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S. Novello

Moderator of

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    PLEN 02 - Lung Cancer: IASLC Global Initiatives (ID 51)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 2
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      PLEN02.01 - 2015 WHO Classification of the Pathology and Genetics of Tumors of the Lung (ID 2041)

      08:15 - 09:45  |  Author(s): W.D. Travis

      • Abstract
      • Presentation

      Abstract:
      The 2015 WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published with numerous important changes from the 2004 WHO classification, due in part to remarkable advances in lung cancer genetics and therapy.[1] Multiple major changes for the common lung cancers mostly follow the 2011 lung adenocarcinoma classification sponsored by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS).[2 ] This 2015 edition follows previous WHO Classifications of Lung Tumors in 1967 and 1981, of Lung and Pleural Tumors in 1999 and Tumors of the Lung, Pleura, Thymus and Heart in 2004.[3, 4] Through support of its Pathology Committee, the IASLC has played a key role in the last three WHO Classifications.[5] With each subsequent classification, new techniques were introduced resulting in increased complexity, but greater ability to personalize therapeutic strategies that are now frequently dependent on histology and genetics. The most significant changes in the 2015 Classification involve: 1) Use of immunohistochemistry throughout the classification, when possible, not only for small biopsies/cytology, but also for resected specimens in certain settings such as solid adenocarcinoma, nonkeratinizing squamous cell carcinoma, large cell carcinoma, neuroendocrine tumors and sarcomatoid carcinomas. 2) A new emphasis on genetic studies, in particular integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients. Due to the therapeutic implications, molecular testing for EGFR mutation and ALK rearrangement is today recommended in tumors classified as adenocarcinoma and in cases where an adenocarcinoma component cannot be excluded.[2, 6] 3) A new classification for small biopsies and cytology similar to that proposed in the 2011 IASLC/ATS/ERS Classification[2] proposes that tumors that have clear morphologic patterns of adenocarcinoma or squamous cell can be diagnosed as adenocarcinoma or squamous cell carcinoma, respectively, without immuhistochemistry, unless a pneumocyte marker such as TTF-1 is desired to address primary versus metastatic adenocarcinoma. However, in the setting of poorly differentiated tumors that do not show clear differentiation by routine microscopy, a limited immunohistochemical workup is recommended to allow for an accurate diagnosis and also to preserve as much tissue for molecular testing as possible. Most tumors can be classified using a single adenocarcinoma marker (e.g. TTF-1) and a single squamous marker (e.g. p40 or p63). Nonsmall cell carcinomas (NSCC) that show no clear adenocarcinoma or squamous cell carcinoma morphology or immunohistochemical markers are regarded as NSCC not otherwise specified (NOS). If a tumor with this morphology stains with pneumocyte markers (i.e. TTF-1), it is classified as NSCC, favor adenocarcinoma and if it stains only with squamous markers (i.e. p40) it is classified as NSCC, favor squamous cell carcinoma. Using this approach, a diagnosis of NSCC-NOS can be avoided in up to 90% of cases.[7, 8 ] 4) According to the 2011 IASLC/ATS/ERS Classification of lung adenocarcinoma, adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) were defined as entities to have 100% or near 100% disease free survival if completely resected, respectively. Also, invasive adenocarcinomas are classified according to the predominant pattern using comprehensive histologic subtyping (CHS). Multiple studies have shown prognostic significance to this approach with favorable outcome for lepidic adenocarcinomas and poor outcome for solid and micropapillary adenocarcinomas. CHS can be helpful in staging as well: 1) along with other morphologic features, it can be useful in comparing multiple lung adenocarcinomas in a single patient in order to distinguish multiple primary tumors from intrapulmonary metastases and 2) it can also help in measuring invasive size in lepidic adenocarcinomas. Micropapillary or solid predominant subtyping also appears to predict improved responsiveness to adjuvant chemotherapy compared to acinar or papillary predominant tumors in surgically resected lug adenocarcinoma patients when analyzed by disease free survival and specific disease free survival.[9] 5) The diagnosis of large cell carcinoma is restricted only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories. 6) Squamous cell carcinomas are reclassified into keratinizing, nonkeratinizing and basaloid subtypes with the non-keratinizing tumors requiring immunohistochemistry proof of squamous differentiation. 7) Neuroendocrine tumors are grouped together in one category, although new genetic data supports previous clinical, epidemiologic and pathologic data showing that low and intermediate grade typical (TC) and atypical carcinoids (AC) are distinct from the high grade small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). Ki-67 is useful to distinguish carcinoids from SCLC and LCNEC especially in small crushed biopsies. However, published data do not support incorporation into the classification, particularly in separating TC from AC. Spread through air spaces (STAS) is a newly recognized pattern of invasion which consists of micropapillary clusters, solid nests or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma, It probably contributes to the significantly increased recurrence rate for patients with small stage 1 adenocarcinomas who undergo limited resections.[10] Future clinical trials and large scale genetic studies such as The Cancer Genome Atlas (TCGA) need to incorporate the new pathologic criteria for both small biopsies and resection specimens which now require immunohistochemistry to precisely classify poorly differentiated tumors such as solid adenocarcinoma or nonkeratinizing squamous cell carcinoma. Despite promising preliminary data, additional work is needed to develop a histological grading system for lung cancer. Acknowledgement: This abstract is presented with gratitude on behalf of the WHO Panel and the IASLC Pathology Committee. References: 1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015. 2. Travis WD, Brambilla E, Noguchi M, et al. The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. JThoracic Oncol 2011;6:244-85. 3. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, in collaboration with LHS, Countries pf. Histological Typing of Lung and Pleural Tumors. Berlin: Springer; 1999. 4. Travis WD, Brambilla E, Mller-Hermelink HK, Harris CC. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC; 2004. 5. Tsao MS, Travis WD, Brambilla E, Nicholson AG, Noguchi M, Hirsch FR. Forty years of the international association for study of lung cancer pathology committee. J Thorac Oncol 2014;9:1740-9. 6. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J ThoracOncol 2013. 7. Nicholson AG, Gonzalez D, Shah P, Pynegar MJ, Deshmukh M, Rice A, Popat S. Refining the Diagnosis and EGFR Status of Non-small Cell Lung Carcinoma in Biopsy and Cytologic Material, Using a Panel of Mucin Staining, TTF-1, Cytokeratin 5/6, and P63, and EGFR Mutation Analysis. JThoracOncol 2010;5:436-41. 8. Loo PS, Thomas SC, Nicolson MC, Fyfe MN, Kerr KM. Subtyping of Undifferentiated Non-small Cell Carcinomas in Bronchial Biopsy Specimens. JThoracOncol 2010;5:442-7. 9. Tsao MS, Marguet S, Le Teuff G, Lantuejoul S, Shepherd FA, Seymour L, Kratzke R, Graziano SL, Popper HH, Rosell R, Douillard JY, Le-Chevalier T, Pignon JP, Soria JC, Brambilla EM. Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection. J Clin Oncol 2015. 10. Kadota K, Nitadori JI, Sima CS, Ujiie H, Rizk NP, Jones DR, Adusumilli PS, Travis WD. Tumor Spread Through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences Following Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      WHO CLASSIFICATION
      Adenocarcinoma
      Lepidic adenocarcinoma
      Acinar adenocarcinoma
      Papillary adenocarcinoma
      Micropapillary adenocarcinoma
      Solid adenocarcinoma
      Invasive mucinous adenocarcinoma Mixed invasive mucinous and non-mucinous adenocarcinoma
      Colloid adenocarcinoma
      Fetal adenocarcinoma
      Enteric adenocarcinoma
      Minimally invasive adenocarcinoma Non-mucinous Mucinous
      Preinvasive lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ Nonmucinous Mucinous
      Squamous cell carcinoma
      Keratinizing squamous cell carcinoma
      Non-keratinizing squamous cell carcinoma
      Basaloid squamous cell carcinoma
      Preinvasive lesion Squamous cell carcinoma in situ
      Neuroendocrine tumors
      Small cell carcinoma Combined small cell carcinoma
      Large cell neuroendocrine carcinoma Combined large cell neuroendocrine carcinoma
      Carcinoid tumors Typical carcinoid Atypical carcinoid
      Preinvasive lesion Diffuse idiopathic pulmpnary neuroendocrine cell hyperplasia
      Large cell carcinoma


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      PLEN02.02 - Revised (8th) Edition of TNM Staging System for Lung Cancer (ID 2042)

      08:15 - 09:45  |  Author(s): R. Rami-Porta

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The changes introduced in the 7[th] edition of the tumour, node and metastasis (TNM) classification for lung cancer derived from the analyses of the International Association for the Study of Lung Cancer (IASLC) database. These analyses were conducted by the members of the IASLC Staging and Prognostic Factors Committee (SPFC) and the biostatisticians of Cancer Research And Biostatistics (CRAB). For the first time in the history of the TNM classification for lung cancer, the 7[th] edition was based on a truly international database of more than 80,000 evaluable patients collected in 45 different sources in 20 countries and treated with all treatment modalities from 1990 to 2000. (1) The changes recommended by the IASLC were accepted by the Union for International Cancer Control (UICC) and by the American Joint Committee on Cancer (AJCC) and were eventually published in their staging manuals. With this involvement of the IASLC in the revision of the TNM classification for lung cancer, the IASLC became the most important provider of data to the UICC and the AJCC for future editions of the classification. A similar process was used for the revision of the 7[th] edition into the 8[th] edition. The IASLC made an international call for submission of more data to the IASLC database. (2) The resulting international contribution amounted to more than 77,000 evaluable patients diagnosed with either non-small cell lung cancer (70,967 patients) or small cell lung cancer (6,189 patients) from 1990 to 2010. They were submitted from 35 different databases located in 16 countries in Europe, Asia, North and South America, and Australia. (3) The different subcommittees of the Lung Cancer Domain of the IASLC SPFC were in charge of analysing the data pertaining to the T, the N and the M component of the classification, as well as the stages and the small cell lung cancer. For the T component, the prognostic impact of the T descriptors was analysed in five different populations: pT1-4N0M0R0, pT1-4anyNM0R0, pT1-4anyNM0anyR, i.e., including incomplete resections, either microscopically incomplete, R1, or macroscopically incomplete, R2; and cT1-4N0M0 and cT1-4anyNM0. Survival analyses were completed with univariate and multivariate analyses adjusted by histological type, gender, region and age. The main results showed that the capacity of tumour size to separate tumours of different prognosis was greater than that shown in previous analyses, and that its influence could be spread to all T categories; the role of visceral pleura invasion as a T2 descriptor was confirmed; the prognostic impact of endobronchial location less than 2 cm from the carina (T3 in 7[th] edition) and of total atelectasis/pneumonitis (T3 in 7[th] edition) was found to be similar to that of their T2 counterparts; diaphragm invasion was found to have worse prognosis than that of other T3 descriptors; and mediastinal pleura invasion was found to be scarcely used as a T descriptor. (4) For the N component, the present N descriptors (N0, N1, N2 and N3) were found to separate tumours of different prognosis in clinically and pathologically (both in the R0 and any R populations) staged tumours. The impact of tumour burden in the lymph nodes could also be assessed when survival was analysed according to the number of nodal stations, but this could only be analysed in the population of patients who had undergone tumour resection and systematic nodal dissection, and could not be validated at clinical staging. (5) For the M component, the 7[th] edition M1a descriptors were validated, as all showed similar survival. However, when the M1b descriptors were analysed in detail, single metastasis (one metastasis in one organ) had better prognosis than multiple metastases in one or several organs. (6) Table 1 shows the changes recommended by the IASLC SPFC based on the analyses of the new IASLC database. The described changes implied some modifications in the stage grouping, creating more stages for early and advanced disease, (7) and were also applicable to small-cell lung cancer. (8) The IASLC recommendations emphasize the prognostic impact of tumour size; simplify the T descriptors by combining some of them; maintain the current N descriptors; separate tumours with single metastasis in a distinct group; and establish more stage groupings to refine prognosis based on anatomic extent of disease. They improve our capacity to indicate prognosis, which is one of the objectives of the TNM classification, and, therefore, they should be implemented in the 8[th] edition of the TNM classification. Table 1

      Descriptor 7th edition 8th edition (recommended classification)
      T component
      T1a T1a
      >1-2cm T1a T1b
      >2-3cm T1b T1c
      >3-4cm T2a T2a
      >4-5cm T2a T2b
      >5-7cm T2b T3
      >7cm T3 T4
      Bronchus <2cm from carina T3 T2
      Total atelectasis/pneumonitis T3 T2
      Invasion of diaphragm T3 T4
      Invasion of mediastinal pleura T3 -
      N component
      No involvement or involvement of regional lymph nodes N0, N1, N2, N3 N0, N1, N2, N3
      M component
      Metastases within the thoracic cavity M1a M1a
      Single extrathoracic metastasis M1b M1b
      Multiple extrathoracic metastases M1b M1c
      References 1. Goldstraw P, Crowley JJ. The International Association for the Study of Lung Cancer international staging project on lung cancer. J Thorac Oncol 2006; 1: 281-286. 2. Giroux DJ, Rami-Porta R, Chansky K et al. The IASLC Lung Cancer Staging Project: data elements for the prospective project. J Thorac Oncol 2009; 4: 679-683. 3. Rami-Porta R, Bolejack V, Giroux DJ et al. The IASLC Lung Cancer Staging Project: the new database to inform the 8[th] edition of the TNM classification of lung cancer. J Thorac Oncol 2014; 9: 1618-1624. 4. Rami-Porta R, Bolejack V, Crowley J et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol 2015;10:990-1003. 5. Asamura H et al. J Thorac Oncol 2015; in preparation. 6. Eberhardt WEE et al. J Thorac Oncol 2015; in preparation. 7. Golstraw P et al. J Thorac Oncol 2015; in preparation. 8. Nicholson AG et al. J Thorac Oncol 2015; in preparation.

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Author of

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    HOD 04 - Highlights of the Previous Day: Biology, Pathology, Molecular Testing, Prevention, Tobacco Control, Screening and Early Detection (ID 236)

    • Event: WCLC 2015
    • Type: Highlights of the Day
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      HOD04.02 - Prevention, Tobacco Control (ID 3416)

      07:00 - 08:00  |  Author(s): S. Novello

      • Abstract
      • Presentation

      Abstract not provided

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    MINI 01 - Pathology (ID 93)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI01.05 - Local Diagnostic Practices for Advanced Non-Small-Cell Lung Cancer in Europe and Japan: ASSESS Study (ID 2629)

      10:45 - 12:15  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background:
      ASSESS (a large, multicentre, non-interventional, diagnostic study; NCT01785888) evaluated local diagnostic practices for patients with advanced non-small-cell lung cancer (aNSCLC) in Europe/Japan.

      Methods:
      Eligible patients: local/metastatic aNSCLC; chemotherapy-naïve, newly diagnosed/recurrent disease after resection; ineligible for curative treatment. We report diagnostic assessments and epidermal growth factor receptor (EGFR) mutation test turnaround times (secondary endpoints) associated with tissue/cytology samples from patients in Europe/Japan.

      Results:
      1311 patients enrolled (300 Japan). Immunohistochemistry (IHC) was used to confirm pathological diagnosis in 727/960 (76%) and 142/146 (97%) patients in Europe and Japan, respectively (where data were available); the following markers were assessed using IHC: TTF-1 (Europe 96% and Japan 79%); p65 (4% and 8%); and p40 (9% and 24%). EGFR mutation tests were not performed on samples from 110 patients and tested samples from 17 patients did not yield results. The most common reason for not testing was insufficient material provided (Europe 60% [47/78 responses]; Japan 56% [5/9 responses]). The percentages of neoplastic cells in samples (data available: Europe n=281; Japan n=20) were: <20% tumour cells: Europe 15% vs Japan 35%; 20–50% tumour cells: 23% vs 45%; >50% tumour cells: 61% vs 20%. Considering sampling methodologies, the most common sampling sites (data available: Europe n=996; Japan n=291) were the lung parenchyma (Europe 73%; Japan 79%) or lymph nodes (Europe 9%; Japan 9%); the most common sample collection method was bronchoscopy (Europe 39%; Japan 68%; Table 1). Median EGFR mutation test turnaround time was longer in Europe (11 days) versus Japan (8 days; Table 2). Mutation test success rates for Europe and Japan were 98.3% and 99.6%, respectively.

      Conclusion:
      Diagnostic assessments, sampling methodologies and EGFR mutation testing practices vary between and within Europe and Japan; further understanding of local practices will drive improvements and enable more patients to receive appropriate personalised treatment. Figure 1 Figure 2





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    MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI16.06 - AZD9291 in Pre-Treated T790M Positive Advanced NSCLC: AURA Study Phase II Extension Cohort (ID 943)

      16:45 - 18:15  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background:
      AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selective for both EGFR-TKI-sensitizing (EGFRm) and T790M resistance mutations. The Phase I AURA study was a dose escalation/expansion study in patients with EGFRm positive advanced non-small cell lung cancer (NSCLC) who had progressed after EGFR‑TKI treatment. The 80 mg once daily (qd) dose was chosen for further evaluation in a Phase II extension cohort of the AURA study, and in an additional Phase II study (AURA2). Here we report efficacy and safety of AZD9291 from the AURA study Phase II extension cohort (NCT01802632) in patients pre-treated with EGFR-TKI and with centrally confirmed T790M positive advanced NSCLC.

      Methods:
      Eligible patients had measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. A mandatory tumor sample was taken after disease progression on the most recent line of therapy, for prospective confirmation of T790M positive status by central laboratory testing (cobas™ EGFR Mutation Test). Patients received AZD9291 at 80 mg qd until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (assessed by independent central review, ICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), investigator-assessed ORR, and safety. Planned enrollment was 175 patients to give an estimate of the ORR with 95% CI within ±8%. Data cut-off was January 9, 2015 after all patients should have undergone the second tumor assessment.

      Results:
      201 patients were dosed in the extension cohort of the study; two patients without measurable disease at baseline by ICR were excluded from the evaluable-for-response set. By central testing, EGFR mutation subtypes were: T790M, 98%; Ex19del, 71%; L858R, 25%; other, 3%. Median age was 62 years; female, 66%; Asian, 57%; WHO PS 0/1/2, 34%/66%/1%; second/≥third-line, 30%/70%. At the data cut-off, median treatment exposure was 4.9 months and 168 patients remain on treatment. ORR by ICR was 58% (115/199; 95% CI 51, 65) and DCR was 92% (95% CI 87, 95). ORRs were similar across lines of therapy (second-line, 59.0% [36/61] vs ≥third-line, 57.2% [79/138]). Investigator-assessed ORR was 68% (137/201; 95% CI 61, 75). Median DoR and median PFS have not been reached (maturity 2% and 21%, respectively). The most common all-causality adverse events (AEs) were diarrhea, 41% (0.5% Gr≥3) and grouped rash terms 37% (0.5% Gr≥3); 42 (21%) patients experienced Gr≥3 AEs. Interstitial lung disease grouped terms were reported in five (2.5%) patients, one of which was fatal (0.5%) and considered possibly causally related to AZD9291 by the investigator. Eight patients (4%) discontinued treatment due to an AE. Updated results from a later data cut-off will be available for presentation.

      Conclusion:
      In the AURA study Phase II extension cohort, AZD9291 80 mg qd demonstrates clinical activity, manageable tolerability, and a low discontinuation rate in patients with centrally confirmed EGFR T790M positive advanced NSCLC that has progressed on or after EGFR‑TKI treatment. These data provide further validation of the results from the Phase I study cohorts.

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    MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      MINI17.07 - Efficacy of Nintedanib/Docetaxel after Bevacizumab, Pemetrexed or Taxanes Therapy (ID 1521)

      16:45 - 18:15  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background:
      Nintedanib is a triple angiokinase inhibitor of receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor and fibroblast growth factor. The randomized, placebo-controlled, Phase III LUME-Lung 1 study (NCT00805194; 1199.13) investigating nintedanib/docetaxel was the first trial of an antiangiogenic agent to demonstrate significant overall survival (OS) benefit in previously treated patients with non-small cell lung cancer (NSCLC) of adenocarcinoma histology; nintedanib/docetaxel is approved in the European Union for the treatment of patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after 1[st]-line chemotherapy. Here we report LUME-Lung 1 data from the adenocarcinoma population who received 1[st]-line chemotherapy containing bevacizumab, pemetrexed or taxanes.

      Methods:
      In LUME-Lung 1, 1314 patients with Stage IIIB/IV recurrent NSCLC received either nintedanib/docetaxel or placebo/docetaxel. Primary endpoint was centrally assessed progression-free survival (PFS); OS was a key secondary endpoint. Prior treatment with anti-VEGF agent bevacizumab was a stratification factor. Analyses of the adenocarcinoma population (n=658) according to prior treatment with bevacizumab (n=45 in either arm), pemetrexed (1[st]-line [n=126] or maintenance [n=27]) or taxanes (n=142) were performed to determine if 1[st]-line regimens could influence subsequent outcomes for nintedanib/docetaxel.

      Results:
      Patient characteristics were generally well-balanced across prior-treatment subgroups. For the adenocarcinoma population, there was no interaction between 1[st]-line treatment with bevacizumab, pemetrexed or taxanes and treatment outcome with nintedanib/docetaxel. Independent of pretreatment, nintedanib/docetaxel-treated adenocarcinoma patients had an OS benefit (Table). In the overall patient population, efficacy outcomes for these subgroups were also similar regardless of prior treatment. Furthermore, there was no significant effect on nintedanib/docetaxel outcomes for the few adenocarcinoma patients who received maintenance pemetrexed. The adverse event (AE) profile for nintedanib/docetaxel in each subgroup was consistent with that reported for the adenocarcinoma population in LUME-Lung 1, with diarrhea and reversible liver enzyme elevations among the more frequently reported AEs. Among patients who received nintedanib/docetaxel, there was no difference between prior-treatment subgroups in the frequency of AEs commonly associated with the prior treatment, such as hypertension with bevacizumab, mucositis with pemetrexed and peripheral neuropathy with taxanes.

      Conclusion:
      In LUME-Lung 1, regardless of whether a patient with NSCLC of adenocarcinoma histology received 1[st]-line chemotherapy containing bevacizumab, pemetrexed or taxanes, subsequent treatment with nintedanib/docetaxel led to improved OS.

      Table: OS results in patients with NSCLC of adenocarcinoma tumor histology stratified by ± prior 1st-line bevacizumab, pemetrexed or taxanes treatment
      No BEV BEV No PEM PEM No TAX TAX
      N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D
      Patients, n 298 315 24 21 261 271 61 65 245 271 77 65
      Median OS, months 12.6 10.6 14.9 8.7 13.4 10.8 12.0 8.0 12.2 10.3 15.1 11.6
      HR (95% CI) 0.85 (0.71–1.01) 0.61 (0.31–1.20) 0.83 (0.68–1.00) 0.79 (0.53–1.18) 0.86 (0.71–1.05) 0.75 (0.51–1.11)
      Interaction p-value p=0.24 p=0.90 p=0.61
      BEV, bevacizumab; CI, confidence interval; HR, hazard ratio; N/D, nintedanib/docetaxel; NSCLC, non-small cell lung cancer; OS, overall survival; PEM, pemetrexed; Pl/D, placebo/docetaxel; TAX, taxanes.

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      MINI17.08 - Tumor Growth Over Time with Nintedanib/Docetaxel or Placebo/Docetaxel in Adenocarcinoma NSCLC: Analysis From the LUME-Lung 1 Study (ID 1405)

      16:45 - 18:15  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background:
      Nintedanib (N; Vargatef[®]), a triple angiokinase inhibitor, is approved in the EU in combination with docetaxel (D) for the treatment of patients with advanced NSCLC of adenocarcinoma histology (ACH) after 1[st]-line chemotherapy. In the randomized, placebo-controlled, Phase III LUME-Lung 1 study (NCT00805194; 1199.13), N+D significantly improved overall survival (OS; secondary endpoint) vs D in patients with ACH (median OS: 12.6 vs 10.3 months (m); HR: 0.83 [95% CI: 0.70–0.99]; p=0.0359) and in patients who progressed either during or within 9 m of 1[st]-line therapy (time[T]<9m) (median OS: 10.9 vs 7.9 m; HR: 0.75 [95% CI: 0.60–0.92]; p=0.0073). We explored the impact of on tumor growth over time as a treatment effect of N+D, with a specific focus on early progressors (T<9m) and patients who had progressive disease as best response to 1[st]-line therapy (PD-FLT).

      Methods:
      Tumor growth was evaluated using all available tumor measurements. Mixed-effects models were used to quantify the non-linear individual relationships between time from randomization and tumor burden, measured as the sum of longest diameter of target lesions (SLD) and assessed by independent central review (RECIST 1.0). Analyses were conducted for the entire population of patients with ACH, T<9m and PD-FLT.

      Results:
      Estimated mean baseline SLD was 82.5 mm in all patients with ACH, 88.3 mm in T<9m and 98.1 mm in PD-FLT. N+D showed a significant reduction of tumor growth over time (p<0.0001) in patients with ACH compared to D. Treatment difference at 6 months (SLD D group – SLD N+D group) for patients with ACH was 9.7 mm. This treatment difference was even more pronounced in the T<9m group (16.8 mm) and in patients with PD-FLT (19.7 mm). Tumor growth over time for N+D showed a non-linear J-shaped curve, indicating a decline in SLD at the beginning of treatment, which was maintained over time followed by a linear increase (see Figure for curves for the T<9m group). This relationship was consistently observed between populations. For patients treated with D, a linear increase in SLD from baseline over time in all ACH patients, T<9m and PD-FLT was observed. Figure 1



      Conclusion:
      In the LUME-Lung 1 study, N+D significantly decreased tumor burden and decelerated tumor growth over time compared to D in all patients with ACH and in the groups of patients with the poorest prognosis.

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    ORAL 04 - Adjuvant Therapy for Early Stage Lung Cancer (ID 99)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
    • +

      ORAL04.03 - Preliminary Results of the International Tailored Chemotherapy Adjuvant Trial: The ITACA Trial (ID 1262)

      10:45 - 12:15  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background:
      In resected early stage (II-IIIA) non-small cell lung cancer (NSCLC) adjuvant chemotherapy improves overall survival but the benefit is limited and pharmacogenomics tailored treatment is a potential way to further improve outcome. A phase III multicenter randomized trial comparing adjuvant pharmacogenomics-driven chemotherapy, based on thymidylate synthase (TS) and excision-repair cross-complementing-1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected Stage II-IIIA NSCLC recently completed patients’ (pts) enrolment (EudraCT #: 2008-001764-36).

      Methods:
      The mRNA ERCC1 and TS expression by qRT-PCR was centrally assessed on paraffin-embedded, post-surgical tumor specimens in all registered pts. Immunohistochemistry (IHC) straining for ERCC1 (using 2 monoclonal antibodies, 8F1 and 4F9) and TS protein expression was also performed. Randomization was stratified by stage and smoking status. Trial was emended on February 2011 to include the 7th staging system. The primary end point of the study 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. Study design was already reported [Novello S et al, JTO 2013; 8 (Suppl 2) P3.12-023].

      Results:
      Enrolment was concluded in August 2014 and at that time all gene expression data were available. Recruitment and gene expression results were completed in August 2014. 386 pts were included in the control arm, 375 in the tailored arm and 41 were excluded as screening failures (14) or are not yet fully evaluable (27). Statistical correlations to compare treatments received, toxicity profiles and pts’ survival data in the tailored and control groups are ongoing. Further data analyses will include the correlation between biomarker ERCC1/TS mRNA and protein expression levels, as well as compare ERCC1-IHC scores with the 2 ERCC1 antibodies. The distribution of some baseline characteristics depending on the molecular profile is shown in Table 1. Figure 1



      Conclusion:
      This trial will provide robust evidence if a tailored therapeutic strategy based on selected gene expression profile may contribute to improve efficacy and to ameliorate toxicity of adjuvant chemotherapy in completely resected early stage NSCLC.

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    ORAL 22 - Moving Beyond a Smoking Related-Cancer to the Young, Never-smokers and Inherited Disease (ID 117)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL22.05 - The Genomics of Young Lung Cancer Study (ID 503)

      10:45 - 12:15  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background:
      Primary lung cancer is increasingly understood as a heterogeneous disease made up of genomically defined subtypes requiring distinct treatment strategies. We hypothesize young age at diagnosis (< 40 years) is a clinical characteristic associated with an increased chance for a targetable genomic alteration. Our ALCMI study prospectively characterizes the somatic and germline genomics of young lung cancer (GYLC). Our goals are to identify a genomically enriched subtype of lung cancer, facilitate delivery of targeted therapy and lay groundwork for further studies of heritable and environmental lung cancer risk factors.

      Methods:
      Accrual opened July 2014. Patients are eligible if they were diagnosed with bronchogenic lung cancer less than age 40. A study website allows for virtual consenting so patients can participate remotely from anywhere in the world; and use social media to share our trial. We have an integrated data and bio repository that allows for seamless communication and completion of study activities like remote consenting and routing of blood and tumor specimens. We have defined 7 genomic alterations of interest based on the Lung Cancer Mutational Consortium (LCMC) (EGFR, KRAS, HER2, BRAF, ALK, ROS1, RET). We aim to demonstrate that the prevalence of targetable genomic alterations will be greater in our population compared to the LCMC and have powered our study to show an increase from 35% to 50%; and an improvement in use of targeted therapy from 22% to 40%. On study subjects without a known genotype will undergo comprehensive genomic profiling with the FoundationOne test to ensure that all of these genes have been tested. Subjects with advanced adenocarcinoma who are wild type for all 7 genes will receive additional genomic profiling using the FoundationOne Heme test; with the goal of identifying novel oncogenic drivers. Additional investigational genomics will include blood for germline analysis and plasma genomics. All on study genomic analysis is at no cost to the participant.

      Results:
      Preliminary results of the first 33 subjects show: Average age at diagnosis: 33 years; Range 22-39; Histology: adenocarcinoma n=29, squamous cell n=4; Stage at diagnosis: stage 4 n=26 (79%) stages 1-3 n=7 (21%). Of those with stage 4 adenocarcinoma (n=24); 18:24 (75%) have either an ALK re arrangement n=10 (42%), an EGFR activating mutation n=5 (21%) or a ROS1 fusion n=3 (13%).

      Conclusion:
      The trial is currently accruing (NCT02273336) https://www.openmednet.org/site/alcmi-goyl. We have accrued patients from the USA, Europe and Australia. Thus far in our prospective series those diagnosed with primary NSCLC < age 40 tend to have stage 4 adenocarcinoma. Preliminary results exceed our statistical expectation with 75% of our metastatic adenocarcinoma patients having an actionable mutation. We plan on presenting data for the first time at WCLC-2015 on the first 50 subjects. (Study, supported by grants from BJALCF, Beth Longwell Foundation, Peter Barker Foundation, Genentech, Schmidt Legacy Foundation, and Upstage Lung Cancer)

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    ORAL 27 - Care (ID 123)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Advocacy
    • Presentations: 1
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      ORAL27.02 - Patients' Attitudes and Physicians' Perceptions Toward Maintenance Therapy for Advanced NSCLC: A Multicenter Italian Survey (ID 1448)

      10:45 - 12:15  |  Author(s): S. Novello

      • Abstract
      • Presentation
      • Slides

      Background:
      Pemetrexed maintenance therapy (MT) after induction with platinum-based chemotherapy plus pemetrexed has recently become a concrete strategy of treatment for advanced non-squamous NSCLC patients, by extending survival, delaying disease progression, and maintaining quality of life. However, the benefit of the MT has to be weighed against the potential burden of a long-term treatment, and thus patients’ perception and preferences should be taken into account in the definition of the strategy of treatment.

      Methods:
      After conducting a focus group with 8 physicians dealing with NSCLC and concerning their opinions about the MT from a clinical and emotional point of view, a 12 questions-anonymous survey has been carried out in 13 Italian Oncologic Institutions and supported by WALCE (Women Against Lung Cancer in Europe), with the aim to evaluate patients' attitude toward the MT, the benefit they expected and to provide data about physicians awareness about patients’ inclinations. The Distress Thermometer Questionnaire has also been employed to perform a bio-psycho-social-spiritual assessment of the evaluated patients. Patients' evaluations have been performed at the beginning of chemotherapy (T0) and at the beginning of MT (T1), while physicians fill the survey only once during the study.

      Results:
      The survey has been prospectively (1st of December 2014-28th of February-2015) administered to 92 newly diagnosed advanced non-squamous NSCLC patients (58,7% male, median age 63,9 years), EGFR wilde-type, consecutively enrolled and suitable for first-line platinum/pemetrexed-based chemotherapy, and to 37 referring physicians (equally distributed per gender, with median age 41 years). To date, after platinum-based induction chemotherapy (median number of cycles 3,3, equally distributed between cisplatin and carboplatin), 24 of 92 patients enrolled (26,1%) have already started the pemetrexed MT. Main results are shown in Table 1. Most of the patients (73,9%) are in favor of MT. Until life expectation is over 3 months, data show agreement between patients' and physicians' perceptions of patients. When OS benefit drops at 1 month the two perceptions split: a lower percentage of patients (44,5%) would perform MT. By contrast, even without OS benefit, 71,3% of patients accept MT if it can increase symptom control. Figure 1



      Conclusion:
      Study is ongoing and data about T1 evaluations are still immature. Our preliminary data suggest the importance, when MT communication is done by the referral physician, to stress more symptoms control rather than survival rates.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      P1.01-044 - Cost-Effectiveness of Chemotherapy Based on the Tumor Genetic Profile in Elderly Patients with Advanced Non-Small-Cell Lung Cancer (ID 1656)

      09:30 - 17:00  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background:
      Platinum-Based chemotherapy is still the cornerstone in the treatment of Non-Small Cell Lung Cancer (NSCLC), in non oncogene-addicted patients (pts). Therapeutic algorithm is established on the basis of patient and disease characteristics, such as histology and radiologic features. Pharmagenomic-driven trials are investigating the role of different markers in predicting efficacy and toxicity in NSCLC pts. A better selection of a right therapy for the right patient would improve outcomes ameliorating tolerability and optimize the resources available. The aim of the present study is to carry out a cost-effectiveness analysis, in order to evaluate the economic efficiency of 1st line chemotherapy within a clinical trial (EPIC eudract N 2012-001194-81), in elderly pts affected from advanced NSCLC, looking at efficacy and tolerability.

      Methods:
      The study population consisted in Elderly Patients Individualized Chemotherapy (EPIC) trial enrolled at San Luigi Hospital (Orbassano-Italy, coordinating centre) from July 2012 to August 2014. Main recruitment criteria: chemotherapy-naïve pts diagnosed with stage IV NSCLC, aged≥70 years, no activating EGFR mutations. We evaluated 48 pts randomised (2:1 ratio) to receive pharmacogenomics-driven chemotherapy assessed according to the genetic profile of primary tumours based on expression of ERCC1, RRM1 and TS evaluated by “Real-Time PCR” (arm A) or standard chemotherapy (arm B). Costs of treatments were calculated using National Health System (NHS) direct costs and 12 months time-horizon. Effectiveness was estimated as Progression Free Survival (PFS). The Incremental Cost-Effectiveness Ratio (ICER) was calculated and pharma-economic analysis was performed setting the Willingness To Pay (WTP) threshold value at 40,000€ per free-disease month gained. The reliability of results was assessed by a probabilistic sensitivity analysis based on “Monte Carlo” method (10,000 simulations) changing the costs and effectiveness variables simultaneously. Number and grade of adverse events were used to determine the tolerability profile.

      Results:
      The average cost per patient was 10,278.38€ (arm A) and 8,659.53€ (arm B). Related ICER was 4,496.80€ per free-disease month gained and 53,961.73€ per year gained (over the WTP threshold). The scatterplot generated in the sensitivity analysis indicated that higher densities of ICERs, calculated for each simulation, took place at the cross over of the Cartesian axes indicating that there is no clear prevalence of treatment cost-effectiveness. Moreover, the Cost-Effectiveness Acceptability Curve (CEAC) was calculated. This curve demonstrated that treatment A had 35% of probability to be cost-effectiveness.

      Conclusion:
      This preliminary evaluation, conducted in a subgroup of pts, suggests the relevance of pharmacoeconomic analysis within a clinical trial looking at the best way to identify a tailored treatment in non-oncogene addicted NSCLC pts. Further data will be collected in a larger simple size. Personalised chemotherapy is a potential method addressing both the optimisation of the effectiveness of therapeutic agents and the minimisation of adverse events, objectives even more relevant for elderly and fragile patients, given the possibility to optimize the use of scarce resources available.

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      P1.01-086 - TIGER-3: A Phase 3 Open-Label, Randomized Study of Rociletinib vs Chemotherapy in NSCLC (ID 949)

      09:30 - 17:00  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background:
      Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) that has demonstrated efficacy against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X, a Phase I/II dose-ranging trial, has provided evidence that rociletinib is associated with durable response and is well tolerated in patients with NSCLC and positive T790M status following progression on a TKI.[1 ]Efficacy has also been noted for patients with T790M negative status in TIGER-X.[2] TIGER-3 is designed to investigate single agent rociletinib vs chemotherapy in patients who have failed EGFR therapy and platinum-based doublet chemotherapy, which is a setting of acquired resistance and high unmet need for targeted therapeutic options. TIGER-3 will evaluate patients with T790M positive and negative status based on tumor biopsies and plasma, and biomarkers of response and/or resistance.

      Methods:
      Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC, with radiological progression on the most recent therapy will be enrolled in this phase 3, randomized, open-label study (NCT02322281). Patients must have documented evidence of a tumor with ≥1 EGFR activating mutations excluding exon 20 insertion, and prior treatment with an EGFR TKI and platinum-containing doublet chemotherapy. Patients will be randomized 1:1 to receive rociletinib twice daily (500 mg) or single agent cytotoxic chemotherapy (investigator choice specified before randomization) until disease progression according to RECIST 1.1. Patients will be stratified by presence or absence of brain metastases, ECOG performance status (0 vs 1), and race (Asian vs non-Asian). The primary endpoint is progression-free survival (PFS). Secondary endpoints include safety, objective response rates, duration of response, disease control rate, and overall survival. Kaplan-Meier methodology will assess time to event variables. The stratified log-rank and the hazard ratio will be used for comparing PFS distributions. Serial assessment of safety will be carried out based on standard adverse event reporting. Planned enrolment is 600 patients; enrolment has been open since March 2015. Sequist LV J Clin Oncol. 2014 Soria J-C EORTC-NCI-AACR 2014

      Results:
      Not applicable

      Conclusion:
      Not applicable

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-104 - Lung Cancer Patients Derived Xenografts: Prospective Molecular Profiling and Potential Evaluation of Drug Resistance (ID 1278)

      09:30 - 17:00  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background:
      The discovery of “driver mutations” such as the Epidermal Growth Factor Receptor (EGFR) and the Anaplastic Lymphoma Kinase (ALK) has led to a remarkable improvement in the outcomes of lung adenocarcinoma, which accounts 50% of the non-small cell lung cancer (NSCLC) diagnoses. Up today, no druggable molecular targets have been identified for squamous carcinoma or small cell lung cancer, which are still treated with the “one-fits-all” therapeutic approach, as it is for a relevant percentage of adenocarcinomas too. The precise definition of molecular profile and, possibly, the description of predictive factors are research priority in the thoracic oncology field. The vast majority of preclinical data are based on in vitro studies, but cell lines models do not entirely reflect tumour characteristics and are hampered by genetic divergence from primary tumours. Patient derived tumour xenografts (PDTX) are a valuable alternative to closely reproduce tumour biology and to prospectively characterize in vivo mechanisms of cancer growth and therapeutic response. Through the generation of a cohort of lung cancer xenopatients, the project aims to confirm the reliability of such models in this disease and to prospectively characterize its biomolecular features.

      Methods:
      Metastatic and early stages lung cancer cases are considered for the enrolment. Written informed consent is requested from each patient. Fresh tumour tissue from lung biopsies or lung resections is collected and kept in serum free medium (4° C), embedded in 20% matrigel and subcutaneously engrafted into NSG and NOD SCID mice, within 24 hours from sample collection. The exponentially growing tumours are passaged subcutaneously to other mice for a second passage after which they are archived for subsequent analyses (formalin fixed, snap frozen and RNA later). Each sample from surgical resection is also stored to create a DNA lung cancer bank.

      Results:
      Fourteen samples from TC-guided lung biopsies and sixty-six from radically resected NSCLC were engrafted in NSG and NOD SCID mice lineage in a 1:1 ratio. Due to the low engraftment rate and high morbidity observed in NGS mice in the first 73 samples, subsequent engraftments and expansions were performed in NOD SCID mice only. The overall engraftment rate in biopsy samples was 0 % in NGS and 7.14 % in NOD SCID mice as opposed to 0 % in NGS and 27,27 % in NOD SCID for surgical samples (50% adenocarcinomas, 44,45% squamous carcinomas and 5,55% sarcomatoid carcinomas). Nineteen samples underwent the second passage: of those, 10 samples have been archived after the second successful passage and will be used for further analyses.

      Conclusion:
      The trial is still ongoing and a longer follow-up is needed. In biopsy-derived samples, engraftment is deeply limited by the paucity of tissue. The results of this study will possibly confirm the reliability of PDTX in lung cancer and provide prospective biomolecular characterization for different histological types.

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    P1.05 - Poster Session/ Prevention and Tobacco Control (ID 215)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Prevention and Tobacco Control
    • Presentations: 1
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      P1.05-005 - Italian Multicentric Survey on Smoking Cessation in Lung Disease Patients and the Role of Healthcare Workers in This Contest (ID 1343)

      09:30 - 17:00  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background:
      Smoking is a risk factor for several lung diseases. Quitting smoking provides positive outcomes and gives the best chance for the treatment in patients with pulmonary diseases, including lung cancer diagnoses. Currently few centers in Italy offer counseling for smoking cessation in cancer patients (and for patients with other lung diseases), despite the demonstrated efficacy of it.

      Methods:
      408 patients with pulmonary diseases (72% with lung cancer) were prospectively and sequentially evaluated from January 2013 to February 2015. An anonymous survey was developed with the aim to understand if current or former smoker patients received information by healthcare workers about smoking cessation before or after the diagnosis, their reaction and the actions adopted for quitting smoking. The survey included the Fagerström test for assessing the intensity of addiction to nicotine and it was conducted in several Italian Thoracic Oncology Units and Pulmonology Divisions.

      Results:
      After a pulmonary disease diagnosis, 72% of patients state to quit smoking, 20% to smoke less or not feel the same pleasure as before and only 8% confirms to continue to smoke or smoking even more. Among former smokers (298 people), 150 patients state how long they quitted smoking and in 45% of the cases was at the time of diagnosis or even later, about 35% 10 years before the diagnosis and 8% between 5 and 10 years earlier, while 12% more recently. Most of current smokers state that they continue because smoking helps them to control the stress, others because they like it or are not able to quit and very few because is a repetitive gesture. Data show that 39% of patients did not receive information about smoking cessation by health professionals, 26% received it before the diagnosis, 12% after it and 23% received it both before and after the diagnosis. Concerning the reaction to the counseling, 53% considers positively the health care provider action, even if 28% hoped they could have helped them more quit smoking and 19% reports a warning and paternalistic attitude of them. Only 23% of patients who attempted to quit smoking considers the gradual termination as the most effective measure, more than the sudden interruption. Regarding the smoking-cessation method or specific therapy adopted, 65% disclosed they simply quitted smoking overnight and 80% confirmed it as the most effective technique, while only 16% used electronic cigarettes, 8% a nicotine replacement treatment, 7% books and 4% attending a dedicated clinic. The Fagerström Test confirms that 50% has a low to moderate dependence to nicotine, while 50% has a high dependence.

      Conclusion:
      The survey was distributed to 293 lung cancer patients and 115 with pulmonary disease (mainly COPD patients). The result analysis underlines that the vast majority quitted smoking after having received their diagnosis. No main differences were seen evaluating the group with malignant and non-malignant diseases. Although many of them got advice by healthcare workers, the recourse to the use of techniques, drugs or access to specific clinic is still very low, especially considering that 50% of patients result highly dependent to nicotine.

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    P1.10 - Poster Session/ Advocacy (ID 228)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Advocacy
    • Presentations: 1
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      P1.10-005 - Immunotherapy, What Lung Cancer and Melanoma Patients ...and Physicians, Know (ID 1058)

      09:30 - 17:00  |  Author(s): S. Novello

      • Abstract

      Background:
      Advances in the understanding of the role of the immune system in tumor immune-surveillance have led in the last few years to the development of a series of new drugs rapidly affirmed as new paradigm of treatment for certain cancers, like advanced melanoma. The recent re-evaluation of the immunogenicity of Non-small Cell Lung Cancer (NSCLC) has opened a new field of research, with a new attempt to apply immunotherapy also to this disease.

      Methods:
      A 9 question-anonymous survey has been carried out by AIOM (Associazione Italiana di Oncologia Medica) and supported by WALCE (Women Against Lung Cancer in Europe) with the purpose to investigate patients’ knowledge about the immunotherapy, their expectations in terms of toxicity and efficacy, but also to evaluate how much physicians are becoming confident about the immunotherapy and their expected impact on daily clinical practice. The survey has been distributed, between 10th of November 2014 and 19th of March 2015, to 77 NSCLC patients (prevalently men and over 60 years old) and 89 melanoma patients (equally distributed for gender and age) within various Italian Oncologic Units. A similar electronic survey has been filled out by 128 and 68 physicians dealing with NSCLC and Melanoma, respectively, who reported to employ immunotherapy in their clinical practice in 55% and 74% of cases, respectively, and to have participated into clinical trials with immunotherapy in 39% and 41% of cases.

      Results:
      Patients' knowledge and expectations about immunotherapy resulted to be extremely heterogeneous. Only 19% of NSCLC patients, compared to 73% of melanoma patients, declared to have performed immunotherapy in their clinical history. Main results about patients' perception about immunotherapy are shown in Table 1. NSCLC and melanoma physicians globally reported a positive attitude for this new kind of treatment, postulating a general improving of their clinical practice in the next future (88% and 99% of cases, respectively). They have speculated a non-limiting toxicity profile of this drugs in 77% and 76% of cases, respectively. Figure 1



      Conclusion:
      Although the role of immunotherapy for NSCLC treatment, as already happened for melanoma in the past few years, still need a confirmation by the results of the ongoing clinical trials, patients and physicians widely express great expectation on this kind of treatment, waiting for a large anti-cancer efficacy together with a low toxicity.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      P2.01-090 - A Phase 2, Single Arm Study of Lucitanib in Patients with Advanced/Metastatic Lung Cancer and FGF, VEGF, or PDGF-Related Genetic Changes (ID 2878)

      09:30 - 17:00  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background:
      Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors A/B (PDGFRA/B). Clinical activity was observed in a phase 1/2 study of lucitanib monotherapy in cancer patients with tumor amplification of FGF-related genes or in tumors with predicted sensitivity to VEGF inhibitors. Genomic evidence of FGF, VEGF or PDGF axis aberrancy is seen in up to 15% of patients with lung cancer, which provides a strong rationale to assess lucitanib in this setting.

      Methods:
      The current study evaluates daily oral lucitanib monotherapy in 40 patients with amplification or activating mutations in FGF, VEGF or PDGF-related genes. This is an international, multicenter, open-label, single-arm study. The primary endpoint is objective response rate (ORR; RECIST 1.1) with secondary endpoints of response duration, clinical benefit rate, progression-free survival, and safety. Exploratory objectives include volumetric assessment of tumor growth kinetics, serial circulating tumor DNA measurement, and identification of additional biomarkers of lucitanib activity. Key inclusion criteria include: patients with advanced/metastatic non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) or large cell lung cancer and tumor tissue evidence of relevant genomic aberrancies. Patients must have measurable disease and at least one previous treatment for advanced disease. Key exclusion criteria include: carcinoid histology, symptomatic CNS metastases, anti-cancer treatment for lung cancer within 28 days or 5 half-lives before first dose of lucitanib. This study is enrolling patients in the United States and Europe at centers skilled in the identification of patients with relatively uncommon genetic tumor alterations.

      Results:
      not applicable

      Conclusion:
      not applicable

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      P2.01-096 - Randomized, Double-Blind, Placebo-Controlled Trial of Evofosfamide (TH-302) in Combination with Pemetrexed in Advanced ns-NSCLC (ID 659)

      09:30 - 17:00  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background:
      Tumor hypoxia is associated with chemo- and radioresistance and is a prevalent characteristic in tumors of patients with non-small cell lung cancer (NSCLC). Evofosfamide (previously known as TH-302) is a hypoxia-activated prodrug designed to release the bis-alkylating DNA crosslinker bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. In a Phase 1/2 study (NCT00743379) that included a single arm evofosfamide in combination with pemetrexed in 18 patients with relapsed/refractory non-squamous NSCLC, median PFS was 7.0 months and median OS was 14.9 months. Response in 15 evaluable patients: 6 partial responses (4 confirmed), 6 stable disease and 3 progressive disease. The most common adverse events were fatigue, anemia, stomatitis and nausea.

      Methods:
      An international, multicenter, randomized, double-blind, placebo-controlled trial was initiated to evaluate evofosfamide in combination with pemetrexed versus placebo and pemetrexed as a potential second-line treatment for patients with non-squamous NSCLC (NCT02093962). Approximately 440 patients will be enrolled with histologically confirmed stage IIIB or IV NSCLC with non-squamous histology, measurable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients have recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance. EGFR-activating and ALK rearrangements status must be known, and if identified, patients must have received a targeted kinase inhibitor. Evofosfamide (400 mg/m[2]) or matched placebo is administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m[2]) is administered by IV infusion 2 to 4 hours after evofosfamide administration on Day 1. Overall survival (OS) is the primary endpoint; secondary endpoints include safety, progression-free survival and RECIST response rate. The study design has 85% power to detect a 40% improvement in OS with a one-sided alpha of 0.025. The first patient was enrolled in June 2014; recruitment is ongoing.

      Results:
      not applicable

      Conclusion:
      not applicable

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 3
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      P3.04-015 - Immunohistochemistry With 3 ALK Antibodies and Thymidylate Synthase Evaluation of FISH-Positive ALK-Rearranged Lung Adenocarcinomas (ID 1430)

      09:30 - 17:00  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background:
      ALK-rearranged lung tumors represent approximately 2-7% of all Non-Small-Cell Lung Cancers (NSCLCs). Young age, never/light smoking habit, adenocarcinoma (ADK) histology and good response to chemotherapy with pemetrexed characterize ALK-positive patients (pts). Current treatment strategies in this molecular setting are based on ALK-kinase inhibition with small molecules including first (crizotinib/CZT) and second generation TKIs. The FDA-approved companion diagnostic test for CZT treatment is the Vysis break-apart FISH probe, but several works support the immunohistochemistry (IHC) as a sensitive and specific test. The European Medical Agency (EMA) recently approved CZT for second-line treatment of ALK-rearranged NSCLC as detected by "an accurate and validated ALK assay", thus endorsing IHC for eligibility purposes. Here, we retrospectively assessed ALK status in 28 pts with known FISH-positive ALK-rearranged NSCLC performing IHC with 3 different antibodies in order to assess their diagnostic accuracy as compared to the FISH assay. Moreover, we evaluated thymidylate synthase (TS) expression using real-time polymerase chain reaction (RT-PCR) given the conflicting literature data on pemetrexed sensitivity in those tumors. As a secondary end point we will compare molecular and clinical outcomes.

      Methods:
      FISH was performed with Vysis break-apart FISH probe. IHC was performed with 3 different antibodies: ALK1 (DAKO), 5A4 (Novocastra) and D5F3 (Ventana/Cell Signaling Technology). For ALK1 and 5A4 an IHC scoring value between 0+ and 3+ was used, as previously proposed, while a positive or negative score was used with D5F3 and Ventana KIT. TS gene expression was measured through Real Time PCR, TaqMan method.

      Results:
      28 specimens of ALK-rearranged ADK diagnosed between 2010 and 2013 from 7 different Italian Oncology Centres were evaluated. Pts median age at diagnosis was 55 (range: 25-78), 9 pts were female. 25/28 (89.3%) specimens were D5F3 positive. 13/28 (46.4%) had 5A4 3+ positivity, 12 (42.8%) showed 2+ positivity while the remaining 3 were negative. 3/28 specimens (10.7%) had ALK1 3+ score, 9 (32.1%) 2+, 13 (46.5%) 1+ and the remaining 3 (10.7%) were negative. Among the 3 FISH-positive and IHC-negative cases, 2 pts underwent CZT treatment, both progressing within 2 weeks and with low percentage of rearranged tumor cells at FISH testing (16-20%) When considering 3+ and 2+ scores as positive, 12 specimens (42.8%) resulted to be positive with all the 3 antibodies, while score 1+ was observed only with ALK1 in 13 (46.4%). Only 3 cases resulted strongly positive with all clones. TS gene expression median value on 25 cases was 6.27 (range 2,8-14-94). 65% of cases had low expression as compared to a population of ALK-negative lung ADK (personal data).

      Conclusion:
      IHC proved to be a reliable tool to diagnose ALK-rearranged lung tumors, especially with D5F3 and 5A4 antibodies. As the two IHC negative and FISH positive patients who received CZT didn’t respond to treatment, IHC should be used as screening tool or a confirmatory test in case of low-rearranged FISH-positive cases. TS expression appeared to be lower in ALK-positive lung tumors as compared to ALK-negative lung ADK. Further comparisons between clinical and molecular data are ongoing.

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      P3.04-053 - SPECTAlung: Screening Patients with Thoracic Tumors for Efficient Clinical Trial Access (ID 1386)

      09:30 - 17:00  |  Author(s): S. Novello

      • Abstract

      Background:
      The identification of molecular alteration and its targeting has completely changed the treatment and prognosis of lung cancer. However, designing and implementing clinical trials in small subsets of patients with a particular molecular alteration is challenging because of lack of uniform screening program. Across Europe, screening for molecular alterations is center or country dependent and, generally limited to a small subset of genes. SPECTAlung is the first European standardized, quality-assured molecular screening program of the European Organization for the Research and Treatment of Cancer (EORTC) in collaboration with the European Thoracic Oncology Platform (ETOP) to facilitate clinical trial access for patients with thoracic tumors. It is expected to test 500 to 1000 patients each year with the overall goal of offering patients clinical trials with targeted agents.

      Methods:
      Patients sign the informed consent for their tumor tissue to be collected, centralized and processed according to defined international quality control standards at Gustave Roussy Biobank (Villejuif, France). Next Generation Sequencing (NGS) is performed at Sanger Institute (Cambridge, UK) where a panel of about 360 genes is analyzed for mutation, rearrangements and gene copy number. Eligible patients will be those having a pathological diagnosis of any thoracic tumor (lung cancer, malignant pleural mesothelioma and thymic malignancies) at any stage of disease, availability of tumor tissue, age at least 18 years, PS 0-2, life expectancy > 3 months, no active malignancy in the 5 years before study entry and absence of any exclusion criteria that may prevent inclusion into clinical trials. A molecular report will be released to the investigator highlighting identified molecular alterations and also the trials for which the patients might be eligible. The study has been submitted to ethical committees of 15 selected highly specialized and qualified thoracic centres in 12 countries in Europe. EORTC and ETOP will promote the implementation of clinical trials in molecularly selected groups of patients at the SPECTAlung centers. SPECTAlung offers innovative and attractive models of collaboration with commercial and research organizations, by improving patient access to novel therapeutic clinical trial and support the development of personalized medicine. Clinical trial registry number NCT02214134.

      Results:
      Not applicable

      Conclusion:
      Not applicable

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      P3.04-060 - Non Small Cell Lung Cancer in Women: Identification of Molecular Biomarkers Towards Sex Specific Tailored Treatments (ID 1272)

      09:30 - 17:00  |  Author(s): S. Novello

      • Abstract
      • Slides

      Background:
      Lung cancer is the leading cause of cancer mortality in both men and women in more developed countries, with a four-fold increase in lung cancer in women in US over the past 30 years. This was confirmed in Europe where, in the last 5 years, lung cancer mortality fell in men (−6%) and increased in women (+7%). Several studies documented sex differences in lung cancer in terms of clinical presentation, survival, pathological patterns and treatment related toxicities; younger age at diagnosis, higher frequency of adenocarcinoma histology, different metabolism of tobacco-related carcinogens, differential gene expression are commonly seen in women. Furthermore, previous studies showed in female gender the expression of functional aromatase enzyme in lung tumor tissues as well as the interaction between Estrogen Receptors (ERs) and Epidermal Growth factor Receptor (EGFR) pathways in lung cancer cells. The aim of this study is to collect a prospective series of advanced stage non small cell lung cancers (NSCLC), to identify, through the Next Generation Sequencing (NGS) technology, potential gender sex differences of selected tumor-associated genes, assessing their both mutational status and gene expression levels.

      Methods:
      One hundred patients, including 50 women and 50 men, with newly diagnosed stage IV NSCLC will be prospectively enrolled. Smoking history, clinical and anamnestical data will be collected for all patients. Female patients will also provide obstetrical-gynecological anamnesis, while men will provide urological one, if present. Formalin fixed, paraffin embedded diagnostic sample of each patient will be collected and sectioned to obtain: a DNA genomic library to define the mutational profile of a selected panel including 50 tumor-associated genes, a mRNA library to obtain gene expression levels of the corresponding transcripts and protein expression of estrogen receptor Beta (ERß) and DNA repair enzyme ERCC1. Immunohistochemistry reaction, for both ERCC1 and ERβ, will be scored according to the H-score method. NGS analyses will be performed by means of the Ion Torrent Personal Genome Machine (PGM, Life Technologies, Grand Island, NE). Tumor tissues will be tested with commercial library kits: Ion AmpliSeq Cancer Hotspot Panel v.2 to investigate 50 cancer-associated genes and significant gene variations will be further confirmed using Sanger Sequencing method; Ion AmpliSeq™ RNA Cancer Panel to define also gene expression of the same 50 cancer-associated genes (Life Technologies). Correlations among mutational profile, transcriptional pattern, protein levels and clinico-pathological characteristics will be assessed.

      Results:
      Not Applicable

      Conclusion:
      Lung cancer incidence in women is increasing worldwide and genetic predisposition, sex hormones or specific molecular features could all account for the clinical differences observed between females and males. Up to the current date, the clinical approach to lung cancer treatment does not rely on gender. The identification of differential status of specific biomarkers can deepen knowledge on the molecular basis of this disease, guiding clinicians towards sex-based treatments.

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    PRC 03 - Press Conference 3 (ID 198)

    • Event: WCLC 2015
    • Type: Press Conference
    • Track: Other
    • Presentations: 1
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      Daily Theme: Lung Cancer: A Women's Disease - Dr. Silvia Novello, Associate Professor, Department of Oncology, University of Turin-Italy (ID 3625)

      09:45 - 10:45  |  Author(s): S. Novello

      • Abstract
      • Presentation

      Abstract not provided

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    YIS - Young Investigator Session incl. Q & A with Longstanding IASLC Members (ID 238)

    • Event: WCLC 2015
    • Type: Young Investigator Session
    • Track: Other
    • Presentations: 1
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      YIS.06 - Making the Most of the WCLC: A Guide for First Time Attendees (ID 3516)

      07:30 - 11:00  |  Author(s): S. Novello

      • Abstract
      • Slides

      Abstract not provided

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