Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

B. Melosky



Author of

  • +

    ED11 - Advanced NSCLC: State-of-the-Art Treatment (ID 280)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • +

      ED11.01 - Systemic Therapy for Advanced Oncogene-Driven NSCLC (ID 6485)

      11:00 - 11:25  |  Author(s): B. Melosky

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Oncogene-driven lung cancer remains the embodiment of personalized medicine. Since the first description of EGFR activating mutations found in patients with what was then called bronchiolalveolar carcinoma of the lung (BAC) in 2004, the topic of oncogene-driven lung cancer has grown rapidly and expanded to now encompass a number of additional mutation- and fusion-related entities. Recent updates to molecular testing guidelines, such as those of IASLC, have added several new oncogenes to the initial EGFR and ALK recommendations, including ROS1 and RET fusions, MET amplification or mutation, and HER2 mutations (1,2,3). Although the efficacy of tyrosine kinase inhibitors (TKI) in the treatment of some of these disease subsets is well established, the treatment decision-making process at the time of each relapse is becoming more complex as our knowledge of resistance pathways grows and more treatment options become available, with 2[nd] and 3[rd] generation drugs now in play. Subtping of progressive disease (PD) in oncogene-driven lung cancer into systemic PD versus oligo-PD or CNS-santuary PD can assist in determining the most appropriate therapeutic approach, as shown in Figure 1 below(4).Further, the methods by which we assess tumor at the time of initial or re-biopsy are also rapidly evolving, from single gene or multiplexed gene panels to highly sensitive and specific next generation sequencing (NGS). Lastly, we and others (4,5) have proposed algorithms for possible substitution of plasma cell free DNA by NGS platforms for tissue re-biopsy or for serial monitoring in plasma, as demonstrated in Figure 2.In this presentation we will present a step-wise approach to molecular testing and personalizing treatment for patients with oncogene-driven NSCLC, focusing on EGFR-mutated and ALK-rearranged subsets, since the treatment paradigms are most well established. We will emphasize some of the real world challenges faced by treating physicians. Decision criteria for selecting the best first-line therapy will be reviewed, the importance of re-biopsy upon disease progression to determine the most appropriate next-line therapy highlighted, and third line therapy and beyond discussed. The emerging role of liquid biopsy for assessment of plasma cell free DNA will be discussed, as well as a rationale for substituting liquid biopsy for initial or repeat tumor biopsy in some clinical settings. Algorithms designed to facilitate treatment decision-making will be presented. Two examples in EGFR-mutated lung cancer are shown below.Figure 1: Algorithm for management by Progressive Disease SubtypingEGFR-mutated NSCLCFigure 1Figure 2: Algorithm for Re-Biopsy and/or Plasma cf DNA AnalysisIn EGFR-mutated NSCLCFigure 2 References 1. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J et al: 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. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2013, 8(7):823-859. 2. Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ramalingam SS, West H, Whitlock S, Somerfield MR: Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists Guideline. Journal of Clinical Oncology 2014. 3. Ettinger, D. S., Akerley, W., Borghaei, H., Chang, A. C., Cheney, R. T., Chirieac, L. R., ... & Grant, S. C. Non–small cell lung cancer, version 2.2013. Journal of the National Comprehensive Cancer Network, 2013, 11(6), 645-653. 4. Gandara DR, Li T, Lara PN, Kelly K, Riess JW, Redman MW, Mack PC: Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clinical lung cancer 2014, 15(1):1-6. 5. Oxnard, G. R., Thress, K. S., Alden, R. S., Lawrance, R., Paweletz, C. P., Cantarini, M., ... & Jänne, P. A. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non–small-cell lung cancer. Journal of Clinical Oncology, 2014, JCO667162.





      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    ISS08 - A prIME Oncology Satellite Symposium Supported by Boehringer Ingelheim Pharma GmbH & Co. KG.: Reaching New Heights in the Management of Non-Small Cell Lung Cancer: Focus in EGFR-Targeted Therapy (ID 441)

    • Event: WCLC 2016
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 1
    • +

      ISS08.03 - Managing EGFR–Mutant Adenocarcinoma: What is the Optimal First-Line Approach? (ID 7148)

      18:00 - 18:20  |  Author(s): B. Melosky

      • Abstract

      Abstract not provided

  • +

    P1.02 - Poster Session with Presenters Present (ID 454)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
    • +

      P1.02-011 - Comparison of EGFR and KRAS Mutations in Archival Tissue and Circulating Tumor DNA: The Impact of Tumor Heterogeneity (ID 4504)

      14:30 - 14:30  |  Author(s): B. Melosky

      • Abstract

      Background:
      In non-small cell lung cancer (NSCLC), circulating tumour DNA (ctDNA) has gained acceptance as a potential alternative to tissue biopsies to identify targetable mutations. Individual ctDNA platforms have varying abilities to detect specific mutations. A prospective, multicenter study was conducted to determine concordance, sensitivity, and specificity of ctDNA genotyping, with archival tissue DNA (atDNA) as the reference standard.

      Methods:
      Patients with incurable advanced NSCLC at the BC Cancer Agency were enrolled over 14 months. Next-Generation Sequencing (NGS) and high-throughput multiplex amplification of a 27-gene panel (Raindance) was used for atDNA analysis. Four mL of plasma was collected in Streck (Cell Free DNA BCT) tubes for ctDNA genotyping using the Boreal Genomic OnTarget. Analysis of concordance, sensitivity, and specificity was conducted with atDNA used as the standard.

      Results:
      Seventy-six patients were enrolled, median age 66, 33 (44%) male, 69 (91%) metastatic disease, 47 (62%) with primary disease in-situ. Twenty-six EGFR mutations in 22 atDNA samples, and 12 mutations in 11 ctDNA samples were detected, with a concordance of 78%, sensitivity of 39%, and specificity 98%. One EGFR T790M mutation was positive by ctDNA alone. Twenty-one KRAS mutations in 21 atDNA samples were detected. Within this subgroup, 10 ctDNA samples had KRAS mutations with a concordance of 76%, sensitivity of 50%, and specificity of 80%. Fourteen KRAS mutations were detected by ctDNA only. The interval between archival tissue and ctDNA collection, and time between treatment and ctDNA collection, did not significantly impact the rate of concordance (p> 0.05).

      Conclusion:
      Although the sensitivity is limited, the Boreal Genomic OnTarget ctDNA analysis is specific in identifying clinically relevant EGFR mutations and has acceptable concordance rates between ctDNA and atDNA testing. Targetable EGFR and KRAS mutations were detected in ctDNA but not atDNA, which may reflect site of biopsy, tumor heterogeneity, or technical limitations of assays used. Given the high specificity and non-invasive nature of this test, positive results in EGFR mutations can be used to direct therapeutic decisions, especially accounting for clonal evolution overtime in detection of resistance mutations.