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N. Pavlakis

Moderator of

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

    • Event: WCLC 2013
    • Type: Pro/Con Session
    • Track: Medical Oncology
    • Presentations: 5
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      PC02.0 - N/A - Chair Intro (ID 627)

      • Abstract

      Abstract not provided

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      PC02.1 - Introduction: Detection of EGFR Mutations (ID 628)

      F. Hirsch

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PC02.2 - Pro: Patients with EGFR Mutations Should Receive Adjuvant EGFR TKIs (ID 629)

      K. Nakagawa

      • Abstract
      • Presentation
      • Slides

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

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      PC02.3 - Con: Patients with EGFR Mutations Should Not Receive Adjuvant EGFR TKIs (ID 630)

      C.K. Liam

      • Abstract
      • Presentation
      • Slides

      Abstract
      Adjuvant therapies are required to prevent disease recurrence and improve patient survival after surgery in early stage (stage I–IIIA) non-small cell lung cancer (NSCLC). In advanced disease, patients whose tumours have activating EGFR mutations have an approximately 60%-75% response rate to EGFR tyrosine kinase inhibitors (TKIs) treatment as first-line therapy and a progression-free survival that is significantly superior to standard chemotherapy. Although adjuvant TKI therapy is an appealing treatment strategy, can the remarkable efficacy of EGFR TKI in advanced EGFR-mutant NSCLC be extrapolated to stage I-IIIA disease? While adjuvant cisplatin-based chemotherapy prolongs survival with just 3-4 months of treatment, no trial to date has studied the value of a few months of adjuvant EGFR TKI. The phase III BR.19 trial by the National Cancer Institute of Canada designed to study 1,160 patients with fully resected stage IB, II and IIIA NSCLC randomised to receive 2 years of adjuvant gefitinib at 250 mg daily or 2 years of adjuvant placebo was greatly underpowered because enrolment was stopped prematurely when, in 2008, the SWOG 0023 investigators reported a worse overall median survival with maintenance gefitinib after definitive chemoradiation in a patient population not enriched for the presence of EGFR mutations with inoperable stage III NSCLC. EGFR mutation status was tested post-hoc in two thirds of 537 patients enrolled. There was no overall survival (OS) benefit for adjuvant gefitinib over placebo (HR 1.58; 95% CI, 0.83 - 3.0; P = 0.16) in 76 patients with EGFR mutant tumours. Despite an underpowered study, the negative finding should caution us about recommending adjuvant EGFR TKI therapy outside of a protocol setting. The phase III Randomized, Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT) compares 2 years of adjuvant erlotinib, at 150 mg orally per day, to 2 years of placebo following complete resection of stage I-IIIA NSCLC in 945 patients who were selected based on having either EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by FISH. At the 2009 ASCO meeting, the RADIANT investigators presented the results of the biomarker analyses from the first 655 patients enrolled which showed an EGFR mutation-positive rate of 12%, which suggests that in the final result there will be approximately 38 EGFR mutation-positive patients on the placebo arm and about 76 on the erlotinib arm. This study is unlikely to provide sufficient power to a draw a firm conclusion about genotype-directed adjuvant therapy for patients with EGFR mutations. Investigators from the Memorial-Sloan Kettering Cancer Center reported a retrospective series of 167 patients at their centre with resected stages I-III NSCLC which were EGFR mutation-positive, among whom 32% received adjuvant EGFR TKI therapy. An improved 2-year disease-free survival (DFS) was observed in patients who received adjuvant TKI therapy compared to those who did not (89% vs 72%) (HR, 0.53; 95% CI, 0.28 - 1.03; P = 0.06). A trend toward more favorable 2-year OS in recipients of EGFR TKI therapy was also seen (96% vs 90%; HR 0.62, CI 0.26-1.51, P = 0.296). When the number of patients with resected EGFR mutant lung cancers was increased to 222, the same investigators in a more recent publication, showed treatment with adjuvant erlotinib or gefitinib was associated with a lower risk of recurrence or death, DFS HR 0.43 (95% CI: 0.26-0.72, P = 0.001), and a trend toward improved OS. The phase II SELECT (Surgically resected EGFR-mutant Lung cancer with adjuvant Erlotinib Cancer Treatment) trial is a single-arm, prospective study of two years of adjuvant erlotinib in 100 patients with resected, state IA to IIIA EGFR mutation positive NSCLC. Preliminary results presented at the 2012 ASCO meeting for the first 36 patients showed a DFS of 94% compared to a historical control of 70% with a median follow-up of 2.7 months. The answer provided by the SELECT trial is also unlikely to be definitive. The phase II/III Tailored Post-Surgical Therapy in Early Stage NSCLC (TASTE) trial by the French Collaborative Intergroup compares 4 cycles of standard cisplatin/pemetrexed (CP) adjuvant chemotherapy (arm A, n = 74) with customised adjuvant treatment (arm B, n = 76) based on EGFR and ERCC1 status in patients with completely resected stage IIA, IIB or IIIA (non-N2) (6[th] TNM edition) nonsquamous NSCLC. In the experimental arm, EGFR mutated patients received erlotinib 150 mg for one year. ERCC1 negative pts received four cycles of CP. EGFR mutation was identified in only 10 patients (3 in arm A, 7 in arm B). All 7 patients with EGFR mutation in arm B received erlotinib for a median duration of 276 days. The phase III was cancelled due to the unexpected unreliability of the ERCC1 immunohistochemistry read-out. Two randomised studies comparing gefitinib 250 mg daily for 2 years with adjuvant chemotherapy (4 cycles of cisplatin/vinorelbine) in patients with surgically resected stage IIA, IIB and IIIA EGFR mutation-positive adenocarcinoma are ongoing in Japan and in China (ADJUVANT CTONG 1104). In conclusion, it remains unclear whether targeted therapies improve outcomes over traditional chemotherapy in the adjuvant setting in NSCLC, and it is premature to recommend adjuvant EGFR TKI therapy outside well-designed clinical trials as there is currently no conclusive data on its role in early- and locally advanced NSCLC harbouring EGFR mutations. Given the consistent development of acquired resistance to EGFR TKI therapy in patients with metastatic NSCLC, there is good reason to question whether it is advisable to use EGFR TKI for adjuvant therapy in patients who have no evidence of disease and who can develop resistance to an otherwise effective treatment. Furthermore, the optimal duration of adjuvant therapy is yet to be defined and it is unknown whether EGFR TKI is merely by suppressing the growth of residual disease after surgery rather than eradicating minimal residual disease. Given the fact that adjuvant therapy needs to be given post-operatively for a prolonged period, the quality of life of patients while on therapy and the financial cost involved also need to be considered.

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      PC02.4 - Adjudication and Discussion (ID 631)

      M. Kris

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    C - Inaugural Cochrane Workshop (ID 78)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 2
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      C.00 - Inaugural Cochrane Workshop (ID 4023)

      N. Pavlakis

      • Abstract

      Abstract
      The Cochrane Collaboration is an international, independent, not-for-profit organisation of over 28,000 contributors from more than 100 countries, dedicated to making up-to-date, accurate information about the effects of health care readily available worldwide. Cochrane contributors work together to produce systematic reviews of healthcare interventions, known as Cochrane Reviews, which are published online in The Cochrane Library. Cochrane Reviews are intended to help providers, practitioners and patients make informed decisions about health care, and are the most comprehensive, reliable and relevant source of evidence on which to base these decisions. Over 5,000 Cochrane Reviews have been published so far, online in the Cochrane Database of Systematic Reviews, part of The Cochrane Library. The Collaboration also prepares the largest collection of records of randomised controlled trials in the world, called CENTRAL, published as part of The Cochrane Library. Work from the Cochrane Collaboration is internationally recognised as the benchmark for high quality information about the effectiveness of health care. The Collaboration believes that effective health care is created through equal partnerships between researcher, provider, practitioner and patient. Cochrane Reviews are unique because they are both produced by, and are relevant to, everyone interested in the effects of human health care. Based on the best available evidence, healthcare providers can decide if they should fund production of a particular drug. Practitioners can find out if an intervention is effective in a specific clinical context. Patients and other healthcare consumers can assess the potential risks and benefits of their treatment. The Cochrane Collaboration's contributors are a mix of volunteers and paid staff who are affiliated to the organisation through Cochrane entities: healthcare subject-related review groups, thematic networks (called 'fields'), groups concerned with the methodology of systematic reviews, and regional centres. Many are world leaders in their field of medicine, health policy, research methodology or consumer advocacy, and our entities are situated in some of the world's finest academic and medical institutions. The Cochrane Collaboration is named after Archie Cochrane (1909-1988), a British epidemiologist, who advocated the use of randomised controlled trials as a means of reliably informing healthcare practice. The Collaboration is an independent, not-for-profit organisation, funded by a variety of sources including governments, universities, hospital trusts, charities and personal donations. The Collaboration is registered as a charity in the United Kingdom. To tie the organisation together, there are a number of overarching structures, led by the Steering Group, which provides policy and strategic leadership for the organisation. Members of this group are democratically elected from, and by, contributors. The Cochrane Operations Unit, is based in Oxford, UK, which manages the financial, legal and administrative work of the organisation, led by the Chief Executive Officer of the Collaboration; and a Cochrane Editorial Unit, based in London, UK, which supports Cochrane Review production, editorial processes, and training and methods development, led by the Editor in Chief of The Cochrane Library. There are annual conferences, known as "Colloquia", which are open to everyone. Colloquia are designed to bring people together in one place to discuss, develop and promote our work, and to shape the organisation's future direction In addition to the core mission of producing Cochrane Reviews, contributors are involved in a number of related activities, including advocacy for evidence-based decision-making, providing training in Cochrane Review preparation, developing the methodology for preparing reviews, and translating them from English into a variety of different languages. This session includes providing an introduction to developing a Cochrane Review and is kindly supported by the Cochrane Lung Cancer Review Group, based in Barcelona Spain (website ) and uses high quality training materials developed by the Cochrane Collaboration (grateful acknowledgement of for allowing the use of the training materials) delivered by volunteer Cochrane Collaborators. The session will address topics including; Introduction to systematic reviews, Writing a Cochrane protocol, Searching for studies, Collecting data, Risk of bias, Meta-analysis, Types of data, Heterogeneity, Analysing data and Interpreting results Other training resources include Online Learning Modules as part of a self-directed learning initiative of The Cochrane Collaboration. They provide an introduction to the core skills and methods required for new authors of Cochrane systematic reviews of interventions. The modules are intended to complement other learning opportunities such as face-to-face workshops and webinars, and the guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions.

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      C.05 - Collecting Data (ID 806)

      N. Pavlakis

      • Abstract
      • Slides

      Abstract not provided

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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.10 - DISCUSSANT (ID 3953)

      N. Pavlakis

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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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      P2.06-015 - Novel plasma proteins associated with prognosis in malignant pleural mesothelioma (ID 1337)

      N. Pavlakis

      • Abstract

      Background
      The search for novel biomarkers to define more successful and individual treatment approaches represent an important challenge for those involved in the care for patients with malignant pleural mesothelioma (MPM). In this exploratory study, we have systematically investigated the proteins present in plasma of MPM patients and correlated their levels with disease outcomes.

      Methods
      Plasma samples from twelve MPM patients (6 ‘short-’ and 6 ‘long-term’ survivors from parallel phase II studies investigating thalidomide) were used for proteomic analyses. Our series included samples from 9 patients with epithelial MPM and 3 patients with biphasic MPM. Plasma samples were immuno-depleted of the 14 most abundant proteins prior to labelling for isobaric tag for relative and absolute quantitation (iTRAQ) analysis using mass spectrometry. The most promising candidates and mesothelin were chosen for selected reaction monitoring mass spectroscopy (SRM-MS) quantification and enzyme-linked immunosorbent assay (ELISA) validation. Statistical analyses using T-Test of peak areas were used to identify proteins that were differentially expressed between the short- and long-term survivor groups.

      Results
      Median survival of short- and long-term survivors (1.2 and 38.3 months, respectively) differed significantly (p = 0.001). This was also the case for the neutrophil-to-lymphocyte ratio (NLR) that was significantly higher in the group of short-term survivors (p=0.03). Other baseline characteristics did not reveal major differences between the short- and long-term survivors. The total number of proteins identified was 226 (1% false discovery rate) in iTRAQ. A number of those were found to be differentially expressed between short- and long-term survivors (≥1.2-fold change; p≤0.05) by iTRAQ: selenoprotein P; tetranectin; insulin-like growth factor-binding protein 2 (IBP2); osteonectin (SPARC); platelet basic protein (CXCL7); and attractin. Mesothelin was assessed to validate the proteomic methodology: SRM-MS quantification was highly correlated with the MESOMARK ELISA values with a Pearson correlation of 0.82 (p=0.001). SRM-MS quantification revealed that the concentrations of attractin (p=0.02), tetranectin (p=0.003) and selenoprotein P (p=0.001) were higher in long-term survivors. In contrast, there was a trend for an increase in the concentration of SPARC (p=0.32), IBP2 (p=0.12) and CXCL7 (p=0.19) to be correlated with shorter survival. Furthermore, quantification by ELISA demonstrated an association between long survival and low concentration of SPARC (p=0.07) as well as high tetranectin (p=0.13).

      Conclusion
      We have demonstrated the feasibility of using the iTRAQ and SRM-MS proteomic techniques to investigate potential prognostic protein markers in plasma of MPM patients. Potential prognostic biomarkers worthy of further studies include SPARC and tetranectin and we plan to validate these in a larger clinical cohort.