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T. Mok

Moderator of

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    PLEN 03 - Science Drives Lung Cancer Advances (ID 52)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 6
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      Introduction (ID 2099)

      • Abstract

      Abstract not provided

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      PLEN03.01 - Lung Cancer Genomes - Adenocarcinoma (ID 2043)

      M. Meyerson

      • Abstract
      • Presentation

      Abstract not provided

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      PLEN03.02 - Lung Cancer Genomes - Squamous Cell Carcinoma/Small Cell (ID 2044)

      R.K. Thomas

      • Abstract
      • Presentation

      Abstract not provided

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      PLEN03.03 - Molecular Mechanisms of Drug Resistance (ID 2045)

      P.A. Jänne

      • Abstract
      • Slides

      Abstract not provided

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      PLEN03.04 - Personalized Medicine (ID 2046)

      J. Remon, J. Soria

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Platinum-based doublet chemotherapy is the standard first-line treatment for non-selected patients with advanced non-small cell lung cancer (NSCLC) who have a good performance status . However, some tumors are highly dependent on the function of specific oncogenes for proliferation and survival. This “oncogenic addiction” has leaded the development of targeted anticancer therapies and their ad hoc biomarkers as predictors of their efficacy. This fact has changed the diagnostic and treatment approach in NSCLC . Moreover, this ‘‘personalized medicine’’ approach, in which tumors might potentially benefit from a biology-guided treatment, has an impact in patients’ outcome . Personalized medicine is also feasible in other malignancies such as metastatic breast cancer, even for patients with rare genomic alterations (SAFIR01 trial) , and in other refractory malignancies (SHIVA trial) , reinforcing that the establishment of a comprehensive tumour molecular profile is feasible and compatible with clinical practice. Unlike “basket trials”, where researchers test the effect of a single drug on a single mutation in a variety of cancer types, “umbrella” trials are designed to test the impact of personalized medicine with different drugs on different mutations in a single type of cancer on the basis of a centralized molecular portrait . The phase II BATTLE (Biomarker-integrated Approaches of Targeted Therapy for lung Cancer) trial was the first prospective, biopsy-mandated, biomarker-based study, that adaptively randomised 255 pre-treated NSCLC patients to erlotinib, sorafenib, erlotinib plus bexarotene, or vandetanib, based on molecular biomarker analysed in fresh core needle biopsy specimens. Overall results included a 46% 8-week disease control rate (primary endpoint). This trial established the feasibility of “real-time” biopsies and personalized treatment in lung cancer. BATTLE-2 (NCT01248247), a phase II, randomised, multi-arm study in advanced pre-treated EGFR wild type and ALK non-rearranged NSCLC patients is currently ongoing. The SPECTA-lung (NCT02214134), included within the SPECTA-platform, is a program aiming at Screening Patients with thoracic tumors (lung cancer, malignant pleural mesothelioma, thymoma or thymic carcinoma at any stage) to identify the molecular characteristics of their disease for Efficient Clinical Trial Access. Second-generation trials encompass within the trial design to access to targeted therapies and usually incorporate a randomization process. SAFIR02-Lung (NCT02117167) is an open-label, multicentric randomised, phase II trial. Advanced no EGFR-activating mutation or ALK translocation NSCLC patients are biopsied during the two initial platinum-based chemotherapy cycles. A comparative genomic hybridisation (CGH) array and a next-generation sequencing are performed and analysed during the two subsequent cycles as a therapeutic decision tool. Only patients with a molecular alteration are randomized to maintenance targeted drug arm (AZD8931, Vandetanib, Selemutinib, AZD5363, AZD4547, AZD2014); or standard maintenance treatment (pemetrexed or erlotinib) after completion of four cycles of chemotherapy to test an improvement in progression free survival (PFS). Lung-MAP (NCT02154490) trial is a phase II/III multidrug, multi-sub-study, and biomarker-driven clinical trial in advanced second-line squamous lung cancer patients. Patients are randomized to standard second-line treatment (docetaxel / erlotinib) or five experimental drugs (four targeted therapies according NGS results and an anti-PDL1 immunotherapy based on immunochemistry results). The primary end-point of the trial is PFS. Approximately 500 and 1000 patients will be screened per year for over 200 cancer-related genes for genomic alterations. ALChEMIST trial (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) is designed to assess whether adjuvant therapy with erlotinib (ALCHEMIST-erlotinib, NCT02193282) or crizotinib (ALCHEMIST-crizotinib, NCT02201992) for 2 years will improve survival over placebo for patients with completely resected stage IB-IIIA EGFR-mutant or ALK-rearranged NSCLC tumors following standard post-operative therapy. ALCHEMIST-screening trial (NCT02194738) will screen about 6,000 to 8,000 participants over 5 to 6 years, with 400 patients enrolled per arm. The RTOG1306 is a phase II trial in EGFR-mutant or ALK-rearranged unresectable stage IIIA (pN2) or IIIB (pN3) NSCLC patients. The aim of the study is to asses whether induction therapy with erlotinib or crizotinib for 12 weeks prior to chemo-radiotherapy improves PFS compared to those treated with standard care therapy alone. Molecular screening is also tested across prospective trials in different malignancies. The MOSCATO trial (NCT01566019) includes metastatic solid tumors and the primary objective is to use high throughput molecular analysis (CGH Array and sequencing) to guide treatment of patients with targeted therapeutics in order to improve the PFS compared to the previous treatment line. IMPACT trial (Initiative for Molecular Profiling in Advanced Cancer Therapy Trial, NCT00851032), is an umbrella protocol in 5,000 patients with advanced malignancies. The goal is to correlate the molecular profile with response to phase I therapies. The NCI-MATCH trial (Molecular Analysis for Therapy CHoice) trial is an umbrella protocol for multiple single-arm, phase II trials. Biopsies from as many as 3,000 patients will be screened by next-generation DNA sequencing to identify 100 actionable mutations, with 1000 participants being enrolled (25% of whom will have rare cancers). Co-primary end-points are overall response rate and PFS rate at 6 months. Finally, for advanced and refractory cancer patients who do not have recognised genetic abnormalities WINTHER trial (NCT01856296) aims at selecting rational therapeutics based on the analysis of matched tumors and normal biopsies according to micro arrays and gene expression profiling results. The main objective is to compare the PFS of the current treatment versus the previously prescribed treatment. Models of personalized medicine implementation (no organized compared with organized framework) , optimal technology for molecular profile , and the optimal patients’ selection are some of challenges to be overcome in personalized medicine. Moreover, the actual model of personalized medicine does not take in account secondary events, which will be involved in cancer resistance. A major challenge in molecular medicine will be to target these secondary events early enough, in order to avoid treatment resistance . Intratumoral heterogeneity plays a critical role in tumor evolution. However, molecular characterization of the tumor is provided from a single biopsy and at single time point. Multiregional evaluations to determine geographical heterogeneity, and molecular characterization of different samples collected over space and time to ascertain clonal evolution are not routinely carried out . The prospective TRACERx trial (TRAcking non-small cell lung Cancer Evolution through therapy [Rx], NCT01888601) in NSCLC patients, aims to define the evolutionary trajectories of lung cancer in both space and time through multi-region and longitudinal tumor sampling and genetic analysis by following cancer from diagnosis to relapse. The study aims to recruit 842 patients . Incorporating an analysis of the tumor immune contexture is also a key challenge and need for the design of new precision medicine trials . In the near future most patients with metastatic tumors will receive targeted therapies or immune modualtors delineated by tumor genotyping and analysis of immune contexture and all of these trials will help to validate current biomarkers facilitating rapid access to innovative therapies.

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      PLEN03.05 - Mouse Models of SCLC and NSCLC (ID 2047)

      A. Berns

      • Abstract
      • Presentation

      Abstract:
      Lung cancer and mesotheliomas belong to the most lethal human malignancies with poor prognosis. The majority of these tumors is associated with carcinogen exposure (smoking and asbestos). Small cell lung cancer (SCLC) and mesothelioma patients show very poor survival statistics due to their late detection, invasive and high metastatic potential, and chemo-resistance. Using the Rbf/f;p53f/f mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells, characterized by mesenchymal and neuroendocrine markers. These cells often share a common origin. Crosstalk between these cells can endow the neuroendocrine component with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating functional tumor properties. Also specific genetic lesions appear to be associated with metastatic potential. We have studied the nature of this crosstalk and identified the components responsible for paracrine signaling and the downstream effector pathway critical for promoting metastatic spread. We have also evaluated the relevance of additional lesions that were frequently acquired in the mouse SCLC, such as amplification of Myc and Nfib. Therefore, we have derived ES cells from Rbf/f;p53f/f, equipped these cells with an exchange cassette in the ColA1 locus, and shuttled a conditional L-Myc and Nfib under a strong promoter into this locus. This accelerated tumorigenesis and resulted also in a shift in the metastatic phenotype. To investigate the cell-of-origin of thoracic tumors, we have inactivated a number of tumor suppressor/oncogene combinations (Trp53, Rb1, Nf2, Cdkn2ab-p19Arf, mutant Kras) in distinct cell types by targeting Cre-recombinase expression specifically to Clara cells, to neuroendocrine cells, alveolar type II cells and cells of the mesothelial lining (origin of malignant mesothelioma) using adenoviral or lentiviral vectors with Cre recombinase driven from specific promoters. Dependent on the induced lesions and the cell-type specific targeting, SCLC, NSCLC, or mesothelioma could be induced. We show that multiple cell types can give rise to these tumors but that the cell-of-origin is an important factor in determining tumor phenotype. Our data indicate that both cell type specific features and the nature of the oncogenic lesion(s) are critical factors in determining the tumor initiating capacity of lung (progenitor) cells. Furthermore, the cell-of-origin appears to influence the malignant properties of the resulting tumors. Sutherland, K., Song, J-Y., Kwon, M-C, Prooost and Berns A. (2014). Multiple cells-of-origin in K-RasG12D induced mous lung adenocarcinoma. Proc. Natl. Acad. SCi. USA, 111, 4952-4957. Kwon, M-C, and Berns, A. (2013) mouse models of Lung Cancer. Mol. Oncol. 7, 65-177. Sutherland, K.D., Proost, N., Brouns, I., Adriaensen, D., Song, J-Y., and Berns, A. (2011). Cell of Origin of Small Cell Lung Cancer: Inactivation of Trp53 and Rb1 in Distinct Cell Types of Adult Mouse Lung. Cancer Cell 19, 754-64. Calbo, J., van Montfort, E., Proost, N., van Drunen, E., Beverloo, H., Meuwissen, R., and Berns, A. (2011) A functional role for tumor cell heterogeneity in a mouse model of Small Cell Lung Cancer. Cancer Cell, 19, 244-56.

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    PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 12
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      Q&A (ID 3537)

      • Abstract

      Abstract not provided

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      Q&A (ID 3538)

      • Abstract

      Abstract not provided

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      Q&A (ID 3541)

      • Abstract

      Abstract not provided

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      Q&A (ID 3540)

      • Abstract

      Abstract not provided

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      PLEN04.01 - A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent Cetuximab in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC): SWOG S0819 (ID 3612)

      R. Herbst, M. Redman, E.S. Kim, T.J. Semrad, L. Bazhenova, G. Masters, K. Oettel, P. Guaglianone, C. Reynolds, A. Karnad, S.M. Arnold, M. Varella-Garcia, J. Moon, P.C. Mack, C.D. Blanke, F.R. Hirsch, D.R. Gandara

      • Abstract
      • Presentation
      • Slides

      Background:
      This abstract is under embargo until September 9, 2015 and will be distributed onsite on September 9 in a Late Breaking Abstract Supplement.

      Methods:


      Results:


      Conclusion:


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      PLEN04.02 - Discussant for PLEN04.01 (ID 3613)

      R. Pirker

      • Abstract
      • Presentation

      Abstract not provided

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      PLEN04.03 - Randomized Phase III Trial of Adjuvant Chemotherapy with or without Bevacizumab in Resected Non-Small Cell Lung Cancer (NSCLC): Results of E1505 (ID 1608)

      H.A. Wakelee, S.E. Dahlberg, S.M. Keller, W.J. Tester, D.R. Gandara, S.L. Graziano, A. Adjei, N. Leighl, S.C. Aisner, J.M. Rothman, J. Patel, M.D. Sborov, S.R. McDermott, R. Perez-Soler, A.M. Traynor, C. Butts, T. Evans, L. Horn, S.S. Ramalingam, J. Schiller

      • Abstract
      • Presentation
      • Slides

      Background:
      Adjuvant chemotherapy for resected early stage NSCLC provides modest survival benefit. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, improves outcomes when added to platinum-based chemotherapy in advanced stage non-squamous NSCLC. We conducted a phase 3 study to evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC. The primary endpoint was overall survival and secondary endpoints included disease-free survival and toxicity assessment.

      Methods:
      Patients with resected stage IB (>4 centimeters) to IIIA (AJCC 6th edition) NSCLC were enrolled within 6-12 weeks of surgery and stratified by chemotherapy regimen, stage, histology and sex. All patients were to receive adjuvant chemotherapy consisting of a planned 4 cycles of every 3 week cisplatin at 75 mg/m[2] with either vinorelbine, docetaxel, gemcitabine or pemetrexed. Patients were randomized 1:1 to arm A (chemotherapy alone) or arm B, adding bevacizumab at 15 mg/kg every 3 weeks starting with cycle 1 of chemotherapy and continuing for 1 year. Post-operative radiation therapy was not allowed. The study had 85% power to detect a 21% reduction in the overall survival (OS) hazard rate with a one-sided 0.025-level test.

      Results:
      From July 2007 to September 2013, 1501 patients were enrolled. Patients were 49.8% male, predominantly white (87.9%) with a median age of 61 years. Patients enrolled had tumors that were 26.2% stage IB, 43.8% stage II and 30.0% stage IIIA and 28.2% of patients had squamous cell histology. Chemotherapy options were utilized with the following distribution: vinorelbine 25.0%, docetaxel 22.9%, gemcitabine 18.9% and pemetrexed 33.2%. At a planned interim analysis, with 412 of 676 overall survival events needed for full information (60.9%), though the pre-planned futility boundary was not crossed, the Data Safety Monitoring Committee recommended releasing the trial results based on the conditional power of the logrank test. At the time of interim analysis, with a median follow-up time of 41 months, the OS hazard ratio comparing the bevacizumab containing arm (Arm B) to chemotherapy alone (Arm A) was 0.99 (95% CI: 0.81-1.21, p=0.93). The DFS hazard ratio was 0.98 (95% CI: 0.84-1.14, p=0.75). Completion of treatment per protocol was 80% on Arm A and 36% on Arm B. Statistically significantly increased grade 3-5 toxicities of note (all attributions) included: overall worst grade (67% versus 84%); hypertension (8% versus 30%), and neutropenia (33% versus 38%) on Arms A and B, respectively. There was no significant difference in grade 5 adverse events per arm with 16 (2%) on arm A and 19 (3%) on arm B.

      Conclusion:
      The addition of bevacizumab to adjuvant chemotherapy failed to improve survival for patients with surgically resected early stage NSCLC.

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      PLEN04.04 - Discussant for PLEN04.03 (ID 3450)

      P.A. Bunn, Jr

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PLEN04.05 - Multiregion Whole Exome and Transcriptome Sequencing Defines the Genomic Spectrum of EGFR+ NSCLC and Reveals Novel Mechanisms of TKI Resistance (ID 3118)

      D.S. Tan, R. Nahar, A. Takano, A. Khng, T. Zhang, T.P. Koh, A. Gogna, T.K. Lim, W.A. Zaw, X. Liu, A. Teo, C. Chan, Y.Y. Lee, G. Iyer, L.H. Chen, M. Ang, Q. Ng, C. Toh, R. Kanesvaran, A. Jain, A. Devanand, V. Krishnan, P. Ng, B.S. Tan, C.H. Lim, B. Chowbay, W. Lim, W.L. Tam, B. Lim, E.H. Tan, W.W. Zhai, A. Hillmer

      • Abstract
      • Presentation

      Background:
      EGFR mutant (M+) NSCLC is an archetypical oncogene-driven solid tumor, typified by high response rates when treated with a tyrosine kinase inhibitor (TKI), and median progression free survival of 10 months, commonly due to emergence of T790M. The genomic architecture and spectra of EGFR M+ tumours may provide insights to mechanisms of treatment failure and has not been well described to date.

      Methods:
      Paired tumor-normal exome/ transcriptome sequencing and SNP array was performed on 30 tbiopsies from 25 patients with TKI resistance (TKI-R) as well as multiple regions (n=46) of 8 treatment naïve (TKI-N), never smoker East Asian EGFR M+ NSCLC (L858R, n=5; exon 19 del, n=2; exon 20 ins, n=1). Genomic alterations were validated with targeted re-sequencing at a mean depth of 2000x. Alterations were identified and annotated using established pipelines.

      Results:
      Exome sequencing of 46 sectors (4-11 sectors/tumor) from 8 resected NSCLC (Stage IA, n=5; Stage IB, n=3), revealed a median of 52.5 validated mutations (Range: 15-112) per tumor. Primary EGFR mutations (including exon 20 ins) were identified as truncal events in all cases, with the notable absence of T790M even at sequencing depths of 2000x. Private mutations comprised 10-33% of all mutations per tumor, and in some cases harbored potential drivers of subclonal diversity including p53, AKT1 and ATXN1. For the 30 TKI-R tumors (T790M+, n=16; T790M-, n=14), exome sequencing revealed a higher mutation burden (median 80 vs 49 in TKI-N), while SNP array and expression data confirmed ERBB2 and MET as common co-existing resistance mechanisms. We next inferred the relevance of alterations and their hierarchical order (trunk, T; branch, B; private, P). In a TKI-N tumor where 11 sectors were subject to exome-sequencing, 39 of 112 mutations were truncal events – with MAP3K19 and PTEN splice site mutations co-existing with EGFR L858R mutation. Strikingly, when comparing the transcriptomic profiles of TKI-N and TKI-R tumors, all 8 evaluated sectors in this tumor clustered together with the TKI-R signature, suggesting that truncal co-mutations can contribute to primary TKI resistance. Finally, we attempted to curate novel genes in the 46 TKI-N sectors that may be implicated in TKI resistance by identifying genes in common with those altered in TKI-R samples with allele frequency > 0.25. We shortlisted approximately 150 recurrent genes or putative drivers – 85% of which were either trunk or branch mutations including TP53 (T,P), PTEN (B), LRP1B (B), GPRIN3 (B), MAP3K19 (T), ARID3A (P) and MED12 (P).

      Conclusion:
      Multi-region sequencing of 8 never smoker EGFR M+ NSCLC revealed a low mutation burden, with a significant proportion of alterations occurring as trunk or branch events. The different activating EGFR mutations were ubiquitous truncal events and T790M was not found in ultra-deep sequencing across 46 sectors. Mutation hierarchy provides a basis for patterns of TKI treatment failure: with co-occurring truncal events (e.g. MAP3K19, PTEN) potentially contributing to primary resistance, and the low incidence of private subclonal drivers consistent with the relatively high prevalence of T790M mutation in the setting of secondary resistance.

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      PLEN04.06 - Discussant for PLEN04.05 (ID 3569)

      R.K. Thomas

      • Abstract
      • Presentation

      Abstract not provided

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      PLEN04.07 - Stopping Smoking Reduces Mortality in Low-Dose Computed Tomography (LDCT) Screening Volunteers (ID 2458)

      U. Pastorino, R. Boffi, A. Marchianò, S. Sestini, E. Munarini, G. Calareso, M. Boeri, G. Pelosi, G. Sozzi, M. Silva, N. Sverzellati, C. Galeone, A. Ghirardi, G. Corrao, C. La Vecchia

      • Abstract
      • Presentation
      • Slides

      Background:
      The National Lung Screening Trial (NLST) has achieved a 7% reduction in mortality from any cause with low-dose computed tomography (LDCT) screening, as compared with the chest radiography arm. Other randomized trials are under way, comparing LDCT screening with no intervention in heavy smokers populations. None of these studies is designed to investigate the impact of smoking habits on screening outcome. In the present study, we have tested the effect of stopping smoking on the overall mortality of volunteers undergoing LDCT screening.

      Methods:
      Between 2000 and 2010, 3381 heavy smokers aged more than 50 years were enrolled in two LDCT screening programmes. Sixty-nine percent were males with median age of 58 years and median smoking exposure of 40 pack-years. Based on the last follow-up information, subjects were divided in two groups: current smokers throughout the screening period, and former smokers. The latter group included ex-smokers at the time of baseline screening (early quitters), and those who stopped smoking during the screening period (late quitters).The effect of smoking on mortality was adjusted according to the following covariates: gender, age, body-mass index (BMI), lung function (FEV1 %) and pack years at baseline.

      Results:
      With a median follow-up time of 9.7 years, and a total of 32,857 person/years (P/Y) follow-up, a total of 151 deaths were observed in the group of 1797 current smokers (17,846 P/Y) and 109 in 1584 former smokers (15,011 P/Y). As compared to current smokers, the Relative Risk (RR) of death of former smokers was 0.77 (95% CI, 0.60 to 0.99, p = 0.0416), corresponding to a 23% reduction of total mortality. Excluding 239 subjects who had stopped smoking from less than 2 years from the end-point of follow-up, RR was 0.64 (95% CI, 0.48 to 0.84, p = 0.0016), with a 36% mortality reduction. A similar risk reduction was observed in the subset of 476 late quitters (27 deaths, 4,777 P/Y), with a RR of 0.60 (95% CI, 0.40 to 0.91, p = 0.0158).

      Conclusion:
      Stopping smoking is associated with a significant reduction of the overall mortality of heavy smokers enrolled in LDCT screening programs. The benefit of stopping smoking appears to be 3 to 5-fold greater than the one achieved by earlier detection in the NLST trial.

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      PLEN04.08 - Discussant for PLEN04.07 (ID 3483)

      N. Yamaguchi

      • Abstract
      • Presentation

      Abstract not provided

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Author of

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    JCHS - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 239)

    • Event: WCLC 2015
    • Type: Joint Chinese/ English Session
    • Track: Other
    • Presentations: 1
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      JCHS.05 - Asian Contributions to Global Drug Development (ID 3455)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI05.08 - Comparison of the Efficacy of Dacomitinib v Erlotinib for NSCLC Pts with Del 19/L858R (ID 775)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Background:
      To date there have been limited randomized comparisons of EGFR tyrosine kinase inhibitors (TKI) in EGFR mutant NSCLC. Dacomitinib is a potent, irreversible EGFR inhibitor that demonstrated robust activity in a phase 2 study for patients with common activating EGFR mutations. Additionally, preclinical data suggests greater activity in patients with common EGFR activating mutations in exon 19 or 21. ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) each compared the clinical activity of dacomitinib (D) versus erlotinib (E) in advanced NSCLC including patients with common activating EGFR mutations; pooled results are presented.

      Methods:
      Patients (pts) with locally advanced/metastatic NSCLC were randomized following progression with 1 or 2 prior chemotherapy regimens to treatment with dacomitinib (D) (45 mg PO QD) or erlotinib (E) (150 mg PO QD). The Phase 2 study (A7471028) was open label while the Phase 3 ARCHER 1009 study was double-blind and double dummy. Archived tumor tissue, ECOG performance status (PS) of 0-2, adequate organ function and informed consent were required. Results of the two studies were previously reported individually. Analyses were performed by pooling patients with common EGFR activating mutations from both studies to compare efficacy of D versus E.

      Results:
      121 patients with any EGFR mutation were enrolled into the two studies with 1 patient randomized but not treated; 101 (53 on D) pts had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median PFS was 14.6 months (95%CI 9.0–18.2) for D and 9.6 months (95%CI 7.4–12.7) for E and unstratified HR 0.717 (95%CI 0.458–1.124) with 1-sided p=0.073. The median OS was 26.6 months (95%CI 21.6–41.5) for D and 23.2 months (95%CI 16.0–31.8) for E and unstratified HR 0.737 (95%CI 0.431–1.259) with 1-sided p=0.132. The corresponding pooled analyses were conducted separately in exon 19 and exon 21. The adverse-event profile did not differ between the activating mutation subset and the overall population. Figure 1



      Conclusion:
      Dacomitinib may be associated with an improved PFS and OS compared to Erlotinib in patients with exon 19/21 EGFR mutations. A prospective P3 study comparing D to another EGFR TKI in 1L EGFR mutated NSCLC is ongoing to verify these observations (NCT01774721).

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    MINI 10 - ALK and EGFR (ID 105)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI10.04 - Discussant for MINI10.01, MINI10.02, MINI10.03 (ID 3399)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MINI 31 - ALK (ID 158)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 4
    • +

      MINI31.04 - Intracranial Efficacy of First-Line Crizotinib vs. Chemotherapy in ALK-Positive NSCLC (ID 1238)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Background:
      The ongoing multicenter, randomized, open-label phase III study PROFILE 1014 recently demonstrated superior efficacy of crizotinib compared with chemotherapy in patients with previously untreated advanced ALK-positive NSCLC (Solomon et al, N Engl J Med 2014). Intracranial efficacy of crizotinib vs. chemotherapy was compared prospectively in this trial.

      Methods:
      Patients with previously untreated advanced non-squamous ALK-positive NSCLC (N=343) were randomized 1:1 to receive crizotinib 250 mg orally BID (n=172) or intravenous chemotherapy (pemetrexed 500 mg/m[2 ]+ cisplatin 75 mg/m[2] or carboplatin at AUC 5–6; all q3w for ≤6 cycles; n=171). Patients with treated brain metastases that were stable for ≥2 weeks with no ongoing requirement for corticosteroids were eligible. Treatment was continued until PD. Continuation of, or crossover to, crizotinib after PD (per independent radiology review [IRR]) was allowed for patients randomized to crizotinib or chemotherapy, respectively. Brain scanning was performed every 6 weeks in patients with baseline brain metastases and every 12 weeks in those without baseline brain metastases. Protocol-specified efficacy endpoints included PFS (primary endpoint), ORR, OS, and 12- and 18-month OS, as well as intracranial TTP. Intracranial DCR at 12 and 24 weeks was also evaluated. Efficacy was evaluated in the ITT population and in two subgroups of patients: those with and without baseline brain metastases.

      Results:
      Of 343 patients in the ITT population, 79 had brain metastases at baseline identified by IRR (23%) and 263 did not (77%; data not reported for one patient). Baseline characteristics of patients randomized to receive crizotinib or chemotherapy were generally well balanced within these two patient subgroups. Among the patients with baseline brain metastases, a significantly higher proportion achieved intracranial disease control with crizotinib than with chemotherapy at 12 weeks (33/39 [85%] vs. 18/40 [45%], respectively; P=0.0003) and at 24 weeks (22/39 [56%] vs. 10/40 [25%]; P=0.006). There was a numerical improvement in prospectively measured intracranial TTP with crizotinib in the ITT population (HR 0.60, P=0.069), as well as in patients either with baseline brain metastases (HR 0.45, P=0.063) or without baseline brain metastases (HR 0.69, P=0.323). The frequency of progression in the brain was low in the ITT population (15%) and in patients with and without baseline brain metastases (27% and 11%, respectively). Overall PFS was significantly longer with crizotinib than with chemotherapy in both subgroups (brain metastases present: HR 0.40, P=0.0007, median 9.0 vs. 4.0 months; brain metastases absent: HR 0.51, P≤0.0001, median 11.1 vs. 7.2 months), as it was in the ITT population (HR 0.45, P<0.0001, median 10.9 vs. 7.0 months). Twenty-five patients in the crizotinib arm of the study experienced intracranial PD; 22 of these patients received crizotinib for ≥3 weeks beyond PD and 19 also received intracranial radiotherapy.

      Conclusion:
      In this prospective assessment of intracranial efficacy, crizotinib demonstrated significantly greater intracranial disease control and overall efficacy compared with chemotherapy in patients with baseline brain metastases. These findings provide further confirmation of crizotinib as the standard of care for patients with previously untreated advanced ALK-positive NSCLC, including those patients with brain metastases at baseline.

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      MINI31.12 - Quality of Life for Crizotinib vs. Chemotherapy in Asian ALK-Positive NSCLC Patients (ID 845)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Background:
      PROFILE 1014 compared the efficacy and safety of the ALK inhibitor crizotinib with platinum based chemotherapy in previously untreated advanced ALK-positive advanced NSCLC (Pfizer; NCT01154140). The primary endpoint was progression-free survival. The main objective of this post-hoc analysis was to compare patient-reported symptom and global quality of life (QOL) between crizotinib and chemotherapy in the subgroup of patients of Asian ethnicity in the ongoing study PROFILE 1014.

      Methods:
      Patients in the ongoing PROFILE 1014 study were randomized to crizotinib (250 mg PO bid; n= 172) or chemotherapy (pemetrexed 500 mg/m[2] + either cisplatin 75 mg/m[2] or carboplatin AUC 5–6; all IV q3w for ≤6 cycles; n= 171). Patient-reported outcomes were assessed at baseline, day 7 and day 15 of cycle 1, day 1 of subsequent 3-week cycles and end of treatment using the validated cancer specific questionnaire EORTC QLQ-C30 and its lung cancer module QLQ-LC13. Validated translations of the questionnaires in Asian languages (Japanese, Chinese, Korean etc) were made available. Higher scores (range 0−100) indicated higher symptom severity or better functioning/QOL. A positive change from baseline score indicates improvement for global QOL/functioning and deterioration in symptoms. Repeated measures mixed-effects analyses were performed to compare change from baseline scores between the treatment arms, with no adjustments made for multiple comparisons.

      Results:
      Of 343 patients randomized, 46% were of Asian ethnicity (crizotinib, n=77; chemotherapy, n=80). Completion rates at baseline were ≥95% in each group and scores were balanced. A statistically significantly greater overall improvement from baseline was observed with crizotinib compared with chemotherapy for global QOL (5.6 vs -7.7; p<0.001), emotional functioning (9.5 vs 2.7;p<0.05), physical functioning (5.0 vs - 2.7 p<0.001) and role functioning (3.7 vs. -7.2;p<0.001). A statistically significantly greater overall improvement was observed with crizotinib compared with chemotherapy for cough (-17.3 vs. -11.2; p<0.05), dyspnea (-9.5 vs.-1.1; p<0.001), pain in arm or shoulder (-11.4 vs.-2.2; p<0.001), pain in chest (-7.3 vs.3.3; p<0.001), pain in other parts (-11.2 vs. -0.4;p<0.001), fatigue (-9.9 vs. 3.9; p<0.001), insomnia (-10.3vs. -2.0; p<0.05), pain (-12.2 vs.-1.2; p<0.001) and appetite loss (-5.3 vs. 5.7; p<0.001). A statistically significantly greater overall deterioration was observed in the crizotinib arm for diarrhea (12.6 vs. 2.4; p<0.001) compared with chemotherapy. No statistically significant differences were observed for social functioning, sore mouth, dysphagia, nausea & vomiting, constipation and alopecia between crizotinib and chemotherapy.

      Conclusion:
      Consistent with previously reported results in the overall study population, treatment with crizotinib showed statistically significantly greater overall improvement in patient-reported lung cancer symptoms and global QOL compared with chemotherapy in the subgroup of patients of Asian ethnicity with previously untreated advanced ALK-positive NSCLC.

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      MINI31.13 - Symptoms and QOL with Ceritinib in ALK+ NSCLC Patients with/without Brain Metastases (ID 1655)

      T. Mok

      • Abstract
      • Slides

      Background:
      In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), showed clinical activity in patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). Here, patient-reported outcomes (PROs) from the recently reported ASCEND-2 study (NCT01685060) are described for chemotherapy- and ALKi-pretreated patients with ALK+ NSCLC with and without baseline BrM

      Methods:
      In ASCEND-2, adult patients with ALK+ NSCLC previously treated with chemotherapy and an ALKi (crizotinib) received oral ceritinib 750 mg daily. PROs were assessed at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days), using the Lung Cancer Symptom Scale (LCSS) and EORTC quality of life and lung cancer surveys (QLQ-C30 and QLQ-LC13, respectively). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.

      Results:
      All 140 patients enrolled (median age [range] 51 [29–80] years; 50.0% male), had received ≥2 antineoplastic regimens and 100 (71.4%) had BrM at baseline. At data cutoff (13 August 2014), median follow-up was 11.3 months. PRO questionnaire compliance was at least 91.2% up to cycle 9. In the overall patient population, investigator-assessed disease control rate (DCR) was 77.1% and median duration of response (DOR) 9.7 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 74.0% [64.3, 82.3] and 85.0% [70.2, 94.3], respectively, while DOR [95% CI] was 9.2 [5.5, 11.1] and 10.3 [7.4, 16.6] months, respectively. Analysis of PROs data demonstrated that treatment with ceritinib improved lung cancer symptoms in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS. In general, mean global quality of life (QLQ-C30) was maintained on treatment for both patient subgroups, with mean change from baseline in QLQ-C30 global health status ranging from -3.06 to +7.25 in patients without baseline BrM and -2.83 to +3.55 in those with baseline BrM. Figure 1



      Conclusion:
      In patients with ALKi-pretreated ALK+ NSCLC who received prior chemotherapy and ceritinib, clinical efficacy was demonstrated and cancer symptoms were mostly improved, with health-related quality of life generally maintained regardless of presence or absence of baseline BrM.

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      MINI31.14 - PROs with Ceritinib in ALKi-Naive ALK+ NSCLC Patients with and without Brain Metastases (ID 1528)

      T. Mok

      • Abstract
      • Slides

      Background:
      In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), demonstrated sustained clinical activity in ALKi-naive patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). ASCEND-3 (NCT01685138) evaluated patient-reported outcomes (PROs) as well as clinical outcomes with ceritinib, in ALKi-naive ALK+ NSCLC patients with and without baseline BrM.

      Methods:
      Adult patients with ALK+ NSCLC previously treated with up to 3 lines of cytotoxic therapy received oral ceritinib 750 mg daily. PROs were assessed using Lung Cancer Symptom Scale (LCSS) and EORTC (QLQ-C30, QLQ-LC13) quality of life and lung cancer surveys at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.

      Results:
      Of 124 enrolled patients (median age [range] 56 [27–82] years; 40.3% male), 50 (40.3%) had BrM at baseline. At data cutoff (27 June 2014), median follow-up was 8.3 months. Up to cycle 9, PRO questionnaire compliance was at least 97.0%. In the overall patient population, investigator-assessed disease control rate (DCR) was 89.5% and median duration of response (DOR) 9.3 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 86.0% [73.3, 94.2] and 91.9% [83.2, 97.0], respectively, while DOR [95% CI] was 9.1 [7.5, Not Estimable] and 10.8 [9.3, 10.8] months, respectively. Mean change from baseline in patients’ total LCSS score ranged from -3.4 to -11.4 while receiving ceritinib, with 82.1% of patients experiencing symptom improvement; symptoms improved in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS in the full patient population and in the subgroups of patients with and without baseline BrM. In general, mean global quality of life (QLQ-C30) was maintained on treatment for all patients. Patients reported diarrhea and nausea and vomiting symptoms were worse than baseline, however, nausea and vomiting symptoms did reduce over time. Figure 1



      Conclusion:
      In ALKi-naive patients with ALK+ NSCLC, treatment with ceritinib demonstrated clinical efficacy and improved cancer symptoms, with health-related quality of life generally maintained regardless of baseline BrM status. Improvements were greatest for the lung-related symptoms, cough and pain.

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    MTE 01 - Endpoints in Clinical Trials in Advanced NSCLC (Ticketed Session) (ID 53)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/07/2015, 07:00 AM - 08:00 AM, 103
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      MTE01.01 - Endpoints in Clinical Trials in Advanced NSCLC (ID 1977)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 16 - Clinical Care of Lung Cancer and Advanced Biopsies (ID 115)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL16.05 - Retrospective Analysis of ctDNA EGFR Mutations in the Phase III, Randomized IMPRESS Study (ID 2106)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Background:
      The majority of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer respond to first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs, e.g. gefitinib) but nearly all eventually acquire resistance. The most common mechanism of acquired resistance is a second-site mutation in the EGFR kinase domain, T790M. The phase III, double-blind IMPRESS study evaluated the efficacy and safety of continuing gefitinib plus pemetrexed/cisplatin versus placebo plus pemetrexed/cisplatin in patients with acquired resistance to first-line gefitinib. Study results did not support the continuation of gefitinib after disease progression (by RECIST criteria) when platinum-based doublet chemotherapy is used as second-line therapy. Here we report the results of a retrospective biomarker analysis of plasma circulating free, tumor-derived DNA (ctDNA) from patients in IMPRESS, including T790M profiling, to help understand the IMPRESS clinical trial outcome.

      Methods:
      Plasma samples for ctDNA isolation were collected at baseline and discontinuation from 151 randomized, non-Chinese patients in IMPRESS (58% of overall IMPRESS population). ctDNA levels of T790M, L858R, and Exon19 deletions were detected using both a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) and a qualitative QIAGEN[®] Therascreen ARMS assay (baseline only). Local EGFR tumor tissue (diagnostic) results were available for 133/151 patients. Mutation concordance rates between tissue and baseline plasma results, and comparisons between the two plasma detection methods, were calculated.

      Results:
      Baseline ctDNA EGFR mutation results were obtained for >99% (150/151) of patients. Using BEAMing, sensitivity and specificity between baseline plasma EGFR sensitizing mutations and local EGFR tumor tests were 78% (69/89) and 98% (42/43), respectively, for Exon19 deletions, and 82% (31/38) and 97% (91/94) for L858R. The T790M detection rate in baseline plasma samples using BEAMing was 56% (84/150). The Therascreen ARMS assay demonstrated a significantly reduced T790M detection rate of 13% (20/150). Likewise, the sensitivity of the Therascreen ARMS assay with respect to tissue for EGFR sensitizing mutations was also reduced compared with BEAMing: Exon 19: 54% (48/89), L858R: 47% (18/38), though the specificity remained near 100%. In the 97 evaluable plasma samples collected at discontinuation, T790M was detected by BEAMing in 52% (50/97) of patients. When compared with matched baseline plasma, 11 patients had newly acquired T790M mutation at discontinuation while T790M reverted to undetectable in 14 patients. Full plasma profiling data from the complete IMPRESS clinical study population (including 108 patients from China) and correlative analyses of plasma EGFR mutation status with clinical outcome (progression-free survival, overall survival, objective response rate) will be presented.

      Conclusion:
      In IMPRESS, T790M was detectable with BEAMing digital PCR in the baseline ctDNA samples of 56% of evaluable patients, a rate comparable to similar mutation analyses in this same second-line, EGFR-TKI-failed setting. EGFR mutation detection in plasma using the Therascreen ARMS assay demonstrated comparable specificity to BEAMing but reduced sensitivity. The T790M detection rate afforded by the BEAMing technology will allow for a comprehensive assessment of correlations between clinical outcome in IMPRESS and EGFR mutational status.

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    ORAL 17 - EGFR Mutant Lung Cancer (ID 116)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL17.08 - Gefitinib/Chemotherapy vs Chemotherapy in EGFR Mutation-Positive NSCLC Resistant to First-Line Gefitinib: IMPRESS T790M Subgroup Analysis (ID 3287)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Background:
      Exon 20 T790M mutation is the most common cause of acquired resistance to first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). The IMPRESS study (NCT01544179; Phase III, double-blind IRESSA[TM ]Mutation Positive Multicentre Treatment Beyond ProgRESsion Study; Lancet Oncology: in press) reported no statistically significant difference in progression-free survival (PFS; primary endpoint) between gefitinib plus cisplatin/pemetrexed (cis/pem) (G) vs placebo plus cis/pem (P) in patients with acquired resistance to first-line gefitinib (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.65–1.13; p=0.273; median PFS 5.4 months in both arms) and other secondary endpoints. Among the subgroup analyses performed for IMPRESS, the most noticeable difference was observed by T790M status as tested via plasma circulating free tumor-derived DNA (ctDNA).

      Methods:
      Patients (age ≥18 years [Japan ≥20 years], chemotherapy-naïve, locally advanced/metastatic NSCLC with an activating EGFR mutation, prior disease progression on first-line gefitinib) from 71 centers (Europe/Asia Pacific) were randomized to G or P (gefitinib 250 mg/day or placebo, plus cis 75 mg/m[2]/pem 500 mg/m[2]). For biomarker analysis, consenting randomized patients provided 10-mL blood samples (at Visit 1 [baseline], 4, 6; then every 6 weeks and at discontinuation) from which to obtain ctDNA. ctDNA levels of EGFR mutations, including T790M, were detected using a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) conducted at a central laboratory (positivity defined as ≥0.02% mutant DNA fraction).

      Results:
      Data are reported for plasma samples from baseline visits (serial data will be available in the future). Blood samples were available for all 261 randomized patients, of whom T790M status was known for 247 (93.2%): T790M mutation-positive n=142 (57.5%; G=81, P=61) and T790M mutation negative n=105 (42.5%; G=46, P=59). Median PFS for the T790M mutation-positive subgroup was 4.6 vs 5.3 months for G and P, respectively (HR 0.97, 95% CI 0.67 to 1.42, p=0.8829). Median PFS for the T790M mutation-negative subgroup was 6.7 vs 5.4 months for G and P, respectively (HR 0.67, 95% CI 0.43 to 1.03, p=0.0745). See Table for additional study endpoints.

      Conclusion:
      Following acquired resistance to first-line gefitinib, these data suggest there were two distinct patient populations defined by T790M genotype. For plasma T790M-positive, gefitinib should not be continued when platinum-based doublet chemotherapy is used as second-line therapy. For plasma T790M-negative, continuation of gefitinib in combination with platinum-based doublet chemotherapy may offer clinical benefit, which would require further confirmation in a prospective randomized study.

      IMPRESS subgroup populations (plasma)
      T790M mutation-positive N=142 T790M mutation-negative N=105
      ORR, % (G vs P) 28.4 vs 39.3 p=0.282 37.0 vs 27.1 p=0.171
      DCR, % (G vs P) 81.5 vs 77.0 p=0.5175 93.5 vs 83.1 p=0.0895
      OS, HR (95% CI)* 2.16 (1.26, 3.82) p=0.0067 0.83 (0.36, 1.85) p=0.6644
      Plasma BEAMing PCR (compared with tumor), % (n/N)
      Exon 19 Deletions L858R
      Sensitivity 73.8 (124/168) 81.6 (62/76)
      Specificity 96.7 (89/92) 95.3 (161/169)
      Concordance 81.9 (213/260) 91.0 (224/247)
      *OS immature, follow up ongoing G: gefitinib plus cisplatin/pemetrexed; P: placebo plus cisplatin/pemetrexed ORR, objective response rate; DCR, disease control rate; OS, overall survival


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    ORAL 38 - Liquid Biopsies (ID 147)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL38.04 - Discussant for ORAL38.01, ORAL38.02, ORAL38.03 (ID 3565)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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: 1
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      P1.01-076 - TIGER-1: A Phase 2/3 Study of First Line Rociletinib or Erlotinib in EGFR-Mutant NSCLC (ID 944)

      T. Mok

      • Abstract

      Background:
      Activating EGFR mutations including the L858R mutation and exon 19 deletions (del19) are key drivers of non-small cell lung cancer (NSCLC) in 10%–15% of patients of European and 30%–35% of Asian descent.[1] Acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib can be driven by additional EGFR mutations, with exon 20 T790M accounting for 50%–60% of cases.[2] Rociletinib (CO-1686) was designed to inhibit T790M as well as L858R and del19 while sparing wild-type EGFR and has demonstrated response rates up to 67% in patients with T790M mutations who had progressed on first or later line EGFR inhibitor therapy. Rociletinib continues to be well tolerated by patients in ongoing studies.[3] Given that T790M mutated subclones commonly emerge during treatment with existing EGFR inhibitors, early targeting of T790M along with initial activating mutations is a rational approach to delay progression.

      Methods:
      TIGER-1 (NCT02186301) is a randomized, open label study of rociletinib vs erlotinib in patients with mutant EGFR NSCLC. Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced treatment-naive NSCLC (no prior therapy in the metastatic setting and no CNS disease), with documentation of ≥1 activating EGFR mutation (excluding exon 20 insertions) and biopsy within 60 days will be enrolled in this 2-part study. All patients will be randomized 1:1 to rociletinib (500 mg twice daily) or erlotinib (150 mg once daily) and treated until death, qualifying adverse events or disease progression. Patients will be stratified by sensitizing EGFR mutation (T790M, del19, L858R, or other) and territory (Asian vs non-Asian geography). The same patient eligibility criteria will be used for the Phase 2 and Phase 3 portions of TIGER-1. The phase 2 portion is currently enrolling and will transition to the Phase 3 portion upon enrollment of the 201[st] patient. The maturing Phase 2 dataset will contribute to decision-making rules for the Phase 3 interim analyses. The Phase 3 portion will incorporate larger cohorts; the final sample sizes will be determined by interim analyses where the chances of success will be estimated at pre-planned enrollment milestones. The primary endpoint is PFS; secondary efficacy endpoints include objective response rate, duration of response, disease control rate and overall survival. Safety will be assessed via standard adverse event reporting. PFS and OS will be summarized with Kaplan-Meier plots. The stratified log-rank and hazard ratio will compare PFS distributions for rociletinib- vs erlotinib-treated patients. Enrollment is ongoing. 1. Herbst R et al. N Engl J Med. 2008 2. Yu H et al. Clin Cancer Res. 2013 3. Sequist LV J Clin Oncol. 2014

      Results:
      Not applicable

      Conclusion:
      Not applicable

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    P1.12 - Poster Session/ Community Practice (ID 232)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Community Practice
    • Presentations: 1
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      P1.12-002 - International Online Tool for Therapeutic Decision Making in NSCLC (V2.0) (ID 2160)

      T. Mok

      • Abstract

      Background:
      Practice guidelines in non-small-cell lung cancer (NSCLC) list multiple therapy choices based on levels of evidence but cannot account for variability in patient (pt)-tumor characteristics between individual patient cases. To provide oncologists with expert guidance and feedback on choice of treatment (Tx) for specific pt scenarios, we previously implemented an interactive Web-based decision support tool in 2012, in which oncologist users input specific pt characteristics and selected among treatment options, then compared their selection with that of an NSCLC expert panel for that scenario. (Chow JTO 2015). Here we report data from version 2.0 of this tool, capturing current Tx trends for advanced NSCLC and investigating the impact of this online tool on oncology practitioners.

      Methods:
      V2.0 was developed based on input from 6 international NSCLC experts who provided Tx recommendations for 1st-line treatment in 96 pt case variations based on histology (nonsquamous vs squamous), EGFR mutational status (positive [+] vs negative [-]), ALK rearrangement (+ vs -), age (< 70 vs ≥ 70 years), performance status (0, 1 vs 2), smoking history (never/former light vs former heavy/current), and pt primary Tx goal (response and survival vs quality of life and low adverse events). As in V1.0, oncologist users input specific pt scenarios, then were prompted for their treatment choice. Once completed, recommendations for that scenario from each of the experts were displayed, and users were prompted to indicate whether the expert recommendations changed their treatment choice. Statistical methods: as previously described (Chow JTO 2015).

      Results:
      V2.0 oncologist users (N = 218 unique users) contributing 314 unique cases were 87% non-USA, 13% USA. As in V1.0, experts agreed on selection of targeted therapies (TKIs) for cases with actionable EGFR mutations and ALK translocations. Choice of a specific EGFR inhibitor by experts varied depending on region and clinical factors. By comparison, among online users of V2.0, an EGFR inhibitor was selected for 67% of EGFR-mutated cases (n = 78), while an ALK inhibitor was selected for 61% of ALK cases (n = 31). For nonsquamous histology cases without actionable mutations, use of pemetrexed was more common among experts compared with oncologist users (91% vs 48% of case scenarios). In 182 cases entered by users who reported on the impact of expert recommendations, treatment choice was affected in 86% of cases (confirmed in 71%); 5.5% disagreed with expert recommendations and 8% indicated barriers to implementing the recommendations. In comparing overall results from V1.0 (2012) to V2.0 (2014), more oncologist users were likely to select TKIs in both EGFR mutation (49% vs 67%) and ALK translocation (35% vs 61%), with a corresponding decrease in use of chemotherapy. A detailed analysis of expert vs user data will be presented, comparing V1.0 (2012) and V2.0 (2014).

      Conclusion:
      Expert opinions were largely unchanged between V1.0 and V2.0, while oncologist users increased use of TKIs. Most oncologist users of V2.0 either confirmed or changed treatment choices based on expert recommendations. This online tool can aid decision making, serve an educational purpose, and capture practice trends.

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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: 1
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      P2.01-097 - Phase 3 Study of Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1<sup>+</sup> NSCLC (ID 2182)

      T. Mok

      • Abstract
      • Slides

      Background:
      Platinum-based chemotherapy with or without maintenance therapy is the standard of care for treatment-naive non-small cell lung carcinoma (NSCLC) that lacks EGFR sensitizing mutations and ALK translocations. The PD-1 pathway is frequently used by tumors to evade an immune response. Pembrolizumab (MK-3475), an anti–PD-1 monoclonal antibody, has demonstrated manageable toxicity and promising antitumor activity in patients with treatment-naive NSCLC enrolled in the phase 1b KEYNOTE-001 study. In this study, a relationship between increased tumor PD-L1 expression and improved pembrolizumab antitumor activity was observed. KEYNOTE-042 (ClinicalTrials.gov identifier NCT02220894) is a randomized, open-label, international, phase 3 study designed to compare the efficacy and safety of pembrolizumab with those of platinum-doublet chemotherapy as first-line therapy for PD-L1–positive advanced NSCLC.

      Methods:
      Eligibility criteria include age ≥18 years, advanced NSCLC without EGFR sensitizing mutations or ALK translocation, no prior systemic chemotherapy, PD-L1 expression in ≥1% of tumor cells, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1. Patients are randomly assigned in a 1:1 ratio to a 200-mg fixed dose of pembrolizumab every 3 weeks (Q3W) or investigator’s choice of carboplatin AUC 5 or 6 plus paclitaxel 200 mg/m[2] Q3W or carboplatin AUC 5 or 6 plus pemetrexed 500 mg/m[2] Q3W. Randomization is stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), region (East Asia vs non-East Asia), and PD-L1 expression (strong [staining in ≥50% of tumor cells] vs weak [staining in 1%-49% of tumor cells], as assessed by immunohistochemistry at a central laboratory). Pembrolizumab will be continued for 35 cycles or until disease progression, intolerable toxicity, or investigator decision; treatment may be continued beyond initial radiographic disease progression in eligible patients. Discontinuation of pembrolizumab is permitted for patients who experience a complete response confirmed on a follow-up scan performed ≥4 weeks after initial observation. Chemotherapy will be given for a maximum of 6 cycles and may be followed by optional pemetrexed 500 mg/m[2] Q3W maintenance therapy in patients with nonsquamous histology. Adverse events will be collected throughout the study and for 30 days (90 days for serious adverse events) thereafter and graded per NCI CTCAE v4.0. Response will be assessed every 9 weeks per RECIST v1.1 by independent central review. Patients will be followed for survival every 2 months. Primary end point is overall survival in the PD-L1–strong-positive stratum; secondary end points are progression-free survival in the strong-positive stratum and progression-free and overall survival in all patients. Enrollment is ongoing and will continue until approximately 1240 patients have been allocated to study treatment.

      Results:
      Not applicable.

      Conclusion:
      Not applicable.

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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.05 - How to Present Data at a Conference (ID 3515)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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