicity during concurrent CT+RT, mainly esophagitis (12.0%), neutropenia (10.7%) and leukopenia (9.3%). G3 mucositis, G3 dysphagia and G3 acute pneumonitis were each reported by 1 patient (1.3%); 6 patients (8.0%) required blood-cell transfusions. Figure 1

      Conclusion
      PEM+CIS induction CT followed by full-dose PEM+CIS with concurrent thoracic RT was well tolerated in this study. Incidences of both G3/4 and low-grade toxicities were low, not only during PEM+CIS induction CT, but also during the subsequent 2 cycles of full-dose PEM+CIS CT with concurrent thoracic RT.

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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O01.07 - Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): Secondary Endpoint Analysis (ID 3276)

      11:35 - 11:45  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR-TKis are more effective in NSCLC patients with EGFR activating mutations. However, about 90% of non-Asian patients are EGFR wild type, and a test for optimizing treatment in pts with wild-type or in patients with undetectable EGFR mutation status or squamous histology is of clinical value. VeriStrat (VS) is a serum protein test that assigns "good" (VSG) or "poor" (VSP) classification and has demonstrated prognostic and predictive utility in retrospective studies. PROSE is the first completed multicenter prospective randomized biomarker validation trial, designed to evaluate the ability of VS to predict survival in 2[nd]- line NSCLC pts treated with E or CT. As reported at 2013 ASCO[1], VSG pts derived similar overall survival (OS) benefit from both agents (hazard ratio (HR) for E=1.06; p=0.71) whereas CT was the superior option for VSP pts (HR for E=1.72; p=0.02). PROSE met its primary endpoint of demonstrating significant treatment*VS interaction with a p-value of 0.031. The present report discusses the results for the secondary endpoints, PFS.

      Methods
      285 pts, stratified by ECOG-PS, smoking, and blinded pre-treatment VS classification, were randomized 1:1 to receive E or CT at standard doses. Primary endpoint was overall survival (OS) and the primary hypothesis was a significant interaction between VS status and treatment. Sample size was calculated based on an estimated 65%/35% VSG:VSP ratio and hazard ratio (HR) for interaction of 2.35, with a 2-sided α=0.05 and 90% power.

      Results
      263 pts (129 CT, 134 E) were included in the per protocol primary analysis. 68% of pts in CT arm and 72% in E arm were classified as VSG, and analysis was performed at 226 survival events.VSP classification was significantly correlated with worse PFS as compared to VSG, in overall comparison (HR=1.75, 95%CI: 1.34-2.95, P <0.001) , in the CT (HR = 1.69, 95%CI: 1.15-2.48, P <0.007) and the E (HR = 1.91, 95%CI: 1.340-2.80, P<0.001) arms, demonstrating its prognostic value also in PFS. In VSG median PFS was 4.8 months (m) on CT, and 2.5 m on E (HR = 1.26, 95% CI: 0.94-1.69, P =0.129); in VSP median PFS was 2.8 m on CT and 1.7 m on E (HR=1.51, 95% CI: 0.96-2.38, P =0.078). No statistical significant interaction was detected (p=0.44)

      Conclusion
      The analysis of PFS and OS indicates that the differential treatment benefit in OS related to VS classification is determined by the combination of prognostic and predictive properties of the test.

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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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      O16.01 - Impact of tumor burden on the overall survival analysis of the LUME-Lung 1 study: a randomized, double-blind phase 3 trial of nintedanib (BIBF 1120) + docetaxel in NSCLC patients progressing after first-line chemotherapy (ID 3284)

      10:30 - 10:40  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background
      Nintedanib is an orally available potent anti-angiogenic agent inhibiting the isoforms of VEGFR, PDGFR and FGFR. LUME-Lung 1 is a placebo-controlled phase 3 trial of nintedanib + docetaxel in second-line NSCLC patients.

      Methods
      Patients with stage IIIB/IV or recurrent NSCLC after failure of first-line chemotherapy were stratified by histology, ECOG PS, prior bevacizumab and brain metastases, and were randomised to nintedanib 200 mg bid + docetaxel 75 mg/m[2] q21d (n=655), or placebo + docetaxel (n=659). The primary endpoint was centrally reviewed PFS after 714 events. The key secondary endpoint was OS after 1,121 events. Predefined sensitivity analyses used baseline sum of longest diameters of target lesions (SLD) and stratification factors, as covariates in the Cox model.

      Results
      The study met its primary endpoint demonstrating a statistically significant improvement in PFS that translated into a 21% reduction in the risk of progression in patients treated with the combination of nintedanib + docetaxel vs placebo + docetaxel (HR 0.79; CI: 0.68, 0.92; p=0.0019; median 3.4 vs 2.7 months), regardless of histology (adenocarcinoma HR 0.77, CI: 0.62, 0.96; p=0.0193; squamous HR 0.77, CI: 0.62, 0.96; p=0.0200). OS was significantly prolonged in adenocarcinoma patients treated with the combination of nintedanib + docetaxel vs placebo + docetaxel (HR 0.83; CI: 0.70, 0.99; p=0.0359; median 12.6 vs 10.3 months) but not in squamous cell carcinoma patients (HR 1.01; CI: 0.85, 1.21; p=0.8908; median 8.6 vs 8.7 months). The intent-to-treat (ITT) analysis of OS in all study patients showed a 1-month improvement that did not reach statistical significance (HR 0.94; CI 0.83, 1.05; p=0.272; median 10.1 vs 9.1 months). When adjusted for SLD, however, a significant OS benefit was seen for the ITT population (HR 0.88; CI: 0.78, 0.99; p=0.0365). Further analyses showed that the impact of SLD was reflected in the squamous cell carcinoma population (HR 0.92; CI: 0.77, 1.10; p=0.3649), with the greatest impact observed for squamous cell carcinoma patients with a large SLD. An impact of SLD was also seen in adenocarcinoma patients but to a lesser extent (HR 0.81; CI:0.69, 0.97; p=0.0186), as compared with the squamous cell carcinoma population. The most common AEs reported for the ITT population were diarrhea (any: 42.3 vs 21.8%; Gr ≥3: 6.6 vs 2.6%) and ALT elevations (any: 28.5 vs 8.4%; Gr ≥3: 7.8 vs 0.9%). Incidence of CTCAE Gr ≥3 AEs was 71.3 vs 64.3%. Withdrawals due to AEs (22.7 vs 21.7%) were similar in both arms, as were Gr ≥3 hypertension, bleeding or thrombosis.

      Conclusion
      Nintedanib + docetaxel significantly reduced the risk of progression in NSCLC patients independent of histology. Adjustment for tumor burden, as represented by the SLD, led to a significant reduction in the risk of death. AEs were generally manageable with dose reductions and symptomatic treatment.

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    O22 - Mesothelioma III (ID 122)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      O22.01 - Next generation sequencing in malignant pleural mesothelioma: preliminary data from a retrospective cohort of 123 patients (ID 2290)

      16:15 - 16:25  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background
      The median survival of patients with advanced stage malignant pleural mesothelioma (MPM) ranges between 9 and 12 months after diagnosis, regardless of the recent achievements with systemic therapies combining cisplatin and antifolates such as pemetrexed or raltitrexed. Since MPM is a relatively rare malignancy and early pre-neoplastic lesions are clinically difficult to be identified, the understanding of molecular pathogenesis including sequential accumulation of genetic/epigenetic alterations for MPM development has lagged behind other common malignancies. According to the COSMIC database the most frequently mutated genes in MPM include CDKN2A, NF2 and BAP1, followed by other 12 genes having been found mutated in a fraction of MPM cases (c-MET, VHL,WT1 among others). Clearly, a better and more systematic understanding of the role of genomic alterations in MPM is needed. In this retrospective study, a consecutive series of 123 formalin-fixed, paraffin embedded (FFPE) MPM tissue samples with clinical annotates, collected at two institutions, was retrospectively analyzed through Next-Generation Sequencing (NGS) technology to enhance knowledge about tumor-specific genomic profiling.

      Methods
      Genomic DNA was extracted by tumour microdissected FFPE samples for all 123 patients. Amplicons NGS libraries for 50 Oncogene included in Ion AmpliSeq™ Cancer Hotspot Panel (CHP) v.2 were generated as indicated by manufacturer, and sequenced in Personal Genome Machine IonTorrent. Variant Caller included in Torrent Suite Software was utilised to identify mutations in the samples, annotation was performed with Annovar software. Genomic analysis for BAP1 and NF2 (not included in the CHP) is separately ongoing.

      Results
      Of 123 advanced stage MPM patients, all treated with pemetrexed-based chemotherapy, 70% were males, current smokers 50%, median age 66.5 (range 36-82) years and histological subtypes were 96/22/5 epithelioid/biphasic/sarcomatous. With a cut off for allele frequency(AF)>=10% a total of 966 non-synonymous, 8 del-ins, 62 nonsense, 637 intronic, 204 regulatory and 1140 synonymous somatic sequence variations were detected in 107 patients already screened. Excluding synonymous mutations and irrespective of AF, the five most frequently altered genes were CSF1R (mut:154, pts:80), KDR (mut:148, pts:73), FLT3 (mut:132, pts:99), PIK3CA (mut:126, pts:60), TP53 (mut:111, pts:66). Evaluating mutations identified at least once, a correlation between HRAS and PIK3CA mutations and patient status (dead or alive) was observed (p=0.017 and p=0.039, respectively). Specifically, HRAS silent mutation p.H27H (rs12628) was responsible for the association (p=0.021) and occurred in 54% of 107 MPM compared to 30% of reported AF in available databases. PIK3CA p.I391M missense mutation (rs2230461; AF 24% in this series) was significantly associated to progression-disease (p=0.003). Among the other SNPs reported in at least 15 pts there are rs3729674(PIK3CA), rs1800863(RET), rs3822214(KIT), rs10006115(KDR), rs75580865(FLT3) and rs5030613(SMARCB1).

      Conclusion
      These extremely preliminary data indicate that NGS technology is feasible in FFPE MPM tissues and some of the detected genetic mutations are novel observations of potential prognostic and therapeutic interest.

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-015 - Assessment of the activity of Pemetrexed and Dasatinib as single agents and in combination in three malignant pleural mesothelioma cell lines (ID 2339)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM), an asbestos exposure related disease, is a highly aggressive tumor. Pemetrexed is a third-generation multitargeted antifolate approved as single agent or in combination with cisplatin as standard of care in first/second line treatment of unresectable MPM. Thymidylate synthase (TS), a key enzyme in the de novo synthesis of thymidine, is the main target of Pemetrexed and its overexpression has been related to Pemetrexed-resistance. Experimental data suggest that c-SRC tyrosine kinase hyperactivation has a key role in MPM. The effect of c-SRC pharmacological inhibition in correlation with TS expression levels and Pemetrexed resistance, has been investigated in three MPM cell lines.

      Methods
      Cell growth inhibitory effects of both Pemetrexed and Dasatinib (10nM-100μM) were evaluated by MTS proliferation assay in epithelial (MPP89, REN) and biphasic (MSTO-211) MPM cell lines. Apoptosis was detected by AnnexinV-propidium iodide method using a FACScan, while drug-mediated changes in invasive ability were tested using “wound healing” scratch assay. Real-Time PCR and Western blot were assessed to identify drugs-associated genes and/or proteins modulation.

      Results
      The cell lines assayed displayed different sensitivity to both Pemetrexed and Dasatinib treatments. Among the three cell lines, MSTO-211 was the most sensitive to Pemetrexed (IC~50 ~0.5 μM); on the contrary REN was the most resistant (IC~50 ~5 μM). A similar trend was observed upon Dasatinib treatment with IC50 values ranging from 1 to 5 μM. The synergistic effect of Dasatinib and Pemetrexed was also evaluated, being significantly relevant in MPP89 and REN after 72h treatment while, in MSTO-211, was already detectable after 48h. Early and late apoptosis assessment confirmed, for both drugs, the ability to induce apoptosis, being MPP89 the most Dasatinib-sensitive and MSTO-211 the most Pemetrexed-sensitive cell line. In MPP89 and REN cells co-administration of Pemetrexed/Dasatinib significantly increased the apoptotic rate of 16 folds and this behaviour was enhanced in MSTO-211 (up to 27 folds). Both TS, gene and protein levels were higher in REN compared to MPP89 and MSTO-211 cells. Pemetrexed administration increased TS levels over time, in those cells most sensitive to the drug. Interestingly, in REN cells Pemetrexed treatment did not affect the high baseline TS levels but Dasatinib administration suppressed TS protein and, to a lesser extent, mRNA expression, thus increasing sensitivity to Pemetrexed. In addition, in REN cells the pretreatment with Dasatinib (5 μM) enhanced Pemetrexed sensitivity leading to a strong cell viability reduction. In all 3 cell lines, SRC was expressed (mRNA and protein), decreasing its levels from MSTO and MPP89 to REN, and activated. Dasatinib impaired also cell migration, as observed by wound-healing assay.

      Conclusion
      In vitro data suggest that inhibition of both TS and SRC might represent a potential therapeutic strategy in MPM. The evidence indicates that Dasatinib plays a role by inhibiting cell motility and, more surprisingly, by down-regulating TS. Dasatinib-mediated TS expression impairment suggests a cross-talk between SRC and TS pathways thus leading to hypothesize a therapeutic use of Dasatinib to sensitize those Pemetrexed-resistant MPM patients’ cohort.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-056 - The Elderly Patient Individualized Chemotherapy Trial (EPIC): A Randomized Phase III Multicenter Trial of Customized Chemotherapy versus Standard of Care for 1st Line Treatment of Elderly Patients with Advanced Non-Small-Cell Lung Cancer (ID 1117)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      This is an ongoing phase III multicenter randomized trial comparing first line pharmacogenomic-driven chemotherapy based on Excision-Repair-Cross-Complementing-1 (ERCC1), Ribonucleotide Reductase subunit M1 (RRM1) and Thymidylate Synthase (TS) gene expression, versus standard first line treatment in elderly patients (pts) with advanced non-small-cell lung cancer (NSCLC). Chemotherapy selection based on an individual patient’s molecular profile is a potentially promising approach to optimize efficacy with the already available cytotoxic drugs. In older pts this is particularly relevant owing to their rapid deterioration of symptoms and their increased propensity to suffer therapy-induced toxicity.

      Methods
      Pts aged >70 years, with ECOG Performance Status (PS) 0 or 1, previously untreated for stage IV NSCLC will be evaluated. In a 2:1 fashion, pts will be randomized to experimental arm (A) or standard arm (B). They must have measurable disease and EGFR negative mutational status. In arm A, treatment with single or dual-agent chemotherapy will be based on histology, ERCC1 (E), RRM1 (R) and TS (T) expression at the mRNA level. Expression of E, R and T is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. The cut off for high or low expression have been previously defined. Pts with squamous NSCLC who are: E low/R high will be treated with single agent carboplatin, E high/R low with single agent gemcitabine, E low/R low with carboplatin and gemcitabine and E high/R high with docetaxel or vinorelbine. In non-squamous NSCLC pts: E low/T high will be treated with carboplatin, E high/T low with pemetrexed, E low/T low with carboplatin and pemetrexed, E high/T high/R low with gemcitabine and E high/T high/R high with docetaxel or vinorelbine. In arm B treatment will be standard of care at the discretion of the care provider. The primary endpoint is overall survival (OS). The secondary endpoints are progression-free survival (PFS), disease response according to RECIST 1.1 and tolerability (using CTCAE version 4.0). Feasibility of treatment selection based on pharmacogenomic parameters will also be assessed. Treatment will continue to a maximum of 6 cycles if tolerated or until disease progression. Switch maintenance treatment is not allowed in either arm. Continuation maintenance (one or more of the agents used in the initial regimen) is allowed at the discretion of the investigator. Treatment upon progression is at the discretion of the care provider. Assuming an exponential survival distribution for both treatment arms and a median survival time of 8 months in the control arm we anticipate to detect an improvement of 3 months in the median survival time in the experimental arm. To have 90% power to detect a three-month improvement in median survival at a significance level of 5% (2-sided) and assuming a 10% failure rate in gene analyses or loss to follow up rate, a sample size of 567 patients is planned to be enrolled.

      Results
      Not Applicable

      Conclusion
      We hypothesize that such tailored approach will improve survival decreasing the exposure to ineffective toxic agents in advanced NSCLC elderly pts. To our knowledge this is the first pharmacogenomic-driven randomized trial in this population.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-033 - Afatinib in EGFR mutant non-small-cell lung cancer patients with acquired resistance to reversible EGFR-TKIs (ID 2285)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      Afatinib, an irreversible EGFR-HER2 dual inhibitor, demonstrated superiority versus standard platinum-based chemotherapy as front-line therapy in non-small-cell lung cancer patients (NSCLC) with activating Epidermal Growth Factor Receptor (EGFR) mutations. In pretreated NSCLC afatinib failed to improve survival when compared to placebo in patients refractory to gefitinib or erlotinib and not selected for EGFR status. Aim of the present study was to evaluate clinical efficacy of afatinib in EGFR mutant NSCLC patients (pts) with secondary resistance to reversible EGFR-TKIs.

      Methods
      We retrospectively analyzed a cohort of 97 EGFR mutant lung cancer pts resistant to EGFR-TKI according to criteria used in the LUX-Lung 1 trial (Miller VA, Lancet Oncol 2012) and treated with Afatinib at the daily dose of 40-50 mg. The drug was given as compassionate use.

      Results
      The study included individuals with a median age of 62,5 year. The majority were females (N=63/64.9%), never/former smokers (N=94/96,9%), with good performance status (ECOG PS 0-1; N=90/90.2%) and pretreated with > 3 therapy lines (N=68/70.0%). EGFR status was assessed in tumor tissue obtained at the time of original diagnosis. The majority of pts (N=64, 66%) harbored a deletion in exon 19, while T790M mutation was detected in two cases including one case with double exon 19 and T790M mutation. Among the 95 pts evaluable for toxicity, 54.7% had any grade skin rash, including 11.6% with grade 3, and 50,5% had any grade of diarrhea, with grade 3 recorded in 10,5%. Among the 87 pts evaluable for efficacy, response rate (RR) was 11.5%, with a median progression free-survival and overall survival of 3.9 months and 7.3 months respectively. In 25 pts a tumor biopsy was repeated immediately before starting Afatinib therapy and 1 patient out of 5 individuals harboring T790M mutation showed a short extracerebral partial response, with following brain progression.

      Conclusion
      Our findings suggest that afatinib is modestly effective in EGFR mutant NSCLC with acquired resistance to reversible EGFR-TKIs.

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    P1.23 - Poster Session 1 - Tobacco Control, Prevention and Chemoprevention (ID 162)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P1.23-001 - The real role of health care professionals in providing smoking cessation counselling among lung cancer patients: preliminary data (ID 1051)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      According to the World Health Organization, one hundred million deaths were caused by tobacco in the 20th century and the expectation for 2030 is equal to 10 million deaths. Lung cancer is the leading cause of cancer death and in the United States cigarette smoking is responsible for an estimated 90% of all lung cancers. About 50% of lung cancer patients are current smokers at the time of diagnosis and 11 to 48% of all smokers continue to smoke. Parsons et al. in a review of 10 studies suggest that smoking cessation after early stage lung cancer diagnosis improves prognostic outcomes and, despite evidences that smoking cessation is related with more effective treatment, reduced chemotherapy and radiotherapy toxicities and a better prognosis, the belief prevails that treating tobacco dependence is less important than the other therapeutic approaches.

      Methods
      122 lung cancer patients referring to the Thoracic Oncology Unit of the S. Luigi Hospital in Orbassano – Italy (31% of the total number of patients referring to this center in this period of time) were prospectively and sequentially evaluated from 02/01/2013 to 30/05/2013. In order to collect data, a dedicated 15 question-anonymous survey was developed with the aim to understand if smoker or former smoker patients had received information by health professionals, about smoking cessation before or after the diagnosis, which reaction they had and which actions were adopted for quitting smoking.

      Results
      The median age of participants was 65 years or more, 75% were men, 25% women. 27% were smokers, 73% former smokers. Among active smokers, most patients (87.8%) reduced the number of cigarettes after being diagnosed. 45.4% of patients report not to have received information on smoking cessation by the healthcare professionals and among patients who received it, the majority (84.2%) declared a good or very good ability of health workers to understand the difficulty of quitting smoking. About 76% considers positively the action of health care providers and a little percentage reports a warning and paternalistic attitude of them. 67.7% of patients who attempted to quit smoking, state the sudden termination as the most effective measure, more than the gradual reduction of cigarettes. Analyzing anti-smoking techniques or therapies adopted, most patients declare not to resort to such methods: only 25% started using electronic cigarettes, 5.5% has used a nicotine replacement treatment, 4.1% is attending an antismoking clinic.

      Conclusion
      The analysis of the study results underline that most lung cancer patients are interested in smoking cessation programs and although many of them receive advice and assistance by healthcare workers, the recourse to the use of techniques, drugs or access to specific clinic is very low. In Italy there are few centers offering counseling for smoking cessation, while in UK, Norway and Netherlands innovative interventions are available and oncology nurses are essential in the identification of and intervention with patients who struggle with this dependence. This is a pivotal experience and other Italian and Spanish centers are already been involved in the questionnaire collection to get more complete and heterogeneous results

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-013 - Genetic profiling of lung cancer in young adults patients: early data assessment using Next-Generation Sequencing. (ID 1189)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      In 3% of cases, lung cancer is diagnosed in patients younger than 45 years. The epidemiology, biology and clinical history of young lung cancer patients is generally different from the adult counterpart: the higher percentage of mutations has the potential to influence both tolerability and response to treatment with consequent impact on quality of life and survival. The biomolecular characterization of the disease in this subgroup will allow the design of clinical studies dedicated to young patients, that will lead to the identification of specific items that are not deducible from trials opened to the general adult population. In this study, Next-Generation Sequencing (NGS) technology has been applied to archival tissue samples to enhance tumor-specific genomic profile knowledge in this selected cohort of young patients (pts).

      Methods
      A retrospective analysis has been performed at the Thoracic Unit of San Luigi Hospital from January 2007 to March 2013, collecting 13 lung cancer-diagnosed pts (10 completely sequenced; in 3 cases the analysis is ongoing), aged between 15-39 years. Genomic DNA was extracted by microdissected formalin-fixed and paraffin embedded (FFPE) tumor samples of all pts and by lymphocytes of three healthy controls (ctrl). Amplicons NGS libraries for 46 oncogenes included in the Ion Torrent Cancer Panel were generated, following manufacture guidelines, and sequenced in Personal Genome Machine (PGM) Ion Torrent instrument. Variant Caller included in Torrent Suite Software was used to identify mutations.

      Results
      Twenty-two non-synonymous, 3 frameshifts, 3 stop-gain and 55 synonymous somatic sequence variations were found in 10 young adult patients (allelic frequency ≥ 10%). Excluding synonymous mutations, the most frequently altered genes in patients were TP53 (7 mutations; 25%), followed by EGFR and KDR (5 mutations; 18%), PI3K (3 mutations; 11%), KIT (7 mutations; 14%), FGFR3-ABL1-MET-ATM-RB1-SMO (1 mutation; 3.6%). Furthermore, 14 of these mutations are annotated in SIFT or in PolyPhen databases as “mutations that could damage affected protein”. Overall, we identified 28 mutations annotated in COSMIC database, among which the most frequent were COSM149673, COSM28026 and COSM6223-COSM22413 with 5,4 and 2 counts, respectively. We also found 93 SNPs in our cohort, including the most frequent rs7688609, rs1873778 and rs1050171 with 13 counts (10 pts; 3 ctrl) followed by rs1800861 (9 pts; 3ctrl); rs41115 (8 pts; 2ctrl); rs1870377 (4 pts; 1ctrl); rs3822214 (2 pts; 2ctrl); rs3729687 (2 pts; 1ctrl); rs2228230 (2 pts) and rs3730358-rs3135898 (1 pt; 1ctrl).

      Conclusion
      The development of new biological techniques, such as the next-generation sequencing, could allow to collect a wide number of mutations. From these preliminary results, some interesting data have been discovered concerning SNPs or mutations. This pivotal retrospective analysis is the basis for the ongoing prospective collection. A better definition of molecular-genetic pattern in this selected young population of patients could increase the knowledge about the lung cancer etiology and suggest age-related new trials design.

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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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      P2.11-023 - BE-Positive: Gefitinib in first-line treatment of advanced non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. A combined retrospective and prospective analysis from Italian patients. (ID 1881)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      Advanced NSCLC patients have an extremely poor prognosis with a 5-year survival rate of less than 5%. In 2009, the European Medicines Agency approved gefitinib, a reversible EGFR tyrosine kinase inhibitor, at the dose of 250 mg daily for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations. As the first-line EGFR mutation positive data at that time were mainly in Asian populations a prospective phase IV, open-label, single-arm study of first-line gefitinib in Caucasian patients was presented: this trial confirmed the activity and efficacy of gefitinib in 106 Caucasian patients (Douillard EMCTO 2013). In the same way, we initially collected retrospectively, continuing then prospectively, the data of NSCLC EGFR-mutation positive Italian patients treated with first-line gefitinib, with the aim to evaluate the therapeutic outcomes and the approaches beyond progression in a “real life population”.

      Methods
      We collected data of patients who started gefitinib from June 2009 until May 2013. Primary endpoint was the evaluation of first line outcomes, in terms of: objective response rate (ORR), duration of treatment, progression-free survival (PFS), overall survival (OS) and safety. Secondary endpoint is the evaluation of the outcomes beyond progression to gefitinib. Here we report the results of first-line gefitinib of a large number of Caucasian patients.

      Results
      Data of 203 patients from 23 Italian Institutions were collected. The main patients characteristics were: median age 67 (range: 33-87), male/female 76/127, ECOG performance status (PS) 0/1/2/3/4 in 89/92/18/2/2 patients, 90.6% adenocarcinoma (in our study the percentage of carcinoma non otherwise specified was 1.5%), never/former/current smoker in 129/64/10, del19/L858R/uncommon in 128/57/18. In one case a T790M mutation ex novo was found in association with the deletion of the exon 19 (not all the patients were tested for this mutation at baseline). A median time for obtaining the EGFR test result was 8-15 days (more than 30% of the patients got the results in less than one week). Patients evaluable at the time of data lock were 168, of these 3 (1.8%) patients achieved a complete response, 72 (42.9%) a partial response for an ORR of 44.7%, 54 (32.1%) patients were stable. Median treatment with gefitinib was 38 weeks. Main toxicities were: grade 3-4 skin rash and diarrhea in 1.8% and 4.2%, respectively. Treatment was definitely stopped due toxicity in 4.2% of patients. After progression in 5 cases a re-biopsy was performed and 94 (56%) received a second-line treatment.

      Conclusion
      BE-Positive is the first study reporting results of first-line gefitinib in a large "real life population" of Caucasian patients. Data were firstly collected in a retrospective fashion, than in a prospective way. This study shows that Caucasian patients reported lower ORR when indirectly compared to Asian counterparts, but this is probably due to the partial analysis of the patients, excluding at this time those who are still on treatment. However, the tolerability profile was excellent and the median time of treatment is quite overlapping to literature data. The outcomes of PFS, OS and treatment beyond gefitinib progression will be reported when mature.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-014 - Impact of Non Small Cell Lung Cancer (NSCLC) immunophenotyping in chemotherapy response. (ID 2679)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      The vast majority of non small cell lung cancers (NSCLC) presents as advanced disease and histological diagnosis is widely based on small biopsy or cytological samples. Recently, the adoption of new pharmaceutical agents targeting individual histotypes requires a precise subtyping of NSCLC. This task is often difficult according to morphological criteria only and the use of immunohistochemistry (IHC) is recommended for small samples or undifferentiated tumors to define the most probable histotype. However, the real impact of IHC characterization of NSCLC-Not otherwise Specified (NOS) in terms of response to therapy and outcome (compared to cases classified by morphology, only) is not well established.

      Methods
      A large series of 224 advanced "non-squamous" NSCLC diagnosed from year 2005 to 2010 on small biopsy or cytological samples and homogeneously treated, was retrospectively selected, all with adequate follow-up data available. All diagnoses were reviewed resulting in two groups of adenocarcinoma (ADC) and NSCLC-NOS. The latter were further characterized by IHC to identify the most probable differentiation lineage. Disease Control Rate (DCR) and Response Rate (RR) were calculated and Overall Survival (OS) curves were analyzed by Kaplan Meier.

      Results
      After review 120/224 (53.6%) cases were ADC based on morphological examination, only (“ADC morphology”) and 104/224 (46.4%) remained NSCLC-NOS. In terms of response to therapy no significant difference was found between the two groups (“ADC morphology” had DCR= 0.66 and RR=0.31; NSCLC-NOS had DCR=0.64 and RR=0.35; Chi-Square p=0.83). The NSCLC-NOS cases that underwent IHC profiling resulted in 66/104 (63.5%) cases that had an ADC phenotype (“NSCLC favor ADC”) and 38/104 (36.5%) cases that lack ADC features (including 5 “NSCLC favor squamous carcinoma” and 33 “NSCLC null phenotype”). The “NSCLC favor-ADC” had DCR and RR similar to “ADC morphology” group (Chi-Square p=0.23), while the “non-ADC” NSCLC group had significantly different both DCR=0.47 and RR=0.29 (Chi-Square p=0.006). Survival curves confirmed no difference in terms of survival between the “ADC morphology” and the “NSCLC favor-ADC” groups, while showed a significantly poorer survival for the “non-ADC” NSCLC group with respect the other two groups (median survival: 8.5 vs 12.3 months, respectively; HR=0.5999; p=0.018).

      Conclusion
      These preliminary findings indicate that the practice of minimizing the NSCLC-NOS diagnoses by means of IHC has an impact on chemotherapy response. Stratifying such tumors by IHC, cases having an ADC immunoprofile had response rates comparable to those of morphologically diagnosed ADC, thus supporting the value of IHC to maximize lung cancer histological typing in the perspective of obtaining the best response to therapy.

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    P2.24 - Poster Session 2 - Supportive Care (ID 157)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P2.24-015 - The role of WALCE (Women Against Lung Cancer in Europe) in helping patients and their caregivers to cope with cancer. (ID 1119)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      The diagnosis and treatment of cancer are traumatic events for patients with cancer and their families. It can be a time of a emotional distress for both and can evoke a wide range of emotions related to poor quality of life. The expression of these feelings is crucial in order to cope with a diagnosis of cancer and with treatment side effects and any action where people perceive that they’re moving those feelings outside may be beneficial to them emotionally and physically. Even patients who receive the best support from family and friends may need to connect with other patients, who are facing the same challenges. Patients may seek emotional and/or practical support from cancer patient organizations and find programs designed with the aim to help them and their families to alleviate the emotional concerns.

      Methods
      During the last five years, WALCE addressed their emotional care needs designing programs to ameliorate the cancer patient quality of life during the treatments. These projects are addressed to caregivers too and are observational studies. - The Look Good ... Feel Better® is active in 25 countries worldwide. WALCE started its collaboration with “La forza e il sorriso – L.G.F.B. Italia” in 2009. From March 2009 to June 2013, 68 make-up workshops were organised at the San Luigi Hospital (Orbassano, Italy) in collaboration with five local cancer centres. 487 ladies attended, guided by 7 voluntary beauticians, with the support of a psycho-oncologist. - Relaxation technique sessions may be helpful to face with stress. They are intended to promote physical, emotional and mental relaxation to get a better recovery of energies. From March 2012 to May 2013, 12 sessions were organised and 28 people attended. - Natural cooking classes are a good opportunity for patients and caregivers to learn that the health is closely related with nutrition and actively get involved during the preparation of food. The natural cuisine plays a key role in healthcare and these lessons provide useful tips for a balanced diet. Participating in these classes can empower people affected by cancer to learn vital skills that enable them to regain control, reduce isolation and restore hope. - Mindfulness Based Intervention (MBI) based on the assumption that a non-judgmental awareness and acceptance of one’s moment-to-moment experience have an effect on the distressing tendencies to escape from or to over-engage with one’s disturbing feelings, emotions and thoughts. MBI can positively impact on coping strategies and on the adaptation to the disease, by encouraging patients to relate differently to their physical and psychological symptoms.

      Results
      NOT APPLICABLE

      Conclusion
      Cancer patients tend to cope better with the illness and daily-life when self-confidence is regained. The sense of well-being shared in a relaxed atmosphere a acknowledging social, emotional and psychological needs, whilst being amongst other people with the same fears or anxieties, is an incentive to fight against cancer. It is important to know that there are ways to relieve the discomfort of most treatment-related side effects and to prevent them from becoming severe.

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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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      P3.02-013 - ATF2 contributes to Platinum resistance in Non Small Cell Lung Cancer and cJUN/ATF2 Celastrol mediated modulation restores Platinum sensitization. (ID 2275)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      ATF2 is a member of the basic helix-loop-helix (b-ZIP) transcription factor family playing important roles in Stress and DNA damage. Several studies reported correlation between ATF2/JNK-mediated activation and resistance to damaging agents. Celastrol is an ATF2 inhibitor extracted from a Chinese plant known as “Tunder of God Vine”. Celastrol is used in traditional Chinese medicine for anti-inflammatory properties. In addition, Celastrol is a triterpene with promising anticancer activity in several cancer models both in vivo and in vitro. The purpose of the present study was to investigate whether ATF2 might play a role in inducing drug resistance in Non-Small Cell Lung Cancer (NSCLC).

      Methods
      In NSCLC cell lines ATF2 expression levels were evaluated by quantitative PCR (qPCR) and Western Blot (WB) and correlated to cisplatin (CDDP) resistance. Celastrol mediated ATF2/cJUN activity was assessed by Luminometry, qPCR and western blotting (WB). Furthermore, matched tumors and corresponding normal tissues of 88 surgically resected NSCLC specimens, were collected and both qPCR and immunohistochemical analyses for ATF2 were performed.

      Results
      NSCLC cell lines CDDP-resistant (H522 and H1395) expressed high levels of ATF2 protein. Moreover, CDDP treatment increased ATF2 phosphorylation levels leading to an enrichment within the nuclear cell compartment. In our study, Celastrol reduced ATF2 activity by decreasing the production of ATF2 mRNA and blocking the CDDP-mediated phosphorylation/mRNA expression of cJUN, a main ATF2 partner. Furthermore, ATF2/cJUN functional inhibition mediated by Celastrol restored the response to CDDP in resistant lung cell Lines. ATF2, at both protein and mRNA level, was significantly up-modulated in NSCLC tumor samples compared to the paired normal lung tissue (mRNA: p<<0.01, mean Log2(FC)=+4.7). Moreover, high expression of ATF2 mRNA was correlated with the smoking status of the patients. Relevantly, smoker or former smoker patients expressed significantly high ATF2 mRNA levels compared to non-smokers (p=0.02 and p=0.04, respectively).

      Conclusion
      This study shows that in NSCLC cell lines a correlation between ATF2 protein expression and CDDP resistance occurs. Furthermore, our results suggest a potential increase of CDDP sensitivity, following the Celastrol-mediated ATF2/cJUN inhibition. For the first time it has been shown in NSCLC an up-regulation of ATF2 mRNA/protein levels compared to normal tissues and consistent with that detected in CDDP resistant cell lines. This data suggest a possible involvement of ATF2 in NSCLC CDDP-resistance.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
    • +

      P3.06-026 - Thymidylate synthase (TS) mRNA and protein expression in advanced non-small cell lung cancer (NSCLC) patients treated with pemetrexed-based therapy. (ID 2355)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      In NSCLC, higher Thymidylate Synthase (TS) levels have been reported in both squamous and large cell carcinomas compared to adenocarcinoma. In clinical practice, Pemetrexed, a potent antifolate inhibitor of TS, showed a selective benefit in patients with "non-squamous" NSCLC. Two retrospective studies have shown that low TS protein levels are associated with better clinical outcome in NSCLC patients treated with pemetrexed. Aim of this study was to explore, in a series of advanced stage IV patients receiving pemetrexed-based regimens in first line of treatment, the association between TS mRNA and protein expression with overall survival (OS) and therapeutic response.

      Methods
      Two series of histologically confirmed non squamous-NSCLC, assessed in formalin-fixed and paraffin embedded specimens from patients treated with pemetrexed-based regimens were collected: the first series at San Luigi Hospital (n=64), the second series at Regina Elena National Cancer Institute (n=8). Due to the limited amounts of tissue specimens available, total RNA extraction was possible in 52 out of 72 cases. TS protein expression was performed using immunohistochemistry (mouse monoclonal TS106 antibody) and scored through H-SCORE method, considering both staining intensity (0 no staining; +1 weak; +2 moderate; or +3 strong) and percentage of tumor cells stained, resulting in semiquantitative H-scores ranging from 0 to 300. TS nuclear and cytoplasmic staining, respectively, were separately scored. Statistical analyses were performed using the STATISTICA10 software.

      Results
      The differential H-SCORE assessment showed a strong importance of TS localisation for clinical outcome prediction: in Cox regression analysis, a statistically significant association was observed between nuclear TS expression and OS (p < 0.009) indicating that lower nuclear TS expression levels were associated with longer OS. In addition, lower nuclear TS levels were significantly associated with a better response to therapy (p<0.001). On the contrary, TS cytoplasmic staining did not affect patients’ survival or clinical response (p>0.05). Four subgroups of patients, based on the dichotomized low/high TS expression in both nucleus and cytoplasm, were obtained: both high, both low, nucleus high/cytoplasm low and nucleus low/cytoplasm high. Significant differences in overall survival among these four groups were detected (p=0.017), confirming the strong and selective influence of nuclear TS, as compared to cytoplasmic TS, expression in clinical outcome. Moreover, Chi[2] test revealed a significant association between low nuclear TS and partial response to pemetrexed treatment, independently of cytoplasmic TS expression (p<0.001). No correlation between TS protein expression data and clinico-pathological data (age, gender) were identified. TS gene expression analyses are ongoing.

      Conclusion
      This retrospective study suggests that TS protein expression, selectively assessed at nuclear level, has a potential predictive role in advanced stage IV patients, receiving pemetrexed in first line of treatment. Patients with low nuclear TS expression showed prolonged overall survival and better response to therapy. Such preliminary results define TS assessment as a potential tool which may select the most appropriate group of patients to be treated with pemetrexed.

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-006 - Respiratory function changes after stereotactic ablative radiotherapy (SABR) in stage I non-surgical NSCLC: preliminary results from a single institution prospective study. (ID 1017)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      Stereotactic Ablative Radiotherapy (SABR) is an alternative to surgery in patients with early stage non-small cell lung cancer (NSCLC) inoperable for medical co-morbidities (mainly cardiovascular or respiratory diseases) or who refuse surgery. We performed a prospective evaluation of lung function parameters, treatment-related radiological and clinical toxicity in a cohort of patients treated with SABR.

      Methods
      We prospectively recruited 26 patients from July 2012 to May 2013. All patients had a histological or cytological diagnosis of NSCLC (n=20) or a lung lesion in dimensional growth with PET positivity (SUV>2.5) (n=6). All patients had stage IA– IB and were judged unfit for surgery or refused it. Each patient did a 4D-TC with slice of 2.5mm/2.5mm, treatment consisted of a single Volumetric Modulated Arc Therapy and the fractionation schedule was dependent on tumor location. Pulmonary toxicity was assessed through the execution of pulmonary function tests and on chest Computed Tomografy (CT). All tests were synchronously performed before treatment and at regular intervals after SABR (the first control at 45 days, then every 90 days until progression). Lung function parameters were obtained performing spirometry, body plethysmography, determination of the diffusion lung capacity of carbon monoxide (DLCO) and arterial blood gas analysis.

      Results
      Of 26 patients enrolled, 17 performed the first evaluation at 45 days, 5 at 135. At 45 days the total lung capacity (TLC) slightly decreased from 5.87±1.50 Liters (L) to 5.62±1.42 (t=1.87; NS), whereas VC, FEV~1~ and FEV~1~/VC ratio showed minimal changes. At 135 days TLC in the 5 patients who ultimate this step showed a slight recovery to 5.75±1.75 L. The pulmonary diffusion capacity for carbon monoxide (D~L~CO), corrected for hemoglobin (Hb) levels, significantly decreased from 14.4±4.9 to 12.9±5.2 (mL min[-1]·mmHg[-1]) at 45 days (p<0.019) with a slight recovery at 135 day to 13.9±2.7. When D~L~CO was corrected for the measured Alveolar Volume (D~L~CO/VA) the change was not significant. The difference between plethysmographic TLC and the dilution VA (TLC-VA) increased at 45 days from 1.24±0.7 to 1.49±0.8 L, suggesting an increase in ventilation inhomogeneity of the lung. Arterial oxygen pressure decreased from 75.8±7.2 to 71.6±10.4 mmHg (p=0.056 NS) and the variation correlated with TLC-VA (r=-0.72, p<0.001) and DLCO variations (r=-0.67, p<0.03). We observed a low toxicity profile during the first evaluation at 45 days, with only 1 RTOG grade 2 and 1 grade 3 post actinic pneumonia, both treated with systemic corticosteroids. Only three patients reported fatigue as the only adverse event. At the first radiological re-evaluation we didn’t observe any progression disease, with a 59% rate of partial response.

      Conclusion
      Preliminary findings suggest that no major changes in lung function can be detected at 45 days after SABR. A slight reduction in D~L~CO can be observed, and this could reflect a transitory increase in pulmonary ventilation inhomogeneity caused by RT rather than a direct membrane damage. Study prosecution will hopefully clear the physiopathological evolution at several months after SABR, and further analyses will be carried out investigating for a potential correlation with radiological toxicity and dosimetric profiles.

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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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      P3.11-040 - Analysis of patient-reported outcomes from the LUME-Lung 1 trial: a randomized, double-blind, placebo-controlled phase 3 study in second-line advanced non-small cell lung cancer (NSCLC) patients (ID 2812)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      Nintedanib is an oral, twice-daily angiokinase inhibitor targeting VEGFR-1–3, PDGFR-α/β and FGFR-1–3. LUME-Lung 1 is a placebo-controlled phase III trial investigating nintedanib plus docetaxel in advanced NSCLC patients after failure of first-line chemotherapy.

      Methods
      Stage IIIB/IV or recurrent NSCLC patients were randomised to receive nintedanib 200 mg bid plus docetaxel 75 mg/m[2] q21d (n=655), or placebo plus docetaxel (n=659). The primary endpoint was centrally reviewed progression-free survival (PFS) analysed after 714 events; the key secondary endpoint was overall survival (OS) analysed hierarchically after 1121 events, first in adenocarcinoma patients and then all patients. Quality of Life (QoL) was included as a secondary endpoint. Lung cancer symptoms and health-related QoL were assessed every 21 days until the first follow-up visit using the EORTC (QLQ-C30/LC13) and EQ-5D questionnaires. Changes of ≥10 points as compared with baseline were considered clinically significant. Analyses of cough, dyspnoea and pain symptoms were prespecified. Time to deterioration (TTD, first 10-point worsening from baseline) was analysed using a stratified log-rank test. An exploratory analysis of all subscales/items from the EORTC QLQ-C30/LC13 questionnaires estimated the respective hazard ratios for TTD using a Cox proportional hazards model.

      Results
      LUME-Lung 1 showed that nintedanib in combination with docetaxel significantly prolonged PFS for all patients regardless of histology (3.4 vs 2.7 months; HR 0.79, 95% CI: 0.68–0.92; p=0.0019), with a trend for improved median OS (10.1 vs 9.1 months; HR 0.94, 95% CI: 0.83–1.05; p=0.272) and significantly improved OS in patients with adenocarcinoma (HR: 0.83; p=0.0359; median 10.3 to 12.6 months). The most common AEs were diarrhoea and reversible ALT elevations. With respect to the QoL assessment, there was a high compliance rate of >80% until treatment course 25 for QLQ-LC13 and QLQ-C30 in both treatment arms. The addition of nintedanib to docetaxel did not influence TTD for cough (HR 0.90; 95% CI: 0.77–1.05; p=0.1858), dyspnoea (HR 1.05; 95% CI: 0.91–1.20; p=0.5203) or pain (HR 0.95; 95% CI: 0.82–1.09; p=0.4373), and maintained global health status/QoL (HR 0.952; 95% CI: 0.83–1.10). There was a significant deterioration in scores for nausea and vomiting, appetite loss and diarrhoea. The results were similar for adenocarcinoma patients with respect to cough (HR 0.97; 95% CI: 0.78–1.20; p=0.7744), dyspnoea (HR 1.04; 95% CI: 0.86–1.26; p=0.6813) and pain (HR 0.93; 95% CI: 0.76–1.13; p=0.4785); however, there was a trend for improved global health status/QoL (HR 0.86; 95% CI: 0.71–1.05). For squamous cell carcinoma patients, there was a trend for delayed TTD for cough (HR 0.84; 95% CI: 0.66–1.07; p=0.1561) and a maintained global health status/QoL (HR 0.975; 95% CI: 0.788–1.206). Further analyses are ongoing and will be presented at the congress.

      Conclusion
      In second-line NSCLC patients, docetaxel plus nintedanib did not result in any significant improvements in cough, dyspnoea or pain compared with placebo and docetaxel. However, PFS was improved in patients of all histologies receiving docetaxel and nintedanib, and OS was improved in patients with adenocarcinoma histology without adversely affecting self-reported QoL.

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      P3.11-041 - Treatment with crizotinib in patients with IV stage non-small cell lung cancer (NSCLC) with ALK translocation: a single institution experience. (ID 2961)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      Crizotinibis is a MET inhibitor, having also an activity on ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) pathways. The ALK translocation is described in 4% of NSCLC and these patients (pts) benefit from crizotinib therapy with a response rate (RR) ranging from 51 to 61%.The drug is already approved by FDA and EMA; in Italy crizotinib is available in first line within controlled clinical trials and, until April 2013, within expanded access program (EAP).

      Methods
      From June 2010 to February 2013, 155 pts with advanced NSCLC were analyzed for Alk translocation using fluorescence in situ hybridization (FISH) at our institution. The selection criteria were: adenocarcinoma histology, never or ex smoker, EGFR status WT. Main pts characteristics were: 59% males, median age 57,5 years (range 26-76), 77 former smoker (76 pts for more than 15 years). Tissue samples were available from primary tumor and metastases in 78 and 22%, respectively, having 73% of cases with cytological material. In 23,2% of the specimens Alk rearrangement was not evaluable due to poor quality and/or quantity issues.

      Results
      Among the 155 pts, 22 (14%) are ALK translocated: 19 were treated within PROFILE clinical trials and 3 patients in the EAP. 20 pts are currently evaluable for response and toxicity: 6 of them received crizotinib as first-line treatment, the others in subsequent lines. The response rate was equal to 70%. The total number of administered cycles is 235.The reduction of the dose (7% of cycles) was necessary in two pts: in 1 case due to bradicardia and fatigue G3 (in first line treatment) and in the other one due to neutropenia G3 (in second line).The observed toxicities were mostly grade 1-2 (fatigue 47%, bradycardia 5,8%, visual disorder 5,8%, anemia 29%, neutropenia 18% and nausea 12%); grade 3-4 was less common. The temporary cessation of treatment was required in 3 pts (range 4-15 days) for grade 3-4 toxicity (mostly neutropenia plus fatigue). No drug interruption for unacceptable toxicity was reported. The most common progression sites were brain (37%) and bone (27%).

      Conclusion
      The introduction of a selection criteria (such as negative EGFR status) leads on an increase of our cases of Alk traslocated pts compared to literature data; this selection is moreover recommended in diagnostic algorithm recently proposed by the Italian Expert Panel (Marchetti A et al, JTO 2013). Efficacy and tolerability profile are consistent with published data.

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    P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.12-023 - International Tailored Chemotherapy Adjuvant Trial: ITACA Trial (ID 1452)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      This is an ongoing phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy, based on thymidilate synthase (TS) and excision-repair cross-complementing-1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected Stage II-IIIA non-small cell lung cancer (EudraCT #: 2008-001764-36).

      Methods
      For all the registered patients (pts) the expression of ERCC1 and TS is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. Randomization is stratified by stage and smoking status. Trial was emended on Feb, 2011 with the 7th staging system. Primary end point is overall survival; secondary end points include recurrence-free survival, therapeutic compliance, toxicity profile and comparative evaluation of ERCC1 and TS mRNA versus protein expression. It is assumed that the 5-year survival rate in the control arm is 45% and the hazard reduction associated to the experimental treatment is 30%. With a power of 90% to detect the estimated effect with log-rank test, a significant level of 5% (2 tails), 336 events have to be observed; the expected total number of pts is 700. The final statistical analysis will compare all pts in the control arms versus all those treated in the tailored chemotherapies groups. Efficacy analysis will be done on an intent-to-treat basis. Cox proportional hazard model will be used for estimating hazard ratios after adjusting for relevant variables. Within 45 days post-surgery, pts in each genetic profile are randomized to receive either a standard chemotherapy selected by the investigator (cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine) or an experimental treatment (tailored arms) selected as follows: 1) high ERCC1 and high TS 4 cycles of single agent paclitaxel 2) high ERCC1 and low TS 4 cycles of single agent pemetrexed 3) low ERCC1 and high TS 4 cycles of cisplatin/gemcitabine 4) low ERCC1 and low TS 4 cycles of cisplatin/pemetrexed. All chemotherapy regimens are administered for a total of 4 cycles on a 3-weekly basis.

      Results
      Not applicable

      Conclusion
      Currently, 558 pts have been randomized from 26 institutions mainly located in Italy and Germany (average enrolment: 19 patients/month). This is one of the pharmacogenomic-driven trial in the adjuvant setting in the European scenario.

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    P3.14 - Poster Session 3 - Mesothelioma (ID 197)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P3.14-009 - High resolution study on survival of pleural mesothelioma from the records of the Piedmont Registry of Malignant Mesotheliomas - report on incident cases 2008-2009 (ID 2302)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      The legacy of occupational and environmental asbestos exposure in Piedmont, Italy, is a continuing epidemic of pleural malignant mesothelioma (MPM). MPM still entails a poor prognosis, but progresses in its medical and surgical treatment have occurred and guidelines started to appear. We aimed to assess: (i) the appropriateness of treatment for MPM cases recently diagnosed in the Piedmont population, taking into account patients’ general conditions and disease stage at diagnosis, (ii) the end results of treatment.

      Methods
      We exploited the Registry of Malignant Mesotheliomas (RMM) records to identify incident cases from 2008 to 2011. Patients diagnosed/treated in hospitals including a thoracic surgery unit and in the Casale Monferrato hospital were known to represent about 70% of all MPM incident cases and were included in this study, as for them not only clinical records on diagnostic procedures, but also on treatment and follow-up were completely retrieved by RMM. Vital status at 31/12/2012 was ascertained for all MPM cases. Current analyses were limited to incident cases 2008-2009, followed at least up to 3 years. Multinomial logistic regression was used to estimate the odds ratio (OR) of receiving a specific treatment (categories: cytoreductive surgery, CRS, chemo/immunotherapy, CIT, best supportive care, BSC), conditional on individual characteristics. Survival was assessed with univariate (Kaplan-Meier) and multivariate (Cox) methods.

      Results
      There were 297 MPM cases. Taking CIT as reference, the OR of receiving CRS was decreased by older age and low performance status (Table 1). That of receiving BSC alone was increased by older age and low performance status as well, and by non-epithelial histotype. Median survival was 13.6 months for patients receiving CIT and 18.3 for those undergoing CRS Figure 1

      Conclusion
      In participating centres, MPM are currently treated in agreement with available guidelines, and treatment outcomes are consistent with expectations.

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    P3.18 - Poster Session 3 - Pathology (ID 177)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P3.18-014 - Implementing systematic histological and genotypic re-evaluation of Non Small Cell Lung Cancer (NSCLC) into routine clinical practice: a monocentric study (ID 2691)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      Cancer is a multistep process in which tumor cells progressively harbour genetic alterations that confer growth and spread advantages. These observations are also confirmed in NSCLCs where specific genetic abnormalities are sensitive to the action of targeted drugs, even if secondary mutations could develop conferring drug resistance. Furthermore, in recent studies, histologic and immunophenotypic changes have been described in patients (pts) with a specific molecular alteration re-biopsied after receiving a targeted therapy. This finding suggest the possibility of a "clonal resistance mechanism" in which genetic-similar cell populations had or acquire selective survival features thus escaping the inhibitory drug effect. In the present study histological examination and wide genetic analyses have been performed in tumor tissue sampled both before and after treatment in an unselected NSCLC patient population in order to elucidate progressive clinic-pathological and genetic abnormalities.

      Methods
      NSCLC pts with adequate tissue samples before and after at least one treatment have been evaluated from July 2006 to March 2013, at Department of Oncology of San Luigi Hospital. All had ECOG Performance Status of 0, median age of 51,5 years and IIIA-IV stage at diagnosis. After histological examination, mutational analyses for EGFR, K-RAS, PIK3CA, B-RAF, and HER2 genes were performed using pyrosequencing or RealtimePCR. ALK and c-MET genomic rearrangement were tested by FISH.

      Results
      A total of 24 (12 males and 12 females) pts were collected. Histological diagnoses were re-confirmed in all but one (4%) case in which morphological and immunophenotypical histology of neuroendocrine small cell lung cancer (SCLC) was found. All samples were adequate for molecular analyses. At the first biopsy EGFR activating mutations were 10/24 (42%) and 3/24 (12,5%) were the exon 20 EGFR p.T790M mutation, 2/3 (66%) associated to EGFR activating mutations. At the second biopsy 6/10 (60%) EGFR activating mutations were maintained and no acquired mutations in EGFR wild type pts at first were found at second biopsy. On the other hand, 6/24 (25%) p.T790M mutation were detected at second biopsy, 5/6 (83%) de novo acquired, 1/6 (17%) maintained and only 1/5 (20%) associated to EGFR activating mutations. The patient who acquired SCLC histology, maintained the L858R EGFR activating mutation after treatment with no other acquired mutation. K-RAS mutations were found in 4/24 (16.7%) first biopsies, while 5/24 (21%) were found at the second biopsies. No mutations were found in BRAF, HER2 and PIK3CA genes. ALK rearrangement was assessed in 5/24 (20,8%) patients; otherwise MET amplification was seen in 3/24 (12.5%) cases only 1/3 (30%) in EGFR mutant cases.

      Conclusion
      These preliminary data showed a complex scenario of basal and acquired alterations on tumor tissue before and after treatment highlighting the need of repeated histological and genotypic assessments to guide at the best treatment decisions.

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    P3.19 - Poster Session 3 - Imaging (ID 181)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P3.19-015 - Should core biopsy with larger needle replace FNAB in assessing lung masses? (ID 2331)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      The distinction between SCLC and NSCLC has been recently replaced by a more detailed re-classification. As 70% of patients with LC are still not eligible for surgery, tumor characterization is often based on needle biopsy. For the management of lung masses (LM), the availability of adequate samples is critical not only for pathological diagnosis, but also for additional molecular studies. In this context, our aim was to evaluate the safety and accuracy of image-guided core biopsies (CB) in our last 4-year series.

      Methods
      480 consecutive patients (325 male; 33-87 y, mean 68; LM diameter 6-150 mm, m 37,4) underwent 439 CT-guided, 35 US-guided and 6 US+CT-guided lung biopsies. In 325/480 cases (68%) a CB was preferred due to the possible requirement of molecular studies. 275 CB were performed with >=18G tru-cut needle, 50 with <18G, both by a coaxial technique (inserted in a 1G larger styleted cannula). 1 to 6 sampling per patient (m 1.5) were performed. Adverse events (including major complications) were recorded and correlated with technical issues (namely, with needle size). To assess the accuracy of CB, surgical specimens, outcome of non-surgical therapy and follow-up imaging were considered as gold standards. Sensitivity, specificity, diagnostic accuracy and positive and negative predictive values of CB were calculated.

      Results
      81/325 (24.9%) adverse events occurred, but only 23 (7%) were major complications (MC) (22 pneumothorax and 1 hemothorax, requiring drainage and prolonged hospitalization). The incidence of MC wasn’t different between either CB and FNAB group (11/155, 7%), or larger and smaller CB needle size (20/275 vs. 3/50, p=n.s). Only the depth of the LM seemed to be significant as negative predictor for MC (p=.0061). Pathological diagnosis was of benign LM in 60 CB (18.4%), malignancy in 265 (81.5%). According to the above gold standard criteria, TP were 265, FN 13, TN 47, FP 0. Sensitivity, specificity and diagnostic accuracy were 95.3%, 100% and 96%, respectively. PPV was 100%, NPV 78.3%.

      Conclusion
      CB is as safe as FNAB in characterizing LM; particularly, needle size doesn’t impact on MC rate. CB is highly accurate in morphological characterization of LM, also providing additional tissue for molecular studies, when needed.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 2
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      P3.24-009 - Histologic and genotypic evolution in lung cancer harboring mutations in the epidermal growth factor receptor (EGFR): a clinical case. (ID 708)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      This is a clinical case of an EGFR-mutant Non-Small Cell Lung Cancer (NSCLC) with adenocarcinoma (ADC) histology: a subsequent diagnosis of high grade neuroendocrine small-cell lung cancer (SCLC) carrying an EGFR mutation was done at the first re-biopsy and further, a sarcomatous cancer was finally diagnosed. Recent publications were focused on drug-resistance mechanisms in patients with a specific biomolecular alteration re-biopsed after receiving the targeted therapy: in some cases morphologic and immunophenotypic changes were described. This finding suggests the possibility of "clonal resistance" with a selective pressure of some groups of cells, even if the histopathological features of these mechanisms have not yet been completely elucidated.

      Methods
      A 62-year-old caucasian man, with past smoking habit, presented with a 2-week history of cough and dyspnea. After a diagnosis of stage IV lung ADC, he received, on March 2010, 1st line treatment with cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 on Day 1 every 21 days, for 6 cycles. He achieved a partial response on computed tomography (CT) and a marked regression of his symptoms. On August 2011, a CT scan revealed a progressive disease (PD); he started treatment with Erlotinib plus ARQ-197/placebo within a clinical trial. As deemed by protocol, molecular analyses were performed on biopsy specimen at time of diagnosis, evidencing exon 21 – point mutation, p.Leu858Arg at EGFR mutational assessment. After 4 cycles, a local progressive disease was described by CT scan and a fibrobronchoscopic re-biopsy was performed in order to define the novel biomolecular profile at that time of the history of the disease. The histological evaluation highlighted a SCLC and molecular analyses confirmed the p.Leu858Arg mutation. Based on new histological diagnosis, he underwent chemotherapy with AUC6 carboplatin on Day 1 every 21 days plus etoposide 100 mg/m2 on Day 1,2,3 every 21 days, for a total of 6 cycles, until May 2012, achieving partial response at CT scan. On August 2012, because of radiological evidence of disease progression, he underwent chemotherapy with Cyclophosphamide 800 mg/m2, Doxorubicine 40mg/m2 and Vincristine 1mg/m2 on Day 1 every 21 days. After 3 cycles, he reported intense swelling in the supraclavicular right fossa and a fine needle aspiration of supraclavicular right lymphadenopathy was performed. The final pathological diagnosis was undifferentiated sarcoma cells (CK-,TTF1-, VIM+) . Patient died, on January 2013, because of worsening of clinical conditions.

      Results
      Not applicable

      Conclusion
      Many studies hypothesize that SCLC either evolved from the previously diagnosed NSCLC or that both arose from a common precursor. Further comparative molecular analysis of these histologically distinct tumors would be of value to better understand the potential role of EGFR in the evolution of lung cancer and the role of selection for an EGFR-mutant SCLC cell subclone as an unusual mechanism of acquired resistance to EGFR inhibitors in NSCLC.

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      P3.24-010 - The efficacy of a Mindfulness Based Intervention Body and Affective Intervention(MB-BAI) with cancer patients and their relatives (ID 1065)

      09:30 - 09:30  |  Author(s): S. Novello

      • Abstract

      Background
      Cancer has a great impact on psychological functioning of patients and relatives and can be associated with various psychological disorders and symptoms. Mindfulness Based Intervention (MBI) is a relatively brief and cost-effective program that has been studied in patients with several diseases. Recent analyses have shown the efficacy of MBI in improving psychological symptoms related with physical illnesses like cancer, chronic fatigue syndrome, fibromyalgia, chronic pain, arthritis, diabetes, heart disease, stroke, and traumatic brain injury. MBI is based on the assumption that a non-judgmental awareness and acceptance of one’s moment-to-moment experience have an effect on the distressing tendencies to escape from or to over-engage with one’s disturbing feelings, emotions and thoughts. MBI can positively impact on coping strategies and on the adaptation to the disease, by encouraging patients to relate differently to their physical and psychological symptoms, resulting in a reduction of the psychological burden and improving patients’ Quality of Life (QoL). MB-BAI integrates MBI basic practices with increased attention to somatic resources and application of mindfulness in relationships.

      Methods
      We aim to evaluate whether a group-based Mindfulness Based Body and Affective Intervention can reduce psychological symptoms like anxiety, depression, perceived stress and improve the QoL of patients with cancer. Furthermore, our study involve patients’ caregivers/relatives in order to decrease the load of stress and difficulties related to the management of a disabling diseases like cancer. This project is designed as an observational study. The subjects currently involved in all are 36, including patients with advanced malignant disease (mostly lung cancer), their caregivers/relatives and the control group. Participants were enrolled at the Oncology Unit of San Luigi University Hospital of Orbassano, Italy, in collaboration with WALCE (Women Against Lung Cancer in Europe). The experimental group underwent a 8 weekly sessions of 3 hours each (plus an all day session) with a group based MB-BAI. The control group hasn’t receive any psychological intervention. The psychological assessment was performed at pre-intervention and after treatment for both groups. The evaluation encompasses the administration of the self-reportquestionnaires: Hospital Anxiety and Depression Scale (HADS), Perceived Stress Scale (PSS), Five Facet Mindfulness Questionnaire (FFMQ), Posttraumatic Growth Inventory (PTGI) and WHOQoL-Brief, patients qualitative reports.

      Results
      not applicable

      Conclusion
      The study is currently ongoing. As far as we know this is the first MBI applicationinadvanced lung cancer. Specific attention to somatic resources and relationships may increase its effectiveness. Preliminary results from patients’ reports suggest that the MB-BAI both reduces symptoms of anxiety and depression and improves resources. Results will be presented after the complete achievement of the after-treatment assessment; we hope they will confirm that MBI favor positively impact on the adaptation to the disease, resulting in a reduction of the psychological burden and improving patients’ Quality of Life (QoL).