CALIFORNIA THORACIC SOCIETY

Transcription

1 CALIFORNIA THORACIC SOCIETY ANNUAL EDUCATIONAL CONFERENCE SATURDAY, JANUARY 27, 2018 REGISTRATION/EXHIBITS Saturday, January 27, :00 a.m. 8:00 a.m.

2 2018 EXHIBITORS CALIFORNIA THORACIC SOCIETY ANNUAL EDUCATIONAL CONFERENCE FRIDAY, JANUARY 26 SATURDAY, JANUARY 27, 2018 American Lung Association in California AstraZeneca Boehringer Ingelheim (2) California Society of Respiratory Care Circassia Electromed Fisher Paykel Healthcare Genentech Gilead Sciences GlaxoSmithKline Grifols Hill-Rom Infocare Healthcare Systems Insmed Novartis Pulmonary Fibrosis Foundation RespirTech Teva Pharmaceuticals Veracyte Inc. Vertex Note that all exhibitors are located in the Club House in the Oak Room, Garden Room and the Ballroom Foyer.

3 INTRODUCTION AND PRE-TEST Lorriana Leard, MD UCSF Professor of Clinical Medicine Saturday, January 27, :00 a.m. 8:05 a.m. Lorriana Leard, MD is Professor of Clinical Medicine at the University of California San Francisco. She received her undergraduate degree from Stanford University and her M.D. from the University of California San Diego. After completing her Internal Medicine residency at the University of Texas Southwestern in Dallas, she came to the University of California San Francisco for her Pulmonary and Critical Care Fellowship. She completed an additional subspecialty fellowship in Advanced Bronchoscopy and Lung Transplantation at the University of California San Francisco. She is currently the Associate Program Director for the Pulmonary and Critical Care Medicine Fellowship and the Vice Chief of Clinical Operations for the UCSF Division of Pulmonary, Critical Care, Allergy and Sleep Medicine. She specializes in the care of patients with lung cancer and advanced lung diseases who are candidates for lung transplants. As an expert at the UCSF Helen Diller Family Comprehensive Cancer Center, she evaluates patients who have lung nodules, lung masses or symptoms suggestive of lung cancer, and she helped to establish the Lung Cancer Screening Program at UCSF.

4 IMAGING OF LUNG CANCER A REVIEW OF THE 8 TH TNM STAGING SYSTEM Travis Henry, MD UCSF Associate Professor of Radiology Saturday, January 27, :05 a.m. 8:40 a.m. Travis Henry, MD received his medical degree from Vanderbilt University, followed by diagnostic radiology residency and fellowship in cardiothoracic imaging at Washington University in St Louis. He was on faculty at Emory for four years before moving to UCSF in 2015, where he currently serves as Associate Professor of Radiology. Dr. Henry is the director of the cardiothoracic imaging fellowship at UCSF, and has committee appointments in many national and international radiology organizations including the American College of Radiology, American Roentgen Ray Society, Radiologic Society of North America, and the Society of Thoracic Radiology.

5 1/8/18 Imaging of Lung Cancer: A Review of the 8 th TNM Staging System Travis S Henry, MD Associate Professor of Clinical Radiology Cardiac and Pulmonary Imaging Section University of California, San Francisco Disclosures: Spouse - Senior Medical Science Director (ophthalmology), Genentech 1

6 1/8/18 Do you have the 7 th TNM Staging System memorized? A. Yes B. At one point I knew it, but not anymore C. No, but I wish I did D. No, and I have no intention of memorizing it E. What is the TNM staging system? 7th TNM Staging System 1 1 Occult Carcinoma TX N0 M0 2 Stage 0 Tis N0 M0 3 Stage IA T1a N0 M0 4 T1b N0 M0 5 Stage IB T2a N0 M0 6 Stage IIA T2b N0 M0 7 T1a N1 M0 8 T1b N1 M0 9 T2a N1 M0 10 Stage IIB T2b N1 M0 11 T3 N0 M0 12 Stage IIIA T1a N2 M0 13 T1b N2 M0 14 T2a N2 M0 15 T2b N2 M0 16 T3 N1 M0 17 T3 N2 M0 18 T4 N0 M0 19 T4 N1 M0 20 Stage IIIB T1a N3 M0 21 T1b N3 M0 22 T2a N3 M0 23 T2b Ne M0 24 T3 N3 M0 25 T4 N2 M0 26 T4 N3 M0 27 Stage IV Any T Any N M1a 28 Any T Any N M1b 1 Adapted from AJCC Lung Cancer Staging 7 th Edition 2

7 1/8/18 The EIGHTH edition of the TNM classification for lung cancer became the worldwide standard January 1, 2017 except in the US, where it is to be adopted in Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The Eighth Edition Lung Cancer Stage Classification. Chest 2017; 151: th TNM Staging System 2 1 Occult Carcinoma TX N0 M0 2 Stage 0 Tis N0 M0 3 Stage IA1 T1a(mi) N0 M0 4 T1a N0 M0 5 Stage IA2 T1b N0 M0 6 Stage IA3 T1c N0 M0 7 Stage IB T2a N0 M0 8 Stage IIA T2b N0 M0 9 Stage IIB T1a-c N1 M0 10 T2a N1 M0 11 T2b N1 M0 12 T3 N0 M0 13 Stage IIIA T1a-c N2 M0 14 T2a-b N2 M0 15 T3 N1 M0 16 T4 N0 M0 17 T4 N1 M0 18 Stage IIIB T1a-c N3 M0 19 T2a-b N3 M0 20 T3 N2 M0 21 T4 N2 M0 22 Stage IIIC T3 N3 M0 23 T4 N3 M0 24 Stage IVA Any T Any N M1a 25 Any T Any N M1b 26 Stage IVB Any T Any N M1c 2 Adapted from Goldstraw P et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology 2016; 11:

8 1/8/18 Any metastases: Stage IV N3 nodes: Stage IIIB Surgery rarely performed beyond IIIA 8th TNM Staging System 2 1 Occult Carcinoma TX N0 M0 2 Stage 0 Tis N0 M0 3 Stage IA1 T1a(mi) N0 M0 4 T1a N0 M0 5 Stage IA2 T1b N0 M0 6 Stage IA3 T1c N0 M0 7 Stage IB T2a N0 M0 8 Stage IIA T2b N0 M0 9 Stage IIB T1a-c N1 M0 10 T2a N1 M0 11 T2b N1 M0 12 T3 N0 M0 13 Stage IIIA T1a-c N2 M0 14 T2a-b N2 M0 15 T3 N1 M0 16 T4 N0 M0 17 T4 N1 M0 18 Stage IIIB T1a-c N3 M0 19 T2a-b N3 M0 20 T3 N2 M0 21 T4 N2 M0 22 Stage IIIC T3 N3 M0 23 T4 N3 M0 24 Stage IVA Any T Any N M1a 25 Any T Any N M1b 26 Stage IVB Any T Any N M1c 2 Adapted from Goldstraw P et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology 2016; 11:39-51 Any metastases: Stage IV N3 nodes: Stage IIIB Surgery rarely performed beyond IIIA 8th TNM Staging System 2 1 Occult Carcinoma TX N0 M0 2 Stage 0 Tis N0 M0 3 Stage IA1 T1a(mi) N0 M0 4 T1a N0 M0 5 Stage IA2 T1b N0 M0 6 Stage IA3 T1c N0 M0 7 Stage IB T2a N0 M0 8 Stage IIA T2b N0 M0 9 Stage IIB T1a-c N1 M0 10 T2a N1 M0 11 T2b N1 M0 12 T3 N0 M0 13 Stage IIIA T1a-c N2 M0 14 T2a-b N2 M0 15 T3 N1 M0 16 T4 N0 M0 17 T4 N1 M0 18 Stage IIIB T1a-c N3 M0 19 T2a-b N3 M0 20 T3 N2 M0 21 T4 N2 M0 22 Stage IIIC T3 N3 M0 23 T4 N3 M0 24 Stage IVA Any T Any N M1a 25 Any T Any N M1b 26 Stage IVB Any T Any N M1c 2 Adapted from Goldstraw P et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology 2016; 11:

9 1/8/18 Any metastases: Stage IV N3 nodes: Stage IIIB Surgery rarely performed beyond IIIA 8th TNM Staging System 2 1 Occult Carcinoma TX N0 M0 2 Stage 0 Tis N0 M0 3 Stage IA1 T1a(mi) N0 M0 4 T1a N0 M0 5 Stage IA2 T1b N0 M0 6 Stage IA3 T1c N0 M0 7 Stage IB T2a N0 M0 8 Stage IIA T2b N0 M0 9 Stage IIB T1a-c N1 M0 10 T2a N1 M0 11 T2b N1 M0 12 T3 N0 M0 13 Stage IIIA T1a-c N2 M0 14 T2a-b N2 M0 15 T3 N1 M0 16 T4 N0 M0 17 T4 N1 M0 18 Stage IIIB T1a-c N3 M0 19 T2a-b N3 M0 20 T3 N2 M0 21 T4 N2 M0 22 Stage IIIC T3 N3 M0 23 T4 N3 M0 24 Stage IVA Any T Any N M1a 25 Any T Any N M1b 26 Stage IVB Any T Any N M1c 2 Adapted from Goldstraw P et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology 2016; 11:39-51 Table the table Objectives Letter-by-letter: findings that alter staging (and what should be in the report) Review changes for the 8 th TNM system 5

10 1/8/18 Staging does not dictate management T4N0M0 Stage IIIA T1BN0M0 Stage IA Staging is a guide to management T4N0M0 Stage IIIA Pneumonectomy 6

11 1/8/18 Staging is a guide to management Radiation Staging is a guide to management and prognosis Year 2 Year 2 7

12 1/8/18 Where does the TNM Staging Apply? Non-small cell lung cancer Small cell lung cancer Bronchopulmonary carcinoid* T primary Tumor N lymph Node involvement M Metastases 8

13 1/8/18 64-year-old man 9

14 1/8/18 What is the minimum M descriptor based on these images? A. M0 B. M1a C. M1b D. M1c M Distant Metastasis Thorax M1a M1a Brain Bone Liver Adrenal Lymph nodes M1b Or M1c 10

15 1/8/18 M Distant Metastasis Thorax M1a M1a Brain Bone Liver Adrenal Lymph nodes M1b Or M1c M Distant Metastasis M1a intrathoracic 65-year-old woman Pleura Pericardium Contralateral lung Pericardiocentesis (+) for adenocarcinoma 11

16 1/8/18 M Distant Metastasis M1a intrathoracic 64-year-old woman Pleura Pericardium Contralateral lung *lymphangitic carcinomatosis not included in TNM 2.3 cm (T1c) adenocarcinoma referred for SBRT Pleural fluid (+ adenocarcinoma) à M1a 12

17 1/8/18 Diffuse adenocarcinoma Bilateral pulmonary disease à M1a M1b 8 th TNM M1c One extrathoracic metastasis Multiple extrathoracic metastasis (in 7 th TNM all extrathoracic metastases were M1b) 13

18 1/8/18 M1b One extrathoracic metastasis M1c Multiple extrathoracic metastasis Eberhardt WE et al. The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol 2015; 10: % of lung cancers have metastases at presentation 1 1 Niu FY et al. Distribution and prognosis of uncommon metastases from non-small cell lung cancer. BMC Cancer 2016; 16:149 14

19 1/8/18 T1bN0 ONE Extrathoracic Metastasis à M1b M1c - Multiple Metastases in one organ 15

20 1/8/18 M1c - Multiple Metastases in one organ 1.7cm T1bN0 M1c - Multiple Organs Adenocarcinoma T2bN0M1c 16

21 1/8/18 M Intrathoracic metastases (M1a)? Pleura/pericardium Contralateral lung Extrathoracic metastases? One metastasis à M1b Multiple à M1c 27-year-old man with LLL squamous cell carcinoma 17

22 1/8/18 This patient s N classification is likely? A. N0 B. N1 C. N2 D. N3 N3 N2 N1 18

23 1/8/18 No Changes to N for 8 th TNM Staging System N3 N2 N1 19

24 1/8/18 N1: T1cN1M0 -Ipsilateral hilar (or further out in the lung) N1 Nodes but metastatic disease (M1c) 20

25 1/8/18 Subcarinal Nodes are N2 (regardless of side of cancer) T2b LLL adenocarcinoma 21

26 1/8/18 N2: Subcarinal Ipsilateral mediastinal N2: Subcarinal Ipsilateral mediastinal Left Lower Lobe Primary 22

27 1/8/18 Right lung cancer Left lung cancer Paratracheal left versus right? N2 (right) N2 (left) The LEFT border of the trachea is midline 23

28 1/8/18 Clinical (c) vs Pathologic (p) staging Clinical (c) vs Pathologic (p) staging ct2an1m0 c = Data obtained before definitive treatment -imaging -physical exam -biopsy/fluid analysis 24

29 1/8/18 At surgery: 2/2 level 4R lymph nodes à positive for adenocarcinoma 1/1 level 2R lymph node à positive for adenocarcinoma Clinical (c) vs Pathologic (p) staging pt2an2m0 p = Data obtained from surgery as part of definitive treatment 25

30 1/8/18 N3 N3 lymph nodes Contralateral mediastinal/hilar Supraclavicular/scalene N3 Contralateral mediastinal/hilar Supraclavicular/scalene (either side) 26

31 1/8/18 Other node chains still not included in 8 th TNM staging N N0 No mets N1 Same lung/same hilum N2: Subcarinal Ipsilateral mediastinal N3: Contralateral mediastinum/hilum Supraclavicular/scalene 27

32 1/8/18 66-year-old woman What is the correct measurement and T-descriptor (8 th TNM)? 2.3 cm A. 2.3cm, T=1b B. 2.3cm, T=1c C. 1.8cm, T=1b D. 1.8cm, T=1c 1.5 cm 28

33 1/8/18 Longest Dimension Measurement for T (short axis for N) 2.3 cm T Tumor Size (cm) 7th 8th 1 T1a T1a >1-2 T1b >2-3 T1b T1c >3-4 T2a T2a >4-5 T2b >5-6 T2b T3 2.3 cm >6-7 >7 T3 T4 29

34 1/8/18 T Tumor Size (cm) 7th 8th 1 T1a T1a >1-2 T1b >2-3 T1b T1c >3-4 T2a T2a >4-5 T2b >5-6 T2b T3 2.3 cm >6-7 >7 T3 T4 Rami-Porta R et al. The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015; 10:

35 1/8/18 Two components of the T descriptor Size: -Longest dimension -1 cm increments Invasion: T2 à Bronchus T3 à Chest Wall/Apex * T4à Everything Else * (Also includes phrenic nerve) 31

36 1/8/18 Size à T1c Invasion à T2 T2 Invasion: Bronchus invasion/ obstruction* *Carina/trachea T4 Distance from carina no longer important in 8 th TNM* 4cm 1cm Both are T2 tumors 32

37 1/8/18 T3 Invasion: Chest Wall Pancoast Tumor Phrenic Nerve 3.2cm tumor; chest wall invasion à T3 T3 Invasion: Chest Wall Pancoast Tumor Phrenic Nerve 33

38 1/8/18 T4 Invasion: (everything else) Mediastinum Heart Great vessels Trachea/carina Vertebral body Diaphragm T4 Invasion: (everything else) Mediastinum Heart Great vessels Trachea/carina Vertebral body Diaphragm 34

39 1/8/18 T4 Invasion: (everything else) Mediastinum Heart Great vessels Trachea/carina Vertebral body Diaphragm Left atrial invasion; tumor still resected T Satellite Nodules Same lobe T3 Same lung, different lobe T4 Other lung M1a 35

40 1/8/18 Two components of the T descriptor Size: -Longest dimension -1 cm increments Invasion: T2 à Bronchus T3 à Chest Wall/Apex phrenic nerve satellite nodules in same lobe T4à Everything Else satellite nodules in same lung SPECIAL SITUATIONS: Small Cell Carcinoma 36

41 1/8/18 TNM applies to Small Cell Carcinoma Prior to 7th staged as limited or extensive 37

42 1/8/18 Few SCC patients treated surgically Underwent LLLectomy and PA resection SPECIAL SITUATIONS: Adenocarcinoma Mixed solid and groundglass nodule Multiple Adenocarcinomas Pneumonic Adenocarcinoma 38

43 1/8/18 Mixed solid and GGO: Solid (invasive component) measured separately (total lesion diameter should also be reported) Carter BW, Godoy MCB, Wu CC, Erasmus JJ, Truong MT. Current Controversies in Lung Cancer Staging. Journal of Thoracic Imaging 2016; 31: Pneumonic type of mucinous adenocarcinoma T3 (same lobe) T4 (same lung) M1a if both lungs 39-year-old (Often have better prognosis) 39

44 1/8/18 Pneumonic type of mucinous adenocarcinoma Original T3 (same lobe) T4 (same lung) M1a if both lungs Pneumonic type of mucinous adenocarcinoma Original T3 (same lobe) T4 (same lung) M1a if both lungs 1 year later 40

45 1/8/18 For multifocal GGO: T stage of largest nodule For multifocal GGO: T stage of largest nodule 41

46 1/8/18 SPECIAL SITUATIONS: Synchronous Lung Cancers Squamous cell carcinoma Synchronous primaries Each TNM separate Small cell carcinoma 42

47 1/8/18 Should you expect a stage in the report? Glastonbury CM, et al. Do Radiologists Have Stage Fright? Tumor Staging and How We Can Add Value to the Care of Patients with Cancer. Radiology 2016; 278:

48 1/8/ cm left upper lobe mass with possible mediastinal invasion à T2a Enlarged, enhancing subaortic lymph node à N2 Left pleural effusion with enhancing nodularity à M1a Conclusion T and M have changed for the 8 th TNM system T Size, Invasion N further away from primary, higher N M: Intrathoracic M1a Extrathoracic One M1b Multiple M1c 44

49 1/8/18 Thank You! For references and more information please see my website (below) Lymph node map app: THrads.com References Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. Journal of Thoracic Oncology 2016; 11: Rami-Porta R, Bolejack V, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015; 10: Asamura H, Chansky K, Crowley J, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015; 10: Eberhardt WE, Mitchell A, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol 2015; 10: Boxer MM, Vinod SK, Shafiq J, Duggan KJ. Do multidisciplinary team meetings make a difference in the management of lung cancer? Cancer 2011; 117: Pillay B, Wootten AC, Crowe H, et al. The impact of multidisciplinary team meetings on patient assessment, management and outcomes in oncology settings: A systematic review of the literature. Cancer Treat Rev 2016; 42: Friedman EL, Kruklitis RJ, Patson BJ, Sopka DM, Weiss MJ. Effectiveness of a thoracic multidisciplinary clinic in the treatment of stage III non-small-cell lung cancer. J Multidiscip Healthc2016; 9: El-Sherief AH, Lau CT, Wu CC, Drake RL, Abbott GF, Rice TW. International association for the study of lung cancer (IASLC) lymph node map: radiologic review with CT illustration. Radiographics 2014; 34: De Ruysscher D, Wanders R, van Baardwijk A, et al. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct ). J Thorac Oncol 2012; 7: Detterbeck FC, Nicholson AG, Franklin WA, et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol 2016; 11: Carter BW, Godoy MCB, Wu CC, Erasmus JJ, Truong MT. Current Controversies in Lung Cancer Staging. Journal of Thoracic Imaging 2016; 31: Kligerman S, Abbott G. A radiologic review of the new TNM classification for lung cancer. AJR Am J Roentgenol 2010; 194: Nicholson AG, Chansky K, Crowley J, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the Clinical and Pathologic Staging of Small Cell Lung Cancer in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2016; 11: AJCC Lung Cancer Staging 7th Edition (accessed ) 45

50 ADVANCING THE DIAGNOSIS: ROLE OF INTERVENTIONAL PULMONOLOGY IN APPROACHES TO DIAGNOSIS, STAGING AND MANAGEMENT OF LUNG CANCER Ganesh Krishna, MD UCSF/Palo Alto Medical Foundation Director of Interventional Pulmonology Saturday, January 27, :40 a.m. 9:15 a.m. Ganesh Krishna, MD did his fellowship in Pulmonary/Critical Care Medicine at Stanford University after completing his Internal Medicine Residency at George Washington University, Washington, DC. He subsequently served as on the faculty at Stanford for eight years. During this time, he took time off to do a six month fellowship in Germany in Interventional Pulmonology. He is board certified in Internal Medicine, Pulmonary Medicine, Critical Care and Interventional Pulmonology. He is currently an Associate Professor of Medicine at UCSF and the Program Director of the UCSF/PAMF Interventional Program

51 PERSONALIZED TREATMENT APPRPOACHES TO LUNG CANCER Matthew Gubens, MD UCSF Associate Professor of Medicine Saturday, January 27, :15 a.m. 9:55 a.m. Matthew Gubens, MD is Associate Professor of Medicine at the University of California, San Francisco where he practices as a thoracic medical oncologist. He serves as Chair of the UCSF Thoracic Oncology Site Committee, which oversees the lung cancer clinical trial portfolio. Dr. Gubens serves on the National Comprehensive Cancer Network (NCCN) Guideline panels for Non-Small Cell Lung Cancer, Mesothelioma, and Thymic Malignancies. He completed his MD at Stanford, and trained in internal medicine at UCSF and in medical oncology at Stanford.

52 Personalized Treatment Approaches for Lung Cancer California Thoracic Society 2018 Annual Carmel Conference January 27, 2018 Matthew Gubens, MD, MS Associate Professor of Medicine Chair, Thoracic Oncology Site Committee UCSF Helen Diller Family Comprehensive Cancer Center Disclosures Consulting AbbVie, ARIAD, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Mersana, Novartis, Pfizer Research Funding (to institution) Celgene, Merck, Novartis, OncoMed, Roche I will discussing non-fda approved treatment/ indications during my presentation today (research findings) 1 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

53 Two themes Targeted therapies 2nd+ generation approaches in old mutations: EGFR, ALK 1st generation approaches in new mutations Immunotherapy Where we re at: PD-1 inhibition in the 2nd and 1st line Where we re going: combos and early stage Two themes Targeted therapies 2nd+ generation approaches in old mutations: EGFR, ALK 1st generation approaches in new mutations Immunotherapy Where we re at: PD-1 inhibition in the 2 nd and 1st line Where we re going: combos and early stage 2 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

54 Targets Li TH. Genotyping and genomic profiling of NSCLC: Implications for current and future therapies. JCO 2013;31(8): Targets Li TH. Genotyping and genomic profiling of NSCLC: Implications for current and future therapies. JCO 2013;31(8): /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

55 Histology?? Targets Li TH. Genotyping and genomic profiling of NSCLC: Implications for current and future therapies. JCO 2013;31(8): /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

56 Targets Li TH. Genotyping and genomic profiling of NSCLC: Implications for current and future therapies. JCO 2013;31(8): Two themes Targeted therapies 2nd+ generation approaches in old mutations: EGFR, ALK 1st generation approaches in new mutations Immunotherapy Where we re at: PD-1 inhibition in the 1st and 2nd line Where we re going: combos and early stage 5 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

57 EGFR Epidermal growth factor receptor 10-30% of NSCLC patients Higher prevalence among: Asians Younger patients Females Never-smokers Adenocarcinoma EGFR 3 approved first line drugs: erlotinib, gefitinib, afatinib 2009 IPASS study (Mok et al in NEJM) 6 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

58 EGFR 1 st line use established since but resistance inevitably develops. Sequist, Sci Transl Med, EGFR 1 st line use established since but resistance inevitably develops. Sequist, Sci Transl Med, /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

59 EGFR resistance: T790M, the gatekeeper EGFR resistance: T790M, the gatekeeper Osimertinib Engineered to inhibit EGFR exon 19/L858R AND T790M, but less inhibitory of normal ( wild-type ) EGFR Effectiveness when erlotinib (or others) fail Fewer toxicities Janne, NEJM /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

60 Osimertinib first line Soria, NEJM EGFR take-home points Cancers evolve Biopsy at the beginning to figure out the driver mutation...and consider biopsy at progression to figure out the resistance mechanism (at least for EGFR) Osimertinib should follow 1st line 1st/2nd gen EGFR agent if T790M found...and should now be 1st line in most patients (pending approval) Future directions: Study resistance to osimertinib? 3rd/4th generation drugs? 9 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

61 EGFR epidermal growth factor receptor ALK anaplastic lymphoma kinase 10-30% of NSCLC patients Higher prevalence among: Asians Younger patients Females Never-smokers Adenocarcinoma 4-7% of NSCLC patients Higher prevalence among: - Younger patients - Never-smokers Adenocarcinoma ALK 2007 detected as an alteration in NSCLC 2011 crizotinib approved Single-arm ORR 50, 61% Vs docetaxel in the 2 nd line, PFS 7.7 vs 3.0 mos Vs platinum combo in the 1 st line, PFS 10.9 vs 7.0 mos Solomon, NEJM /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

62 ALK but resistance inevitably develops. Why? Crizotinib good, not great as an ALK inhibitor, so cancer can overcome it Poor brain penetration, so cancer can thrive there Other mutations develop 2 nd generation ALK inhibitors better ALK activity, better CNS activity Ceritinib approved 2014 (duration 7.1 mos post-crizotinib) Alectinib approved 2015 (duration 7.5 mos post-crizotinib) ALK resistance But what about 2 nd generation first line? ALEX (ASCO 2017, NEJM 2017), alectinib vs crizotinib RR 83 vs 76% FDA approved 11/17 Peters, NEJM /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

63 ALK take-home points Cancers evolve Biopsy at the beginning to figure out the driver mutation And biopsy at progression to determine next drug? Lorlatinib 31% after 3 prior TKIs Gainor, Cancer Discovery, 2016 Two themes Targeted therapies 2nd+ generation approaches in old mutations: EGFR, ALK 1st generation approaches in new mutations Immunotherapy Where we re at: PD-1 inhibition in the 2nd and 1st line Where we re going: combos and early stage 12 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

64 Targets other than EGFR and ALK Li TH. Genotyping and genomic profiling of NSCLC: Implications for current and future therapies. JCO 2013;31(8): Targets other than EGFR and ALK Li TH. Genotyping and genomic profiling of NSCLC: Implications for current and future therapies. JCO 2013;31(8): /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

65 Targets other than EGFR and ALK ASCO 2015 BRAF V600E (more often seen in melanoma), 1-2% Dabrafenib + trametinib ORR 63%, PFS 9.7mo Now FDA approved for NSCLC ASCO 2016 MET exon 14 skipping, 3-4% (often older patients, current/former smokers, sarcomatoid) Crizotinib ORR 44%, PFS not yet reached RET rearrangement, 1-2% Cabozantinib ORR 38% Vandetinib ORR 53% Take-home points on other targets You can t treat a mutation you don t know 14 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

66 The NCCN NSCLC Guidelines panel strongly advises broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC. Take-home points on other targets You can t treat a mutation you don t know Beyond EGFR and ALK, drugs may not be FDA-approved Should we treat? 15 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

67 NCCN on emerging targeted agents Take-home points on other targets You can t treat a mutation you don t know Beyond EGFR and ALK, drugs may not be FDA-approved Should we treat? Consider clinical trials! Access to new drugs, data for everyone. 16 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

68 Two themes Targeted therapies 2nd+ generation approaches in old mutations: EGFR, ALK 1st generation approaches in new mutations Immunotherapy Where we re at: PD-1 inhibition in the 2nd and 1st line Where we re going: combos and early stage Immunotherapy: Not a new idea Cancer Research Institute website 17 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

69 Immunotherapy: PD1/PD-L1 (and CTLA4) Ribas A. NEJM /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

70 Immunotherapy- PD1/PD-L1 High rates of somatic mutations in lung cancer may contribute to increased immunogenicity Therapies targeting the PD-L1/PD-1 pathway will alter the treatment of NSCLC 1 Lawrence MS, et al. Nature. 2013;499(7457): Chen DS, et al. CCR /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

71 Checkmate 017: Nivolumab vs docetaxel in squamous cell NSCLC Nivolumab prescribing instructions Checkmate 017/057: Nivolumab vs docetaxel Squamous Non-squamous Response rate Nivo 20% vs docetaxel 9% Median duration of response Nivo NR vs docetaxel 8.4mo Response rate on 057 Nivo 19% vs docetaxel 12% Median duration of response Nivo 17.2mo vs docetaxel 5.6mo Nivolumab PI, Paz-Ares, ASCO /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

72 Checkmate 057: Nivo vs doce in non-squam NSCLC Paz-Ares, ASCO 2015 Checkmate 057: Nivo vs doce in non-squam NSCLC Paz-Ares, ASCO /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

73 KEYNOTE-010: Pembrolizumab vs docetaxel in PD-L1+ NSCLC Overall survival PD-L1>50% pts Pembro 14.9 vs 17.3 vs docetaxel 8.2 mo All pts PD-L1>1% Pembro 10.2 vs 12.7 vs docetaxel 8.5 mo Herbst, Lancet 2016 OAK: Atezolizumab vs docetaxel, 2 nd or 3 rd line (PD-L1 inhibitor) Barlesi, ESMO /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

74 Safety of PD-1 inhibitors Superior tolerability compared to chemo Immunerelated toxicity is unique: anything -itis Herbst, Lancet 2016 PD-1 inhibitor 2nd line take-home messages Nivolumab, pembrolizumab and atezolizumab with different study strategies, similar benefit and toxicity Nivo and atezo approved for all comers 2 nd line Pembro approved for PD-L1+ >1% 2 nd line Nivo q2w, atezo and pembro q3w Toxicities DIFFERENT than chemo Majority find it better tolerated...but any organ can be inflamed Low threshold to evaluate CT chest (pneumonitis), thyroid function tests (hypo or hyperthyroiditis), etc Consider use of steroid, other immune modulators 23 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

75 PD-1 inhibitor 1 st line? 1 st line trials presented at ESMO 2016 Pembro vs chemo in PD-L1 50% Nivo vs chemo in PD-L1 5% PD-1 inhibitor 1 st line? 1 st line trials presented at ESMO 2016 Pembro vs chemo in PD-L1 50% POSITIVE Nivo vs chemo in PD-L1 5% NEGATIVE 24 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

76 Pembrolizumab 1 st line (PD-L1 50%) Recht, ESMO 2016 Pembrolizumab 1 st line (PD-L1 50%) Recht, ESMO /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

77 Pembrolizumab 1 st line (PD-L1 50%) Recht, ESMO 2016 Pembrolizumab 1 st line (PD-L1 50%) Recht, ESMO 2016 Crossover from chemo to pembro: 66/151 (44%) 26 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

78 Pembrolizumab 1 st line (PD-L1 50%) Recht, ESMO 2016 Nivolumab 1 st line (PD-L1 5%) Socinski, ESMO /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

79 Nivolumab 1 st line (PD-L1 5%) Socinski, ESMO 2016 Take-home points: 1 st line And 2 nd line (if chemo 1 st line): Nivolumab Pembrolizumab (PD-L1>1%) Atezolizumab 28 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

80 Two themes Targeted therapies 2nd+ generation approaches in old mutations: EGFR, ALK 1st generation approaches in new mutations Immunotherapy Where we re at: PD-1 inhibition in the 2nd and 1st line Where we re going: combos and early stage Future of immunotherapy in NSCLC Use PD1 inhibitors with chemo? Motivation: Cancer cell death release cancer cell antigens improved priming and activation might let PD1 inhibitors work better Caveats: Steroids with some chemos General immunosuppressive state post-chemo Compound toxicity Awaiting phase 3 studies of chemo +/- PD1 inhibitors Early data: Langer et al (Lancet Oncol and ESMO 2016), n=123 carboplatin/pemetrexed +/- pembrolizumab RR 55 vs 29%, PFS 13.0 vs 8.9 mo APPROVED by FDA 5/10/17, before phase 3 data released 29 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

81 Future of immunotherapy in NSCLC Use PD1 inhibitors with other immunotherapy? Motivation: PD1 inhibition alone only works in 20% of tumors what about the rest? Can we prime for response to PD1 inhibition? Caveats: Hard to anticipate results based on pre-clinical models Additive (even synergistic) efficacy possible, but so is additional toxicity Awaiting studies of chemo vs PD1 vs PD1/CTLA4 CTLA4 inhibitor already approved in melanoma (ipilimumab) Early data: Hellman et al (ASCO 2016) nivolumab vs nivolumab/ipilimumab Early data: 1 st line nivo/ipi Await data from adequately powered phase 3 trials next year? Hellman, ASCO /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

82 Early data: 1 st line nivo/ipi Hellman, ASCO 2016 Future of immunotherapy in NSCLC Use PD1 inhibitors in early stage disease? Motivation: Potential downstaging, research platform for evaluating treatment effect in vivo Caveats: Toxicity Upstaging if not effective, esp in aggressive tumors Awaiting early studies 31 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

83 Early data: Neoadjuvant nivo UCSF efforts: Neoadjuvant pembrolizumab 2 approved investigator-initiated studies PembroX (Yom, Fong, Gubens, Jablons) Neoadjuvant pembro +/- XRT IO-SPY Lung (Gubens, Fong, Jablons) Neoadjuvant pembro combinations 32 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

84 UCSF efforts: Neoadjuvant pembrolizumab IO-SPY Lung (Gubens, Fong, Jablons) varlilumab = CD27 agonist, epacadostat = IDO inhibitor Future of immunotherapy in NSCLC Chen and Mellman, Immunity /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

85 Future of immunotherapy in NSCLC Chen and Mellman, Immunity 2013 Future of immunotherapy key points Stay tuned for data on chemo combos for data on immunotherapy combos for data on immunotherapy in earlier stage disease Clinical trials are the way forward Special role for immunorefractory patients Value in medicine 34 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

86 35 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

87 Future of immunotherapy key points Stay tuned for data on chemo combos for data on immunotherapy combos for data on immunotherapy in earlier stage disease Clinical trials are the way forward Special role for immunorefractory patients Value in medicine These are expensive drugs...but optimizing them (better combos, better patient selection) may yield superior value by meaningfully improving survival in our patients Thank you! 36 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

88 BREAK EXHIBIT HALL OPEN Saturday, January 27, :55 a.m. 10:10 a.m.

89 2018 EXHIBITORS CALIFORNIA THORACIC SOCIETY ANNUAL EDUCATIONAL CONFERENCE FRIDAY, JANUARY 26 SATURDAY, JANUARY 27, 2018 American Lung Association in California AstraZeneca Boehringer Ingelheim (2) California Society of Respiratory Care Circassia Electromed Fisher Paykel Healthcare Genentech Gilead Sciences GlaxoSmithKline Grifols Hill-Rom Infocare Healthcare Systems Insmed Novartis Pulmonary Fibrosis Foundation RespirTech Teva Pharmaceuticals Veracyte Inc. Vertex Note that all exhibitors are located in the Club House in the Oak Room, Garden Room and the Ballroom Foyer.

90 RADIATION THERAPY FOR LUNG CANCER Megan Daly, MD UC Davis Associate Professor, Radiation Oncology Saturday, January 27, :10 a.m. 10:45 a.m. Megan Daly, MD received her medical degree at Stanford University, and completed residency training in the department of radiation oncology at Stanford. She is currently an Associate Professor in the Department of Radiation Oncology at the University of California Davis, and specializes in thoracic malignancies.

91 1/21/2018 Radiation Therapy for Lung Cancer Megan E. Daly MD Associate Professor Department of Radiation Oncology UC Davis Comprehensive Cancer Center Disclosures Research Funding: EMD Serono 1

92 1/21/2018 Overview: Current use of radiation for Lung Cancer Current Status of SBRT for early stage NSCLC Role in operable patients Next directions Current Status of Radiation for Locally Advanced NSCLC Next directions Lung cancer palliation with radiation Management of radiation induced lung toxicity Radiation for Lung Cancer Early stage medically inoperable disease Early stage medically operable (investigational) Locally advanced (IIIA/IIIB) Small Cell Lung Cancer Palliation of metastatic disease Ablative therapy for oligometastatic/oligoprogressive disease 2

93 1/21/2018 Radiotherapy for Lung Cancer: Key Issues Minimizing Toxicity Small margins (daily setup is crucial) Accounting for lung motion in the planning process Ability to sculpt dose around critical structures Maximizing Tumor Control Ability to deliver ablative doses while sparing normal tissues Treatment Planning Challenges Proximity to critical structures Irregularly shaped target volumes Moving tumors 3

94 1/21/2018 Lung SBRT: Overview and Uses Use of highly conformal radiation using ablative doses over 1 5 treatments Lung Stereotactic Body Radiotherapy (SBRT) Standard of care option for medically inoperable patients with early stage non small cell lung cancer (NSCLC) Non invasive, outpatient procedure over 3 5 sessions High local control rates (>90%) 4

95 1/21/2018 Methods of compensating for respiratory motion Free Breathing ITV Abdominal Compression Respiratory Gating Tumor Tracking Defining an ITV: 4DCT 5

96 1/21/2018 Respiratory Gating Abdominal Compression 6

97 1/21/2018 Lung SBRT: Clinical Outcomes RTOG 0236 (JAMA 2010) Phase II study; medically inoperable pts with T1 2 N0 NSCLC 54 Gy/3 fx 3 yr Primary tumor control 97.6% 3 yr Local Control 90.6% 3 year Distant Failure Rate: T1: 14.7% T2: 47% 3 yr Disease Free Survival 48.3% 3 yr Overall Survival 55.8% 3.6% rate of grade 4 adverse events Current Use of SBRT Standard Option for Medically Inoperable, peripheral early stage (T1 2 NSCLC < 5 cm) 54 Gy in 3 fractions Investigational in medically operable patients Investigational for tumors >5cm Some concerns of increased toxicity for central lung tumors (within 2 cm of proximal bronchial tree), but protracted regimens of 4 8 fractions are generally considered safe Gy in 5 fractions Gy in 5 fractions 60 Gy in 8 fractions 7

98 1/21/2018 Sample SBRT Plan: T2aN0M0 Central NSCLC Sample SBRT Plan: T1N0M0 Peripheral 8

99 1/21/2018 SBRT for Operable Patients: Current Status Several studies have attempted to compare surgery and SBRT in a prospective, randomized fashion and failed to accrue Many retrospective analyses on this topic, but selection bias remains a major problem Propensity matching attempts to limit the bias of retrospective studies by matching patients on baseline characteristics, and reduces influence of varying baseline characteristics Surgical management remains the standard therapy for medically operable patients in absence of completed, randomized trials Prospective Randomized Trials Evaluating SBRT for Operable Patients Trial Eligibility Design Status STARS ROSEL ACOSOG Z0499 T1 2aN0M0 <4 cm, fit for lobectomy T1 2aN0M0 <4 cm fit to tolerable lobectomy Peripheral NSCLC 3 cm; high surgical risk Randomized Phase III comparing lobectomy to SBRT Randomized Phase III comparing lobectomy to SBRT Randomized Phase III comparing sublobar resection to SBRT Terminated due to poor accrual Terminated due to poor accrual Terminated due to poor accrual JoLT Ca STABLE MATES Peripheral NSCLC 4 cm; high surgical risk Pre randomization design; phase III Actively accruing Veterans Affairs Lung Cancer Surgery Or Stereotactic Radiotherapy Trial (VALOR) T1 2N0M0<5 cm fit for lobectomy Randomized Phase III Actively accruing RTOG Foundation 3502 (POSTILV) T1N0M0 3 cm fit for lobectomy Randomized Phase II Actively accruing 9

100 1/21/2018 SBRT Patterns of Failure Primary (in lobe) control 75 98% Locoregional control 60 85% Distant control 55 80% Next Directions in SBRT Strategies to reduce regional/distant failure Adjuvant chemotherapy Immunotherapy Targeted therapy 10

101 1/21/2018 UC Davis Stage I Trial SBRT Gy/fraction QOD x 5 Eligible Early Stage NSCLC patient (n=198) Randomize Priming Concurrent SBRT Gy/fraction QOD x 5 Concurrent Consolidation Follow up Follow up (Chemo)Radiation for Locally Advanced NSCLC Definitive Concurrent Chemoradiation for Unresectable IIIA/IIIB disease Pre operative CRT for well selected, resectable IIIA disease with low burden N2 disease 11

102 1/21/2018 Defining Targets Gross Tumor Volume (GTV): Radiographically involved tumor or nodes Internal Target Volume (ITV): Encompasses tumor excursion due to respiratory motion Clinical Target Volume (CTV): Includes additional margin for microscopic spread Planning Target Volume (PTV): Additional margin for daily setup error Locally Advanced NSLC Technical Advances in RT Planning Intensity Modulated Radiotherapy (IMRT) and Volume Modulated Arc Therapy (VMAT) Allow for concave and convex dose distributions For appropriately selected patients improves sparing of normal tissues Creates sharp dose gradients 4D CT simulation Allows accurate estimation of tumor motion with breathing 12

103 1/21/2018 Lung Cancer Target Definition IMRT T4N0M0 NSCLC 13

104 1/21/2018 IMRT T4N0M0 NSCLC: Sagittal/Coronal IMRT Planning: T2N3M0 adenocarcinoma 14

105 1/21/2018 IMRT Planning: T2N3M0 adenocarcinoma Daily Image Guidance: CBCT 15

106 1/21/2018 Potential Side Effects of Thoracic Radiotherapy Lungs Inflammation Scarring Decreased pulmonary function Heart Pericarditis Scarring/valve damage/increased risk of MI or cardiac death Spinal Cord Myelopathy Esophagus Esophagitis Scarring Radiation induced cancers Reducing Toxicity for Locally Advanced Lung Cancer Pneumonitis Major complication of RT for lung cancer Recent pooled analysis suggests ~30% rate of symptomatic pneumonitis following CRT for stage III NSCLC (Palma et al, 2013) Highest risk groups include elderly and those receiving concurrent carbo/taxol 16

107 1/21/2018 Approaches to reducing pneumonitis risk Reduced margins for setup error and internal motion Daily image guidance Motion management (compression or gating) RT to elective nodal regions is now infrequently used as isolated nodal failure is rare Emerging Approaches to reducing pneumonitis risk Identification and selective avoidance of highfunctioning lung sub regions 4D CT SPECT Other functional imaging techniques 17

108 1/21/2018 4DCT Functional Lung Avoidance 4D CT image Displacement vector field Ventilation image Deformable image registration (DIR) Quantification of regional volume change Slide courtesy of T. Yamamoto PhD, UC Davis Treatment of Radiation Pneumonitis Long prednisone taper is standard for dyspnea 5 6 weeks, starting at 20 mg TID with rapid fall off 18

109 1/21/2018 Radiotherapy for metastatic lung cancer Palliation of painful bone metastases 1 10 fractions Brain metastases Gamma knife (~1 4 lesions) Whole brain radiation (~30 Gy in 10 fractions) SBRT for oligometastatic disease in good performance status patients (investigational) Conclusions Radiotherapy plays an important role in the management of lung cancer SBRT is a standard option for early stage, medically inoperable disease Concurrent or sequential chemoradiation for locally advanced disease Studies are evaluating ways of reducing side effects for these patients Palliation Bone mets, brain mets, airway obstruction, SVC syndrome 19

110 1/21/2018 Thank you! Feel free to me with additional questions 20

111 PULMONARY TOXICITY OF LUNG CANCER THERAPIES Lorriana Leard, MD UCSF Professor of Clinical Medicine Saturday, January 27, :45 a.m. 11:15 a.m. Lorriana Leard, MD is Professor of Clinical Medicine at the University of California San Francisco. She received her undergraduate degree from Stanford University and her M.D. from the University of California San Diego. After completing her Internal Medicine residency at the University of Texas Southwestern in Dallas, she came to the University of California San Francisco for her Pulmonary and Critical Care Fellowship. She completed an additional subspecialty fellowship in Advanced Bronchoscopy and Lung Transplantation at the University of California San Francisco. She is currently the Associate Program Director for the Pulmonary and Critical Care Medicine Fellowship and the Vice Chief of Clinical Operations for the UCSF Division of Pulmonary, Critical Care, Allergy and Sleep Medicine. She specializes in the care of patients with lung cancer and advanced lung diseases who are candidates for lung transplants. As an expert at the UCSF Helen Diller Family Comprehensive Cancer Center, she evaluates patients who have lung nodules, lung masses or symptoms suggestive of lung cancer, and she helped to establish the Lung Cancer Screening Program at UCSF.

112 1/20/2018 Pulmonary Toxicity of Lung Cancer Therapies Lorriana Leard, MD Professor of Clinical Medicine Vice Chief, Clinical Operations Pulmonary, Critical Care, Allergy and Sleep Medicine University of California San Francisco Disclosure Statement I will discuss off label use and/or investigational use of the following drugs/devices: Prednisone The following relevant financial relationships exist related to my role in this session: No relationships to disclosure 1

113 1/20/2018 Outline Drug-related Pulmonary Toxicity can occur with: Chemotherapy (docetaxel, gemcitabine, bleomycin), Targeted therapy Epidermal growth factor receptor inhibitors mtor inhibitors PD-1 and PD-L1 inhibitors Radiation therapy The importance of this new challenge We must develop a working knowledge of the mode of action of these agents and importantly how to diagnose and effectively manage their toxicities. 2

114 1/20/2018 PD-1 Anti-PD-1 monoclonal antibodies nivolumab pembrolizumab (previously lambrolizumab) Pidilizumab Anti-PD-L1 mabs durvalumab atezolizumab PD-1 and PD-L1 mabs Toxicities with anti-pd-1/pd-l1 mabs appear to be less common and less severe 7% to 12% in patients receiving single-agent anti-pd- 1/PD-L1 mabs 3

115 1/20/2018 PD-1 and PD-L1 mabs Adverse events of anti-pd-1/pd-l1 therapy Fatigue Pyrexia, chills, infusion reactions Skin rash (maculopapular, papulopustular, Sweet's syndrome, follicular, or urticarial dermatitis) Diarrhea/colitis Endocrine toxicities (hypophysitis, hypothyroidism, hyperthyroidism, thyroiditis, and adrenal insufficiency) Hepatic toxicities (elevations in AST and ALT levels) Pneumonitis Grade Presentation Diagnostic Testing Management Follow up 1 Asymptomatic with Radiographic changes only Continue therapy Monitor sx q3 days Repeat Chest CT after every cycle or if develops sx Mild / Moderate new symptoms Severe or life threatening Worsening hypoxia Chest CT scanning Consider Bronch +/- other microbial assessment HOLD therapy Monitor sx daily Oral prednisone (1mg/kg/d) STOP therapy Hospitalize IV methylpred 2-4 mg/kg/d If improves to < Grade 1 w/in 3 days, resume therapy. If persists, stop therapy. Taper steroids over 1+ mo. After sx improve to < Grade 1, taper steroids over 6+ wks If worsens, consider additional immunosuppression 4

116 1/20/ year-old man presenting with worsening dyspnea 2004 Adenocarcinoma stage IA RLL lobectomy February 2017 Biopsy proven adenocarcinoma June 2017 Dry cough, low grade fever and progressive dyspnea 7-day treatment for CAP December 2016 Enlarging right middle lobe nodule March 20 th 24 th 2017 SBRT 5000 cgy in 5 fractions June 22 nd 2017 Admitted to UCSF Special thanks to Shoshana Zha, MD for case / slides Other Past Medical History PMH Type-II DM CAD s/p CABG 6/2016, persistent L pleural effusion CHF (EF 50-55%) A-fib & sick sinus with pacemaker HTN CKD stage IV COPD: FEV1 1.4 (67%) MEDICATIONS ASA Atorvastatin Metoprolol XL Bumex 2mg BID Coumadin Glargine Pioglitazone Repaglinide Spiriva daily, Albuterol PRN SH: Smoked pack years, quit ~2003 Occasional alcohol No illicit drug use Special thanks to Shoshana Zha, MD for case / slides 5

117 1/20/2018 Special thanks to Shoshana Zha, MD for case / slides Special thanks to Shoshana Zha, MD for case / slides 6

118 1/20/2018 Special thanks to Shoshana Zha, MD for case / slides Special thanks to Shoshana Zha, MD for case / slides 7

119 1/20/2018 Special thanks to Shoshana Zha, MD for case / slides Differential diagnosis Infection Radiation pneumonitis Organizing pneumonia Diffuse alveolar hemorrhage Hypervolemia Malignancy Special thanks to Shoshana Zha, MD for case / slides 8

120 1/20/2018 Workup/management Started steroids 60mg/day and levoflaxin Radiation Oncology consulted location outside of field was felt to be less likely RP (not centered on fiducial) Bronchoscopy without sign of infection or DAH Began to improve Steroids tapered: 60mg x 6days 40mg x 3 days 20mg daily in setting of rapid improvement + difficult glycemic control Discharged on 20mg/day to be taken until follow-up Special thanks to Shoshana Zha, MD for case / slides Re-presented to ED 34 days later 2-weeks of worsening dyspnea on exertion Low-grade fever Non-productive cough Chest pressure In ED, hypoxic to 82% on room air Special thanks to Shoshana Zha, MD for case / slides 9

121 1/20/2018 Physical exam on initial consultation o Vitals: BP 104/53, HR 84, RR 20, O2 Sat 96% on 10LPM supplemental oxygen o CV: Irregularly irregular. PMI displaced laterally. No murmurs. JVD 7 cm at 30 degrees. Trace edema BLE. o Resp: Speaks in 3-4 word sentences, equal expansion. Bibasilar crackles. Special thanks to Shoshana Zha, MD for case / slides Laboratories/data VBG (ABG not obtained): 7.46 / PCO2 45/ BUN 30, Cr 1.55 (baseline 1.3), Electrolytes WNL WBC 12.2 with N, 0.68 L, 0.84 M, 0.15 E LFTs WNL Troponin 0.1, EKG without significant changes Special thanks to Shoshana Zha, MD for case / slides 10

122 1/20/2018 Special thanks to Shoshana Zha, MD for case / slides Special thanks to Shoshana Zha, MD for case / slides 11

123 1/20/2018 Special thanks to Shoshana Zha, MD for case / slides Special thanks to Shoshana Zha, MD for case / slides 12

124 1/20/2018 Special thanks to Shoshana Zha, MD for case / slides Special thanks to Shoshana Zha, MD for case / slides 13

125 1/20/2018 Special thanks to Shoshana Zha, MD for case / slides Differential diagnosis 14

126 1/20/2018 progression Day after admission, O2 titrated up to 10-12LPM On review with wife, prednisone had been discontinued Special thanks to Shoshana Zha, MD for case / slides improvement Started on prednisone 40mg/day and down to 2LPM within 4 days Discharged to take 20mg/day x 2 weeks, then 15mg/day until follow-up Special thanks to Shoshana Zha, MD for case / slides 15

127 1/20/2018 Radiation induced lung injury Radiation Pneumonitis Radiation Induced Organizing Pneumonia Radiation Induced Fibrosis o < 6 months o 3 6 months o >6 months o o Dry cough Progressive dyspnea o o Dry cough Progressive dyspnea o May be asymptomatic o o o o Low-grade fevers or chills Malaise Pleuritic chest pain Immediately capillary leakiness, delayed exudative alveolitis o o o o Low-grade fevers or chills Malaise More diffuse disease Priming of lymphocytes o High chronic inflammation circulating plateletderived and basic fibroblast growth factor Murray et al, Radiation oncology, 7123 Ding et al Curr drug targets. 14, Giridhar et al, Asian Pac J Cancer Prev, 16(7), Imaging and Radiological grading scale (RTOG) Radiation Pneumonitis I GGO without fuzziness of subjacent pulmonary vessels II GGO extending beyond radiation field or consolidations III focal consolidation +/- elements of fibrosis IV dense consolidation, traction bronchiectasis, volume loss Radiation-induced organizing pneumonia Outside radiation field Often more pronounced in contralateral lung Migrates Relapses Oie et al, Radiation Oncology. 856 Kouloulias et al 2014, Asian Pacific J Cncer Prev, Murai et al, Radiatin Oncology 7:123 16

128 1/20/2018 Risk/Associated factors Smoking History Age >65 Underlying lung disease Tumor location: mid-lower lung Adjuvant chemotherapy Risk with stereotatic (SBRT) 5-10% (up to 28% in older trials) Often lower grade disease Risk stage III with larger tumor Expression of Krebs Von den lungen-6 Ochiai et al, J Radiat Res. 56 (6): Yamashita et al, World J Radiol. 6(9): Corticosteroids Mainstay of therapy since 1950s No standard, but initial dose often Prednisone mg/kg for 2 weeks High risk of relapse, thus slow / prolonged taper is important Literature dating back to 1960s note relapse with rapid withdrawal of steroids Textbooks recommend decrease of 10mg q2weeks no trials/data of support this recommendation Otani et al, Cancer Medicine, 3(4):

129 1/20/2018 Experimental approaches Pentoxyphylline reduced fibrosis in rats (sterreicher et al 2001) Prophylactic anti-inflammatories Inhaled steroids Case reports of azathioprine and cyclosporine Hekenberens et al, Radiation Oncology 11:12 summary Differential diagnosis for a patient presenting after SBRT with subacute dyspnea should include radiation induced lung injury Important to try to differentiate Radiation Pneumonitis from Radiation Induced Organizing Pneumonia If significantly hypoxic, consider steroids but TAPER VERY SLOWLY 18

130 SYMPTOM MANAGEMENT AND PALLIATIVE CARE FOR LUNG CANCER DorAnne Donesky, PhD, ANP-BC, ACHPN UCSF Adult Nurse Practitioner and Professor of Clinical Nursing Saturday, January 27, :15 a.m. 11:45 a.m. DorAnne Donesky, PhD, ANP-BC, ACHPN is an adult nurse practitioner and professor of clinical nursing at University of California, San Francisco, who teaches palliative care and pathophysiology, and directs the Pulmonary Quality of Life Clinic. Her career is dedicated to improving symptoms and quality of life in patients living with serious illness by providing interprofessional palliative care education to students and practicing clinicians in the four core palliative care disciplines of medicine, nursing, social work, and spiritual care. She works with both the American Thoracic Society and Hospice & Palliative Nurses Association to promote outpatient pulmonary-focused palliative care and interprofessional palliative care education. She is currently a Cambia Sojourns Scholar and a Macy Faculty Scholar.

131 Symptom Management and Palliative Care for Lung Cancer DorAnne Donesky, PhD, ANP-BC, ACHPN Dept of Physiological Nursing Disclosures The presenter has no relevant financial relationships to disclose. 1 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

132 Goal for today s session Recognize and be able to manage pulmonary manifestations of lung cancer and toxicities from its therapies Identify elements of palliative care that can be used in caring for patients with lung cancer Pulmonary Manifestations of Lung Cancer Disease-related Treatment-related Comorbidity 2 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

133 Disease-related Conditions Airway obstruction Pleural effusion Ascites Superior Vena Cava Syndrome Complications Pneumonia Anemia Pulmonary emboli Cachexia Deconditioning Treatment-related Conditions Surgery Pneumonectomy Lobectomy Radiation Pneumonitis Fibrosis Chemotherapy Pneumonitis Fibrosis Cardiomyopathy 3 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

134 Comorbid Conditions COPD CHF Asthma Environmental exposures Pneumothorax Chest wall deformity Anxiety, panic, depression, obsessive, hyperventilation Terrified Isolation, dependence Death rattle / terminal secretions Final Common Pathway of Dyspnea Mismatch between respiratory demand and ventilatory mechanics Corollary discharge to cortex and limbic regions of the brain 4 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

135 Evidence based interventions for treating dyspnea in advanced disease and at the end of life A report from the HPNA Dyspnea Task Force Level 1 Interventions for Dyspnea Recommended for practice Long acting beta adrenergic agonist combined with long-acting muscarinic antagonist Immediate release oral morphine for cancer and COPD Oxygen for patients with hypoxemia (PaO2 < 55 mmhg) Pulmonary rehabilitation for patients with COPD Specialist dyspnea service for patients with multiple at-risk diagnoses 5 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

136 Level 2 Interventions for Dyspnea Likely to be effective Short-acting beta adrenergic agonist Short-acting muscarinic antagonist Sustained release once-daily morphine, not available in US Subcutaneous morphine in lung cancer Immediate release oral morphine in heart failure Acupressure Acupoints with transcutaneous electrical nerve stimulation Fans Mindfulness Internet-based dyspnea self-management in COPD Level 3 Interventions for Dyspnea Benefits balanced with harm Non-invasive ventilation for cancer patients with hypercarbia High flow nasal oxygen for patients with cancer with persistent dyspnea Acupuncture Co-enzyme Q10 6 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

137 Level 4 Interventions for Dyspnea Effectiveness not established Nebulized furosemide Immediate release oral morphine in interstitial lung disease Nebulized fentanyl Oral transmucosal fentanyl Oxygen for cancer patients with and without hypoxemia Heliox28 gas mixture for patients with lung cancer and dyspnea on exertion Benzodiazepines for patients with variety of diagnoses Level 5 Interventions for Dyspnea Effectiveness unlikely Nebulized morphine Epidural methadone Oxygen for patients near death with no signs of respiratory distress 7 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

138 Level 6 Interventions for Dyspnea Not recommended for practice Oxygen for patients who are not hypoxemic Nonpharmacologic Dyspnea Strategies Professional Pulmonary rehab Breathlessness Intervention Pacing/Energy conservation Cognitive Behavior Therapy (CBT) Music/distractive auditory stimuli Chest wall vibration Noninvasive ventilation Education Walking aid: rollator/cane Dyspnea Plan Neuromuscular electrical stimulation Self-Management Posture: braced forward lean Pursed lip breathing Abdominal breathing Fan/air movement Exercise Complementary Relaxation / Mindfulness-based stress reduction Biofeedback Spinal movement Acupuncture/ acupressure Yoga/tai chi /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

139 Non-pharmacological Treatments to be Practiced when Patient is Relatively Well Use the strategies they previously found effective Exercise programs tailored to individual Breathing retraining Relaxation, music, and anxiety control techniques Psychological support, patient and caregiver Address fears about breathlessness Education about strategies to manage symptom clusters Assessment for depression and active treatment Adapted from Booth, S. End of life care for the breathless patient General Practice UPDATE January /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

140 Dyspnea Crisis Definition: sustained and severe resting breathing discomfort that occurs in patients with advanced, often life-limiting illness and overwhelms the patient and caregivers ability to achieve symptom relief. Converging factors: Worsened dyspnea Overwhelmed caregiver/environment Psychosocial/spiritual patient response From ATS Dyspnea Crisis workshop report, /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

141 Treatments: Cough Pharmacology Opioids DM Benzonatate (tessalon perles) Demulcents: alleviate irritation Inhaled anticholinergic bronchodilators Lidocaine Productive cough Expectorants Mucolytics Chest PT Avoid the stimulus Humidity Hydration Suction Huffing 11 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

142 What is Palliative Care? Palliative care is specialized care for people with serious illnesses. It focuses on providing relief from the pain, symptoms and distress of serious illness. It is a team-based approach to care involving specialty-trained doctors, nurses, social workers and other specialists focused on improving quality of life. What is Palliative Care? 12 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

143 Timing of Palliative Care Aspects of Care Pulm Rehab PC Holistic approach Interdisciplinary approach Patient centered Based on patient preferences Family Support Focus on Disease modification ++ + Principles applicable throughout disease Focuses on Symptom Mgt and QOL Focuses on Maximizing Functional Status Promotes Self Management Strategies Psychological support Bereavement counseling Formal exercise training Promotes advance directives Spiritual Dimension Retiker, CRD /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

144 Interprofessional Team RN MD Pharmacist Respiratory Therapist Physical Therapist Occupational Therapist Speech Therapist Interpreter Administrator Chaplain Social Service Nutrition Psychologist Patient Caregiver Dental Hygienist CNA/MA/HHA Psychosocial Domain Exploring stressors Depression and anxiety Sleep disturbances Patient and caregivers coping mechanisms Exploring hopes and fears 14 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

145 Psychosocial Domain Explore Loss Loss of personal independence, dignity Loss of previously held expectations of the future Seamark, Palliat Med 2004 Be honest and show empathy Affirm non-abandonment Provide information, support, resources, referrals Spirituality Many people use spiritual or religious beliefs to cope with illness Psycho-spiritual wellbeing enhanced or diminished in patients with advanced cancer Those with enhanced sense of wellbeing are able to cope more effectively with illness and the experience This may include self-awareness, coping and adjusting effectively, satisfying relationships Sense of faith, sense of empowerment and living with meaning and hope Lin, HR J Adv Nurs /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

146 Reading When you think about your health and your lung cancer, what worries you? 16 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

147 Barriers to Communication Lack of training for clinicians Lack of self-efficacy Variable disease trajectory Lack of time for discussions Fear that this will cause patients to give up hope or cause anxiety Patient assumption that clinicians will initiate the discussion Lack of patient education or medical literacy Hardin, COPD 2008 Patel, Respirology 2012 Tips for Conversation Initiating discussions Important part of care Discussing prognosis Ask-Tell-Ask Discuss uncertainty ACP Frame it- Will not diminish focus on survival?dpoa, opinions on cpr and vent support Non-abandonment Curtis, Eur Resp J /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

148 Take Home Points: 1. Prepare and practice the strategies for dyspnea management before a crisis occurs 2. Seek out the input of multiple disciplines and appreciate the value of each unique perspective 3.Palliative care is a resource for seriously ill patients, not just terminal patients 4. Save time and improve understanding by addressing emotion before information Thank you DorAnne Donesky, PhD, ANP-BC, ACHPN doranne.donesky@ucsf.edu 18 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

149 Why is it hard to breathe? Treatment for many cancers can affect the lung, even though you may not have lung cancer or metastases. Side effects of some chemotherapy, immunotherapy and radiation therapy can cause damage to your lungs, called lung toxicity. So what is lung toxicity? Damage to the lungs due to cancer treatment is called pulmonary toxicity or lung toxicity. This may be short term (acute) or long term (chronic). There are different types of lung toxicities. Lung damage caused by inflammation is called pneumonitis. Another type of damage is scarring to the lungs is called pulmonary fibrosis. Drugs that are known to cause this are chemotherapy drugs such as Arsenic trioxide (Trisenox ), Bleomycin (Blenoxane ), Idarubicin (Idamycin ), carmustine (BiCNU, BCNU), methotrexate (Trexall, Otrexup, etc.). Radiation therapy to the chest area can also cause lung toxicity. What are the symptoms? Shortness of breath Dry cough Chest tightness or pain Fatigue Fever (for pneumonitis) When does it happen? Who gets it? For some chemotherapy drugs, it may happen during treatment, and may be dose dependent. For some others, pneumonitis or pulmonary fibrosis can appear years later. People with higher risk factors are Those who have pre-existing lung conditions such as COPD or have inhaled toxic substances, through work, hobbies, or from the environment. Elderly, especially over 70 years old. Radiation therapy to anywhere in the chest area. Received combination chemotherapy drugs. How is it diagnosed? There are no definitive tests for lung toxicity, pneumonitis or pulmonary fibrosis. The doctor will take your history and conduct a physical exam. Other tests they may order are: Chest x-ray CT scan Blood tests Lung function tests bronchoscopy Lung biopsy

150 How do you treat it? The symptoms are treated while we wait for the lung to heal or improve its function. Treatments to keep lungs open include tools such as Incentive Spirometer. Pulmonary rehab can introduce different forms of lung exercises that is appropriate for you. If you are able, physical exercise encourages deep breathing and is highly recommended. Direct therapy such as oxygen therapy could be used when needed. Often we combine multiple methods above with medication What kind of medication? Corticosteroids decreases inflammation of the lungs so it can heal itself. It can also relieve the cough, and some pain. Bronchiodilators inhalers that can widen airways, and make it easier to breath. Opioids - such as morphine can relax the lung enough to allow deep breathing. What can I do to help breathe better? Stop smoking and avoid second hand smoking Learn relaxation techniques like yoga or meditation Deep breathing exercises Incentive spirometer, breathing rehab, physical exercises o It lowers chances of pneumonia o Promotes air circulation in the lungs and body o Prevents small air sacks called alveoli to collapse from disuse. Sit up when not standing you naturally breathe deeper when sitting up than lying down. Use oxygen when needed Prioritize and plan activities pace your activities and plan rests. Reduce anxiety and manage stress Move air some people say they can breathe better when they have a light breeze from a fan moving air around. Learn techniques such as pursed lipped breathing - Pursed-lip breathing is breathing in slowly through the nose, then puckering or pursing the lips and breathing out slowly and gently through the mouth. Read more:

151 THORACIC TUMOR BOARD MULTIDISCIPLINARY PANEL Panel Members: Travis Henry, MD; Ganesh Krishan, MD; Matthew Gubens, MD; Megan Daly, MD; Lorrianna Leard, MD Cases By: Lekshmi Santhosh, MD Saturday, January 27, :45 a.m. 12:15 p.m. Lekshmi Santhosh, MD received her medical degree from Harvard Medical School after completing her bachelor s in behavioral neuroscience at Yale University. She is currently a 3 rd year Pulmonary and Critical Care fellow at UCSF where she also completed her internship residency and chief residency. Her research interests are in graduate medical education.

152 1/20/2018 CTS Multidisciplinary Lung Cancer Case Discussion Saturday, January 27th, 2018 Disclosures I have nothing to disclose. 1

153 1/20/2018 Roadmap for the Hour 1. Rapid fire cases 2. Discussion from multidisciplinary team & audience 3. Brief teaching points 4. Repeat! 5. Time for your cases First: Multidisciplinary Panelist Introductions 2

154 1/20/2018 Case 1: A PET project Case Presentation 57 yo M current smoker (1 pack-per-day), prostate intraepithelial neoplasia, and left schwannoma w/ tinnitus presents with new pulmonary nodule. Has wheezing & dyspnea on exertion at baseline but is worsening over the past 3 months, no systemic sx 3

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156 1/20/2018 Multidisciplinary Discussion 5

157 1/20/2018 Case Conclusion & Teaching Points Patient underwent VATS Pathology showed MAC! Case reports of MAC masquerading as malignancy HIV Lung transplant Patients with history of lung cancer Case 2: Potato vs. potato? 6

158 1/20/2018 Case Presentation 65 yo M prior smoker (60-pack-years) s/p recent SBRT for lung cancer Now presenting with new dyspnea on exertion and new 4 L O2 oxygen requirement [VA CPRS IMAGE OF ORGANIZING PNEUMONIA] 7

159 1/20/2018 Multidisciplinary Discussion Case Conclusion & Teaching Points Post-radiation organizing pneumonia Radiation pneumonitis Part of a spectrum of changes that can occur post-sbrt Occur at predictable time periods Lung that was not radiated can also be affected Treatment often with prolonged courses of corticosteroids 8

160 1/20/2018 Case 3: Use the brain power. Case Presentation 65yoF w/ depression & borderline personality disorder, Hashimoto s thyroiditis, presents w/ 1 month of dizziness & vertigo, found to have multiple rim-enhancing CNS lesions. PET negative but CT showed the following and Pulmonary was consulted 9

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162 1/20/2018 Case Conclusion & Teaching Points IP felt lesion too small to biopsy Patient ultimately underwent brain biopsy of ringenhancing lesions Biopsy showed adenocarcinoma of pulmonary origin Only about ~7% of cases present with brain mets first Prognosis is poor ~3-4 months Case 4: Who is mimicking whom? 11

163 1/20/2018 Case Presentation 74yoM w/ lymphoma s/p chemotherapy found to have new lung nodules and mediastinal lymphadenopathy No new medications, no fevers, chills, sweats, systemic sx 12

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166 1/20/2018 Multidisciplinary Discussion Case Conclusion & Teaching Points Biopsy showed non-caseating granulomas Sarcoid-like reaction has been described in a variety of malignancies, especially lung and breast cancer Also been reported as a drug reaction to many drugs Can result in a false-positive on PET & CT for malignancy How to surveil these patients? 15

167 1/20/2018 Case 5: Occam s Razor or Hickam s Dictum Case Presentation 57 yo M current smoker (1/2 pack-per-day), recently diagnosed with mandibular squamous cell cancer Sent to Pulmonary clinic for large mass seen on PET-CT 16

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169 1/20/2018 Multidisciplinary Discussion Case Conclusion & Teaching Points Biopsy showed small cell carcinoma Second primary rather than metastases Synchronous primary lung cancer in 0.5% of pts w/ lung cancer Mandibular squamous cell cancer is highly morbid compared to other oral cancers mean survival time of ~56 months and 5 year survival of 44% 18

170 1/20/2018 Case 6: Streamlining the Path to OR? Case Presentation 82yoF, former smoker, with GERD and HTN, otherwise healthy, presents with new lung nodule Sent to CT Surgery clinic for consideration of resection 19

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172 1/20/2018 Multidisciplinary Discussion Case Conclusion & Teaching Points Plan for joint OR case with IP and CT Surgery EBUS to interrogate lymph node, if negative resection Physiological criteria to assess readiness for surgery: FEV1 predicted-post-operative DLCO predicted-post-operative Peak oxygen consumption on exercise study 21

173 1/20/2018 Cases from the Audience? THANK YOU! 22

174 LUNCH EXHIBIT HALL OPEN Saturday, January 27, :15 p.m. 1:00 p.m.

175 2018 EXHIBITORS CALIFORNIA THORACIC SOCIETY ANNUAL EDUCATIONAL CONFERENCE FRIDAY, JANUARY 26 SATURDAY, JANUARY 27, 2018 American Lung Association in California AstraZeneca Boehringer Ingelheim (2) California Society of Respiratory Care Circassia Electromed Fisher Paykel Healthcare Genentech Gilead Sciences GlaxoSmithKline Grifols Hill-Rom Infocare Healthcare Systems Insmed Novartis Pulmonary Fibrosis Foundation RespirTech Teva Pharmaceuticals Veracyte Inc. Vertex Note that all exhibitors are located in the Club House in the Oak Room, Garden Room and the Ballroom Foyer.

176 INTRODUCTION TO BRONCHIECTASIS (Presentation of Case) Douglas Conrad, MD UCSD Professor of Medicine Saturday, January 27, :00 p.m. 1:10 p.m. Douglas Conrad, MD received his medical degree from Case Western Reserve University. Post graduate training in Internal Medicine was completed at the University of Minnesota. He completed his Pulmonary and Critical Care Medicine at UC San Francisco. Currently, he is a Professor of Medicine at UC San Diego where he is the Director of the Adult CF Program.

177 1/20/2018 Bronchiectasis Case Presentation California Thoracic Society January, 2018 Bronchiectasis Case Presentation Presents in September, 2017 with progressive dyspnea on exertion Currently walks 2 blocks. Could walk 1 mile a year earlier Cough, chronic sputum production. PMH:GERD, Hiatal hernia, Gastroparesis, LV diastolic dysfunction PMH:MAC Rx a) 1996 x18 months b) 2002 x 13 weeks c) 2004 x 6 months d) 2015 x 8 months e) months to current (fevers, weight loss, cough and dyspnea) Pancreatic Insufficient. Failure to thrive as an infant. Chronic Sinusitis. Recurrent nasal polypectomy 1

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179 1/20/2018 Bronchiectasis Case Presentation Physical Exam Thin. BMI =18.5 Mild maxillary Tenderness Chest: Decreased breath sounds with scattered rhonchi. Rare exp wheezing No clubbing Microbiology Data AFB: MAC/MAI Fungal: Aspergillus intermittently Routine: Pseudomonas aeruginosa Stenotrophomonas maltophilia Laboratory Data CBC: Normal ESR : 110 CRP: 5.2 Chem20: Normal Ig and IgG subclasses: Normal IgE: 4 Bronchiectasis Case Presentation Relevant CF data Sweat Chloride: 25meq/ml Borderline nasal potential difference CFTR genetics a) M470V/M470V b) IVS 5T allele Fecal pancreatic elastase was 52 ug/g (nl > 200ug/g) Vitamins E and A were normal Vitamin D was low Relevant PCD data EM cilia showed normal outer and inner dynein arms and questionable central apparatus. Single DNAH5 variation p.f4392c: uncertain pathogenicity Single DNAH11 variation p.d892v: uncertain pathogencity 3

180 1/20/2018 Bronchiectasis Case Presentation Leading considerations for etiology of bronchiectasis Atypical Cystic Fibrosis Strong clinical phenotype but lacks convincing laboratory confirmation Chronic NTM (MAC/MAI) airway infection Chronic aspiration Atypical PCD PCD is recessive. Unclear if the carrier state is clearly normal Multiple hit concept 4

181 A RADIOLOGIC APPROACH TO BRONCHIECTASIS Travis Henry, MD UCSF Associate Professor of Radiology Saturday, January 27, :10 p.m. 1:50 p.m. Travis Henry, MD received his medical degree from Vanderbilt University, followed by diagnostic radiology residency and fellowship in cardiothoracic imaging at Washington University in St Louis. He was on faculty at Emory for four years before moving to UCSF in 2015, where he currently serves as Associate Professor of Radiology. Dr. Henry is the director of the cardiothoracic imaging fellowship at UCSF, and has committee appointments in many national and international radiology organizations including the American College of Radiology, American Roentgen Ray Society, Radiologic Society of North America, and the Society of Thoracic Radiology.

182 EVALUATION OF PATIENTS WITH DIFFUSE BRONCHIECTASIS Patricia Eshaghian, MD UCLA Assistant Professor, Pulmonary and Critical Care Medicine Saturday, January 27, :50 p.m. 2:30 p.m. Patricia Eshaghian, MD received her medical degree from the Albert Einstein College of Medicine. She completed her residency in Internal Medicine at NYU and subsequently her Pulmonary and Critical Care Fellowship at UCLA. She is currently on the Clinical Faculty at UCLA where she also serves as the Director of the Adult Cystic Fibrosis Program at UCLA which was accredited in 2014.

183 1/20/2018 Evaluation of Patients with Diffuse Bronchiectasis Dr. Patricia Eshaghian, MD Assistant Clinical Professor of Medicine Director, UCLA Adult Cystic Fibrosis Affiliate Program UCLA Division of Pulmonary and Critical Care Medicine Disclosures Advisory Board Member for Gilead in

184 1/20/2018 Objectives Objectives for this lecture will include: Understanding what bronchiectasis is Learning the various etiologies of diffuse bronchiectasis in adult patients Learning when to think of Cystic Fibrosis in an adult and how to evaluate a patient for Cystic Fibrosis Learning a comprehensive evaluation of non-cf Bronchiectasis patients Implementing these objectives into clinical practice to hopefully effect patient outcomes 3 Why investigate for the etiology of bronchiectasis? Finding the etiology can potentially change management in up to 37% of patients A. Shoemark, L Ozerovitch, R. Wilson. Respiratory Medicine 2007; 101: p PJ McShane, E Naureckas, M Strek. CHEST 2012; 142 (1): Patients want to know the cause Further our understanding of bronchiectasis 4 2

185 1/20/2018 What is bronchiectasis? Abnormal chronic dilation of one or more bronchi Irreversible The structural abnormality of the airway predisposes patients to bacterial infections, probably due to impaired mucus clearance Cycle of inflammation, infection >> further damage to airways Symptoms: chronic cough, sputum production, respiratory infections, progressive obstructive lung disease, chest pain, shortness of breath.. 5 3

186 1/20/2018 Etiologies of Bronchiectasis Cystic Fibrosis Primary Ciliary Dyskinesia Immune Deficiency Autoimmunity/inflammatory (associated with RA, Sjogrens, IBD ) ABPA Aspiration Alpha-1 Antitrypsin Post-infectious Idiopathic Other rarer misc diseases (foreign body aspiration, Young s syndrome, congenital anatomical defects) 7 What is Cystic Fibrosis? Most common inherited life-shortening disease in Caucasians of Northern European ancestry Affects the lungs and digestive system of about 30,000 children and adults in the US (70,000 worldwide) About 1000 new cases of CF are diagnosed each year More than 50% of the CF patient population in the United States are > 21 years old 4

187 1/20/2018 History of Cystic Fibrosis 1938: clinical syndrome first described by Dr. Dorothy Anderson, severe malnutrition, hypochloremia, dehydration 1940s: autosomal recessive inheritance : life expectancy <1 year 1980s: CF epithelial cells characterized by abnormal ion transport. Chloride channel affected with exit blocked and sodium reabsorption accelerated 1989: CF gene located to long arm of chromosome 7 What is Cystic Fibrosis? Multisystem disease affecting the digestive system, sweat glands, reproductive tract, and lungs Autosomal recessive disorder caused by mutations in a gene on the long arm of chromosome 7 that encodes for the CFTR protein Most common mutation is a 3 base pair deletion that codes for phenylalanine at position 508 (ΔF508) accounting for 70% of CF alleles in Caucasians >1500 distinct sequence changes in the CFTR gene are associated with clinical disease Disease presentation may vary 5

188 1/20/2018 CFTR protein CFTR protein is a transmembrane protein that functions as a chloride channel Mucociliary Clearance and Obstruction Periciliary Liquid (PCL) Surface Epithelial Cells normal Tenacious Mucus CF 6

189 1/20/2018 Understanding the Complexity of CFTR & the Classes of CFTR mutations Normal I II III IV V No synthesis Block in processing Block in gating Altered conductance Reduced synthesis G542X F508del G551D D1152H kbC >T 12% 87% 5% 5% 5% Does your patient have CF? 7% of adult CF patients are diagnosed during adulthood 14 7

190 1/20/2018 Symptoms suggestive of CF Chronic Cough and sputum production Recurrent sinus infections Idiopathic chronic pancreatitis Inability to gain weight Clubbing Abnormal BMs suggestive of pancreatic insufficiency Diabetes or hepatobiliary disease Sputum cultures S.aureua, S. maltophilia, P. Aeruginosa, B.cepacia, A. xylosoxidans Infertility Male patients with congenital absence of the Vas Deferens 15 Sweat Chloride Test Positive test >60 mmol/l Borderline mmol/l possible CF Negative <30 mmol/l But we now know that some patients with CF can have a normal or negative sweat test! 16 8

191 1/20/2018 Testing. If a sweat test is intermediate/borderline: repeat it Send blood for molecular testing/dna analysis If you find 2 CFTR mutations => CF Send expanded DNA analysis: In California blood can be sent Ambry Genetics for testing (need insurance auth). 508 first Send blood to Johns Hopkins for extended DNA analysis Refer to an Adult CF Center 17 Nasal Potential Difference Measurement Must be done at an experienced center Not widely available 18 9

192 1/20/2018 Primary Ciliary Dyskinesia Genetic disease rendering cilia immotile, dysmotile or missing Symptoms of Chronic cough and sputum production, presenting early in life Recurrent sinus infections/chronic congestion/rhinorrhea Chronic otitis media Infertility in both males and females Situs inversus Testing for CF being ruled out 19 PCD Leigh, Ferkol, Davis, et al. Annals Amer Thor Soc, 2016; 13 :

193 1/20/2018 Diagnostic Tests for PCD Nasal Nitric Oxide is now the diagnostic test for PCD Highly sensitive and specific Noninvasive Fast, inexpensive Electron Microscopy High Speed Video Microscopy Genetic Analysis (only 2/3 of patients will have this) 21 What evaluation should all non CF bronchiectasis patients have? ERS Guidelines suggest a minimal bundle CBC with diff Serum Immunoglobulins (Total IgG, IgA, and IgM) Test for ABPA with total IgE and specific IgE to Aspergillus and IgG to Aspergillus or skin prick test Sputum Culture for Bacteria, AFB and fungus Alpha 1 Antitrypsin Phenotype (not in the ERS Guideline) CT and PFT 22 11

194 1/20/2018 Bronchiectasis evaluation Detailed history: Neonatal history/childhood symptoms Family history GI symptoms Fertility history Symptoms of aspiration Recurrent infections/pneumonias CTD disease symptoms 23 Bronchiectasis evaluation Consider based on history: Swallow evaluation, ph probe study, GERD evaluation CTD disease work up, rheumatoid factor, SSA-SSB Do they need work up for IBD based on symptoms? Investigate for a treatable cause Identifying one etiology doesn t always rule out another etiology 15% of patients can have more than 1 etiology 24 12

195 1/20/2018 Patients NEED to learn appropriate ACTs Bronchiectasis registries

196 MUCUS CLEARANCE STRATEGIES FOR BRONCHIECTASIS Mary Lester, RT Keck Medical Center of USC Los Angeles RT Clinical Coordinator Saturday, January 27, :30 p.m. 3:10 p.m. Mary Lester, RT is a Respiratory Therapist who is currently working in Adult Cystic Fibrosis care at Keck Medical Center of USC in Los Angeles, CA. where she has been employed for last 3 years. Previously she had lived in Charleston, SC where she had worked at The Medical University of South Carolina for 30 yrs. Her RT career at MUSC included: Pediatric medical transport team, pulmonary rehab, and the last 15 years on the Pediatric and Adult Cystic Fibrosis team. Mary has worked on national projects with the Cystic Fibrosis Foundation including the Pulmonary Guidelines Committee, and facilitator of the CF RT Mentoring Program. She has published several papers on CF Respiratory Care, and is currently working on a manuscript on her work with telemedicine as an education tool. Her professional passion is to work with people with CF to help make their tremendous therapy load effective and reasonable so they can live full, long, happy lives.

197 1/20/2018 Airway Clearance Strategies in Bronchiectasis Mary K Lester, RRT, RCP Adult Cystic Fibrosis Program Keck Medical Center of USC Los Angeles, CA mary.lester@med.usc.edu Advisory Board Gilead Pharmaceutical Advisory Board Hill Rom Inc. Speaker for Monaghan Medical Speaker for Respirtech 1

198 1/20/2018 Objectives: Present airway clearance modalities that are available and describe their methods of action Explain how to access the effectiveness of the prescribed airway clearance modality Strategies for getting patients to participate in airway clearance Normal Mucus Movement 2

199 1/20/2018 Defective Airway Mechanics Airway Mucous Plugging Used with permission J. Wagener,

200 1/20/2018 Treatment and Maintenance Bronchial hygiene 1. Mechanical maneuvers triggering cough 2. Goal to increase mucus clearance 3. Multiple modalities Breathing Techniques Hand Held PEP/oscillating devices Hand chest physiotherapy High frequency chest wall oscillation HFCWO: vests Sound resonance devices Exercise Making Appropriate Choices 4

201 1/20/2018 Breathing Techniques Pursed lip breathing Active Cycle Breathing Technique: ACBT Autogenic Drainage Active Cycle Breathing Technique 5

202 1/20/2018 Handheld Devices PEP device Flutter Acapella Aerobika Combining therapies 6

203 1/20/2018 Combine therapies for added effect Components of Effective CPT: Myofascial stretching/relaxation Active Cycle Breathing Technique Chest clapping and positioning Coughing 7

204 1/20/2018 CPT/ Cupping and Clapping Positioning patient Cupping and Clapping Active cycle breathing control Active coughing throughout HFCWO In patient and home use

205 1/20/2018 Making the Most Effective Use of High Frequency Chest Wall Oscillation (HFCWO) Carlos E. Milla, MD Stanford University Cystic Fibrosis Center Lucile Packard Children s Hospital Minnesota Vest Settings Session 1 Hz=6, pressure=10: for 5 min. then pause to huff cough Hz=8, pressure=10: for 5 min. then pause to huff cough Hz=10, pressure=10: for 5 min. then pause to huff cough Session 2 Hz=16, pressure=6: for 5 min. then pause to huff cough Hz=18, pressure=6: for 5 min. then pause to huff cough Hz=20, pressure=6: for 5 min. then pause to huff cough 9

206 1/20/2018 Home HFCWO: portable or mobile units Considerations when prescribing HFCWO Cost Willingness to participate Confirmed bronchiectasis on Chest CT Daily prescription Symptom awareness Effectiveness 10

207 1/20/2018 Sound Resonance devices Frequencier Vibralung 11

208 1/20/2018 Pulmonary Rehab Medicare criteria for COPD: 32 lifetime visits (if lifetime visits fulfilled MD can petition using a LMN) FEV1 between 50 80% (Gold II) Restrictive disease does not have as strict criteria Benefits: Improved survival Improved exercise tolerance Lessened perception of breathlessness Improved quality of life Reduced hospitalization time and hospitalizations per year Decreased anxiety and depression Considerations When Prescribing Airway Clearance Therapies The physician prescribes the therapies but does not always knows what is best. 12

209 1/20/ Airway Clearance is Boring Airway cle Be Creative 13

210 1/20/2018 Keep an open mind Is the therapy working for the patient? Patient reported outcomes N=1 Mucus production Is the patient an active participant 14

211 1/20/2018 Nebulized medication delivery 15

212 1/20/2018 Nebulizer/Compressor discussions: Order of therapies Which drug which cup Compressors Breathing pattern Cleaning and disinfection Replacement Travel 16

213 1/20/2018 Conclusions: Airway clearance is an active process Certain therapies are best for certain patients Some therapies work better combined with other AWC therapies Nebulized medication deposition is patient driven Listen to your patients Questions? 17

214 BREAK EXHIBIT HALL OPEN Saturday, January 27, :10 p.m. 3:40 p.m.

215 2018 EXHIBITORS CALIFORNIA THORACIC SOCIETY ANNUAL EDUCATIONAL CONFERENCE FRIDAY, JANUARY 26 SATURDAY, JANUARY 27, 2018 American Lung Association in California AstraZeneca Boehringer Ingelheim (2) California Society of Respiratory Care Circassia Electromed Fisher Paykel Healthcare Genentech Gilead Sciences GlaxoSmithKline Grifols Hill-Rom Infocare Healthcare Systems Insmed Novartis Pulmonary Fibrosis Foundation RespirTech Teva Pharmaceuticals Veracyte Inc. Vertex Note that all exhibitors are located in the Club House in the Oak Room, Garden Room and the Ballroom Foyer.

216 PRIMARY CILIARY DYSKINESIA Douglas Conrad, MD UCSD Professor of Medicine Saturday, January 27, :40 p.m. 4:10 p.m. Douglas Conrad, MD received his medical degree from Case Western Reserve University. Post graduate training in Internal Medicine was completed at the University of Minnesota. He completed his Pulmonary and Critical Care Medicine at UC San Francisco. Currently, he is a Professor of Medicine at UC San Diego where he is the Director of the Adult CF Program.

217 1/20/2018 Primary Ciliary Dyskinesia Clinical Presentation and Diagnosis Douglas Conrad California Thoracic Society January, 2018 Disclosures Current Funding: NIH RO1 National CF Foundation Gilead Sciences Potential Conflict of Interests: None Acknowledgments: Michael Knowles* (primary slide set) Michelle Manion PCD Foundation 1

218 1/20/2018 OVERVIEW Introduction Motile & Non-Motile Cilia PCD Clinical Presentation Diagnostic Approaches & Challenges Clinical Phenotype Electron Microscopy Genetic Screening Nasal NO (nno) Primary Ciliary Dyskinesia Timeline: 1 st Case Report Kartagener Triad Immotile Cilia Syn (EM Defect) Primary Ciliary Dyskinesia Low nno in PCD 1 st gene defect identified Consortium Formed nno validated 37 known PCD genes

219 1/20/2018 Primary Ciliary Dyskinesia Rare genetically heterogeneous recessive disorder (1 in 15-30,000 live births; ~15,000 patients in U.S.) Disease reflects abnormal ciliary biogenesis, structure, and/or function, and occurs in organs where motile cilia pay an important role: Neonatal respiratory distress ( 80%). Chronic daily wet cough from birth (97%). Chronic airway disease with age-dependent bronchiectasis (100%, adults). Chronic nasal congestion; sinusitis. Recurrent otitis media (90%); glue ear with frequent hearing loss. Reduced fertility (nearly all males). ~50% have situs inversus or heterotaxy (Kartagener s). Types of Cilia CILIUM MOTILE NON-MOTILE (9+0) Primary monocilium (sensory) Planar motion (9+2) Rotary motion (9+0) Multiple cilia on a cell Primary monocilium Airways (Respiratory) Brain (Ependymal) Reproductive Tract (Fallopian tubes, Sperm Flagellum*) Embryo (Nodal cilium) Kidney tubule Bile duct Pancreatic duct Bone, Cartilage Eye (Photoreceptorconnecting) Fibroblasts Stem cells 3

220 1/20/2018 Axoneme (Cilia / Flagella) Structure and Function Ciliary Beat: o Coordinated waves beat in simple backward and forward motion o Frequency 8-15 Hz Ciliary Axoneme o Highly conserved structure and function across the species o Composed of >250 proteins o 9+2 configuration (9 peripheral MT doublet surrounding central pair) o Each MT doublet consists of several dynein HC, IC and LC o ATPase of dynein arms provide energy of ciliary beat Clinical Presentation and Criteria 4

221 1/20/2018 Lobar Collapse Occurred in 70% of PCD Cases but No Controls Mullowney, T., et. al., Pediatrics 2014; 134(6): Specificity and Sensitivity of Rigorous Clinical Criteria for PCD in Children and Adolescents 1. Unexplained neonatal respiratory distress (lobar collapse and/or need for CPAP and/or O 2 24 hrs 2. Daily, year round wet cough starting in 1 st year of life 3. Daily, chronic nasal congestion starting in 1 st year of life 4. Organ laterality defect # Clinical Criteria met (max=4) Sensitivity Specificity Probability of PCD % 99.2% % 97.3% % 77.6% % 53.2% 0.34 Leigh, MW, et al, 2016, Annals ATS 5

222 1/20/2018 Thoraco-Abdominal Asymmetry Situs Solitus Normal (99.99%) Situs Inversus Totalis Heterotaxy (Situs Ambiguus) Hirokawa et al., 2006, Cell McGrath and Brueckner, 2003, Curr. Opin. Genet. Dev. Thoraco Abdominal Asymmetry Situs Solitus Situs Inversus Totalis Abd Situs Inversus Isolated Dextrocardia L H S H S L S H L L H S Heterotaxy (Situs Ambiguus) Situs Solitus Situs Inversus Totalis Bartram et al., 2005, Biol. Neonate Right Isomerism* (Asplenia Syndrome) Left Isomerism* (Polysplenia Syndrome) 6

223 1/20/2018 Situs Status and Congenital Heart Disease in PCD Patients* PCD Patients n=305 Situs Solitus n=143 (46.9%) Heterotaxy n=37 (12.1%) Situs Inversus Totalis n=125 (41%) Vascular Anomalies n=8 (2.6%) Congenital Heart Disease (CHD) n=15 (4.9%) No cardiac or Vascular anomalies n=14 (4.6%) Patients with congenital heart disease and heterotaxy have worse outcome after cardiac surgery; possibly due to PCD and lung complications? New Report: Some patients with CHD and heterotaxy have ciliary dysfunction ƚ. *Shapiro, A, et al 2014, Chest ƚ Nakhleh, N, 2012, Circulation Radiographic (CT) Imaging* in PCD Bronchiectasis: Adults (35; 100%); Pediatrics (56; 70%) *Jain et al., 2007, Clin. Radiol.; Kennedy et al., 2007, AJR; Santamaria et al., 2008, Chest 7

224 1/20/2018 Consensus based PCD Diagnostic Criteria* Newborns (0 to 1 month of age) Situs inversus totalis and unexplained NRD at term birth, plus at least one of the following: Diagnostic ciliary ultrastructure electon micrographs or two mutations in PCD associated gene Children (1 month to 5 years) Two or more major PCD clinical criteria (NRD; wet cough; nasal congestion; laterality defect), plus at least one of the following (nasal nitric oxide included in this age group, since it is not yet sufficiently tested): Diagnostic ciliary ultrastructure on electron micrographs Two mutations in one PCD associated gene Persistent and diagnostic ciliary waveform abnormalities on high speed videomicroscopy, on multiple occasions Children and adults 5 18 years of age Two or more PCD clinical criteria (NRD; wet cough; nasal congestion; laterality defect), plus at least one of the following: Nasal nitric oxide during plateau <77nL/min on 2 occasions, >2 months apart (with cystic fibrosis excluded) Diagnostic ciliary ultrastructure on electron micrographs Two mutations in one PCD associated gene Persistent and diagnostic ciliary waveform abnormalities on high speed videomicroscopy, on multiple occasions * Pediatric Pulmonology, Shapiro et al, Sept 2015 Ciliary Ultrastructure: Electron Microscopy 8

225 1/20/2018 Ciliary Ultrastructural Defects (previously gold std for dx) Samples obtained without anesthesia from the inferior nasal turbinate using brush or curette Dynein Arms Defects Absence/shortening ODA, alone Absence /shortening IDA, alone ( caveat ) Absence/shortening ODA+IDA Absence of IDA + Microtubular Disorganization Central Complex Defects (up to 90% may appear normal) 9+2 configuration Absent IDA + MTD ~ 30% of PCD patients have normal (or non-dx) ciliary ultrastructure. Inner Dynein Arm (IDA) Defect, alone: Transient* IDAs have low contrast on EMS 5 of 21 patients with IDA defect (IDAs missing) were retested, and found to have normal IDAs and normal ciliary function.* IDA may appear (falsely) to be missing, perhaps due to non-specific biological or technical artifacts. Patients with an IDA defect should undergo repeat study to confirm. O Callaghan, C., et. al., Eur. Respir. J., 2011; 38(3):

226 1/20/2018 NOT All PCD has EM Defects Well recognized there are many patients (~30% of PCD) with a strong clinical phenotype for PCD (NRD; respiratory and ear symptoms; situs inversus), and low NO (+/- abnormal HSVM), with normal (or non-diagnostic) EMs. Many of these patients have genetic confirmation of PCD with loss-of-function mutations in DNAH11 or RSPH genes or nexin link genes. PCD cannot be confirmed in such patients by ciliary ultrastructural studies. Confounding Factors for Using Ciliary EMs for Confirmatory Diagnosis of PCD 1. Need ciliated cell biopsies, and inflammation/infection can cause secondary changes to ciliary ultrastructure. 2. Adequate fixation is critical. 3. These small samples are processed by multiple technical steps, including getting adequate ultrathin cross-sections for EM, and technician must select correct images (multiple cells). 4. Evaluation requires an adequate (>20) number of interpretable images from different cells, including good contrast. 5. Interpretation requires recognition of normal variability, and an understanding of EM changes that may occur as non-specific ( secondary ) effects, such as absent central microtubules, extra central and peripheral microtubules, and compound cilia. Further complicated by recent genetic etiologies, where as many as 90% of cilia may appear normal (RSPH; nexin links). 10

227 1/20/2018 Primary Ciliary Dyskinesia Genetics Discovery of PCD-Associated Genes: 37 Genes Sorted by Year of Discovery Years Genes 1999 DNAI DNAH OFD1, RPGR, NME DNAAF2, DNAI2, DNAH DNAAF1, RSPH4A, RSPH DNAL1, CCDC39, CCDC CCDC103, DNAAF3, HEATR2, HYDIN, LRRC ARMC4, C21orf59, CCDC114, CCDC164, CCDC65, DNAH8, DYX1C1, RSPH1, SPAG1, ZMYND CCNO, MCIDAS, CCDC DNAH1, RSPH3, GAS TTC25, DNAJB13 11

228 1/20/2018 Mutation Statistics: Published & UNC unpublished to Mid-2014 Total 509 independent Mutant Alleles from 32 genes Total 673 unrelated cases with biallelic mutations in PCD gene Total 673 Unrelated Cases Top 5 Vs 27 Remaining Genes Top 5 genes (based on published literature): DNAH5 (15-29%), DNAH11 (6-9%), CCDC39 (4-9%), Top 5 genes contributes ~ 2/3 rd of all solved cases (42% of all cases) ~4/5 th alleles are LOF in both DNAI1 (2-10%), CCDC40 (3-4%). Ciliary Ultrastructural Association: Currently 37 Genes Associated with PCD 37 Genes: accounts for ~ 2/3 rd of all PCD 33 Genes: for Ciliary Structure & Function 2 Genes: for Cilia Biogenesis 2 Genes: associated with other Syndromes as well ODA defects DNAH5* DNAI1* DNAI2 DNAL1 NME8 (TXNDC3) CCDC114 CCDC151 ARMC4 ODA+IDA defects DNAAF1 (LRRC50) DNAAF2 (KTU) DNAAF3 LRRC6 C21orf59 HEATR2 ZMYND10 DYX1C1 SPAG1 CCDC103 IDA+MTD defects CCDC39* CCDC40* RS/CP defects RSPH1 RSPH3 RSPH4A RSPH9 HYDIN Nexin-link defects CCDC164 (DRC1) CCDC65 (DRC2) Normal EM DNAH11* Oligocilia CCNO MCIDAS EM not available DNAH8 DNAH1 PCD+other syndrome (n=2) RPGR (X-linked RP+PCD) OFD1 (X-linked MR+PCD) * Top 5 mutated genes Mut in 65% cases (42% of all) 12

229 1/20/2018 Clinical Manifestations in RSPH1 Subjects in Consortium Seem to resemble PCD with dynein arm defects: all had bronchiectasis by mid late teenage years, and most had recurrent otitis media and sinusitis in childhood. HOWEVER All had situs solitus. Neonatal Respiratory Distress: only 50% vs expected >80%. Daily, year round wet cough in 1 st year of life: only 13% vs >90%. Lung function better vs age and gender matched PCD. Subjects N Mean age (years) Mean FEV 1 (% Pred.) RSPH ± ± 23.9 *p=0.043 and p=0.058, worse than RSPH1 (regressed on FEV 1 ; age and gender as covariates. Knowles, All PCDM, et al, 2014, AJRCCM ± ± 22.8* ODA/ODA+IDA ± ±

230 1/20/2018 CCDC39/CCDC40 (FEV 1 % Pred.) Dynein arm defect Dynein arm defect with defined genetic defect: DNAH5, DNAI1, DNAI2, CDC114, ARMC4, LRRC6, HEATR2, SPAG1, DNAAF1, DNAAF2 Microtubular disorganization Microtubular disorganization with defined genetic defect: CCDC39, CCDC40 Age (years) Adult Subjects N Mean age (years) Mean FEV 1 (% Pred.) CCDC39; CCDC * ODA/ODA+IDA *p=0.012, worse than ODA/ODA+IDA Davis, S, et al, 2015, AJRCCM. Ciliary EMs for RSPH1 Mutations (A) Normal Axonemal Structure Absence of Central Pair (B) or Electron Dense Material (C) Translocation of Outer Doublet to Cilia (D) Center or Other Site (E) or Other Changes (e.g., 8+0) (F) (G) Single Microtubule in Center (H) Off-Center Central Pair Mean 80.1% 12.1% 5.1% 1.4% 1.2% Range % % % % 0 6.9% 14

231 1/20/2018 Primary Ciliary Dyskinesia: nasal Nitric Oxide Nasal Nitric Oxide (nno) in PCD (age >5 years) (EM defect; DNAH11) and Healthy Controls* nno Production (nl/min) Healthy Controls (n=78) PCD (longitudinal data; n=103) PCD (cross sect data; n=40) Cut off 77 nl/min Age (years) Also studied >150 Disease Controls, and Replicated at other Consortium Sites. Specificity >0.99; Positive and Negative Predictive Value >0.95 & >0.99, if rule out CF. *Leigh MW, Ann Am Thorac Soc Dec:10(6): UNC SITE 15

232 1/20/2018 Primary Ciliary Dyskinesia: Diagnostic ciliary waveform abnormalities on high speed videomicroscopy Offered at specialized PCD centers of excellence Conclusions 1. PCD is a recessive genetic disease caused by genetic variation in the proteins that are involved in the structure, function and biogenesis of cilia. 2. The clinical presentation of PCD varies considerably but includes a) neonatal respiratory distress syndrome, b) chronic sinopulmonary disease c) recurrent otitis media, d) thoraco-abdominal assymetry including situs inversus and heterotaxy. 3. A PCD diagnosis requires an integrated approach that uses clinical parameters, ciliary electron microscopy, genetic testing, nasal nitric oxide assessments and potentially the use of high speed videomicroscopy. 4. Electron microscopy is normal in 30% of patients and is technically challenging to perform and interpret 5. Genetic screening is commercially available and in some cases informs prognosis but does not currently capture all cases 6. Nasal nitric oxide and videomicroscopy are specialized techniques available at centers of excellence. 16

233 1/20/ Consortium Sites(2004); soon, 24 PCD sites Ottowa Montreal Nova Scotia Original Sites Subsequent Sites PCD Centers PCD Affiliate Centers 17

234 CYSTIC FIBROSIS UPDATE ON NEW THERAPEUTICS Elizabeth Gibb, MD UCSF Associate Professor of Pediatrics Saturday, January 27, :10 p.m. 4:45 p.m. Elizabeth Gibb, MD received her medical degree from Harvard Medical School. She completed residency in Pediatrics and fellowship in Pediatric Pulmonary Medicine at UCSF. Dr. Gibb is an Associate Professor of Pediatrics at UCSF and is co-director of the Pediatric CF Center at UCSF.

235 Cystic Fibrosis: Updates in New Therapeutics Elizabeth Gibb MD Pediatric Pulmonary Medicine January 27, 2018 Overview Cystic Fibrosis manifestations and survival History of Development of CF Theurapeutics CFTR Mutations CFTR Modulators Ivacaftor, Lumacaftor/Ivacaftor, Tezacaftor/Ivacaftor Next generation CTFR modulators Other therapeutics in the pipeline Mucociliary clearance Anti-inflammatory Anti-infective Nutritional/GI 1 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

236 CF Survival Continues to Improve BUT 2 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

237 ... We Have More To Do To Advance Quality of Care Intervene Earlier Diagnose CF earlier (newborn screening) Target CF lung disease before symptoms occur Target genetics to optimize pulmonary and nutritional status Prevent bronchiectasis and loss of lung function Promote good nutrition Develop Comprehensive Treatment Plan (CTP) from Early Age Address comorbidities Add exercise to CTP Address adherence Plan transition to adult care ABcomm, inc CF Drug Development Pipeline in /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

238 History 1989: Discovery of defective CF gene and its protein product (CFTR) 1993: Dornase alfa - first drug developed specifically for CF. 1997: Inhaled tobramycin - first aerosolized antibiotic designed for CF. 2002: Chronic azithromycin shown to improve CF lung health. 2003: Discovery of 3-dimensional structure of a portion of the CFTR protein 2004: Inhaled hypertonic saline 2010: Inhaled aztreonam approved CFTR mutations delf508 55% R117H 2% G542X 3% delf508 G542X R117H 1288insTA G551D R75X TG125T W1282X D1152H L206W N1303K S945L G>A A>G 663delT S549N W1089X G>A 2307insA kbC>T 406-1G>A deli507 R1162X TG135T 1874insT 1952_2035del del9>A del13insAGAAA 2183AA>G G>A A>G 3199del6 3876delA 5'UTR-20G>C* 5'UTR-316A>G* 5'UTR-755C>T 621+1G>T 711+1G>T 712-1G>T A349V A559T c inst* D513G delf311 E1371X E60X F1016S F1052V F1107L* G85E K162E L102R L323P* L997F p.k114del* P205S P67L R117C R31C R352Q R352W R553X R785X S1118F S1235R TG115T V754M W1204X(3744G>A) Y1092X(C>A) Y913X Y917C 4 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

239 Tactics: Lab Practices Ivacaftor CFTR Potentiator Increases time that activated CFTR channel remains open Increases the movement of salt and water through the channel, across the epithelium 5 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

240 History Ivacaftor 2006: Ivacaftor (formerly VX-770) enters clinical trials. 2008: Phase 2 studies of ivacaftor in people with the G551D. 2012: Approved for ages 6 and older with the G551D mutation. 2014: Approved for ages 2 and older with one of 10 CFTR mutations. 2017: Approved for ages 2 and older who have at least one of 28 CFTR mutations 2018: Studies in infants 0-2 are ongoing Ivacaftor Approved Mutations 6 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

241 Clinical Benefits of Ivacaftor Results from STRIVE, ENVISION, PERSIST studies Improved pulmonary function and reduced rate of pulmonary exacerbations 1,2 Less frequent infection with Pseudomonas 3 Improved glucose tolerance, sustained weight gain, and better growth in children 4 Benefit is seen across age and disease severity groups and is sustained after prolonged use 1) Ramsey, et al. N Engl J Med. 2011;365: ) Davies, et al. Am J Respir Crit Care Med. 2013;187(11): ) Heltshe, et al. Clin Infect Dis. 2015;60(5): ) McKone, et al. Lancet Respir Med. 2014;2(11): Prescribing Ivacaftor Take every 12 hours with fat containing foods Available in tablets and granules Monitoring Baseline eye exam, follow up?yearly Common side effects include: Baseline LFTs, follow q 3 months for the first year and then yearly headache upper respiratory tract infection (common cold), including sore throat, stuffy or runny nose gastrointestinal symptoms, including nausea, diarrhea, or gas rash dizziness 7 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

242 Lumacaftor / Ivacaftor Two Step Mechanism of Action Corrector (Lumacaftor) allows CFTR to move to the cell surface Prevents degradation of abnormal protein in the ER Increasing the amount of CFTR at the cell surface Potentiator (Ivacaftor) increases channel opening History of Lumacaftor/Ivacaftor 2015: Approved for people ages 12 and older with CF who have two copies F508del. 2016: Approval extended to children with CF ages 6 to 11 who have two copies of the F508del. 2018: A phase 3 study in ongoing in children aged 2-5 years with two copies of the F508del. 8 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

243 Clinical benefits of Lumacaftor/Ivacaftor Results from TRAFFIC/TRANSPORT /PROGRESS Improved pulmonary function and reduced rate of pulmonary exacerbations Improved weight gain Benefits continue to be observed with longer-term treatment 42% slower rate of ppfev1 decline than matched registry controls Wainwright, et al. N Engl J Med. 2015;373(3): Konstan et al. Lancet Respir Med Feb;5(2): doi: /S (16) Prescribing Lumacaftor/Ivacaftor Take every 12 hours with fat containing foods Monitoring Baseline LFTs, then follow every 3 months for the first year and then yearly Baseline eye exam, then follow yearly? Blood pressure Drug interactions ex hormonal birth control Common side effects: shortness of breath and/or chest tightness upper respiratory tract infection (common cold), including sore throat, stuffy or runny nose gastrointestinal symptoms, including nausea, diarrhea, or gas rash fatigue flu or flu-like symptoms increase in muscle enzyme levels irregular, missed, or abnormal periods (menses) and increase in the amount of menstrual bleeding 9 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

244 CFTR Modulators Of the Future: Tezacaftor-Ivacaftor 2017: Two Phase 3 clinical trials of another corrector (tezacaftor = VX-661) in combination with ivacaftor demonstrate positive results for people with two copies of the F508del (Taylor-Cousar et al, 2017) AND those who have one F508del mutation and a second mutation that results in residual function (Rowe et al, 2017). Taylor-Cousar et al. N Engl J Med Nov 23;377(21): doi: /NEJMoa Taylor-Cousar et al. N Engl J Med Nov 23;377(21): doi: /NEJMoa /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

245 CFTR Modulators Of the Future: Next Generation Modulators 2017: Phase 1 and Phase 2 Clinical Trials Next-generator modulator (VX-440, VX-152, VX-659) + ivacaftor + tezacaftor Improve CFTR folding and increase the amount of CFTR trafficked to the cell surface Promising results in people with Two copies of the F508del One F508del mutation and a second mutation that results in minimal function (ex nonsense mutations, G542X) Vertex Press Release, Jul 18, /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

246 Future With over 2000 mutations there will need to be more drugs developed to target each one Some mutations may need 3 or more drugs!!! 2018: More Phase 2 and Phase 3 trials and studies in adults and children are underway CF Drug Development Pipeline in 2018 New correctors New potentiators PTI Amplifiers - increase the amount of CFTR protein in the cell. This makes more CFTR protein available for other therapies, such as ivacaftor and lumacaftor, to work on. QR-010 is an inhaled oligonucleotide designed to repair CFTR-encoded mrna 12 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

247 CF Drug Development Pipeline in 2018 Bronchitol is an inhaled dry powder form of mannitol (a naturally occurring osmotic agent), which works by drawing water into the airways. OligoG is a dry powder drug that has been shown to decrease the thickness of mucus in the lungs QBW276, SPX-101 and AZD5634 are designed to block the function of the sodium (Na+) channel found in the lungs, to help maintain fluid in airways. CF Drug Development Pipeline in 2018 JBT-101 is an endocannabinoid-mimetic CTX-4430 reduces production of leukotriene B4 (LTB4) LAU-7b is a retinoid related to vitamin A. 13 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

248 CF Drug Development Pipeline in 2018 Gallium is a molecule, nearly identical to iron, that disrupts iron-dependent biological processes and has been shown to kill antibioticresistant strains of Pseudomonas aeruginosa SPI-1005 may protect inner ear damage from use of aminoglycoside antibiotics CF Drug Development Pipeline in 2018 Liprotamase (Sollpura) is a pancreatic enzyme replacement that is not prepared from animal sources. Oral glutathione is an antioxidant which may improve growth and decrease gut inflammation in children with CF. 14 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

249 Acknowledgements Ngoc Ly Meghan McGarry Mary Ellen Kleinhenz Dennis Nielson Diana Dawson My CF Care Teams in Oakland and San Francisco Summary CF survival is improving but there is more to be done There are over 2000 CFTR mutations, with different effects on the CFTR channel CFTR Modulators are targeting these different types of CFTR mutations and can be life changing for affected patients Next generation CTFR modulators may be able to help a wider variety of patients Cystic Fibrosis Foundation website has information on drugs in the CF pipeline and trials which are enrolling 15 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

250 References CF Drug Pipeline Cystic Fibrosis Foundation Vertex Vertex Announces Positive Phase 1 & Phase 2 Data from Three Different Triple Combination Regimens in People with Cystic Fibrosis Who Have One F508del Mutation and One Minimal Function Mutation (F508del/Min). Press release, Jul 18, References Ivacaftor Ramsey, et al. N Engl J Med. 2011;365: Davies, et al. Am J Respir Crit Care Med. 2013;187(11): Heltshe, et al. Clin Infect Dis. 2015;60(5): McKone, et al. Lancet Respir Med. 2014;2(11): Lumacaftor/Ivacaftor Wainwright, et al. N Engl J Med. 2015;373(3): Konstan et al. Lancet Respir Med Feb;5(2): doi: /S (16) Epub 2016 Dec 21. Tezacaftor/Ivacaftor Taylor-Cousar et al. N Engl J Med Nov 23;377(21): doi: /NEJMoa Epub 2017 Nov 3. Rowe et al. N Engl J Med Nov 23;377(21): doi: /NEJMoa Epub 2017 Nov /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

251 In the Phase 2 clinical trial of VX-152 in combination with ivacaftor and tezacaftor (VX- 661), the 10 participants in the study with a single F508del mutation who received the 200 mg dose of VX-152 had a 9.7 percent increase in lung function and a decrease in sweat chloride of 14.1 after two weeks of treatment. The 10 participants in the study who have two copies of the F508del mutation who received the 200 mg dose of VX-152 had a 7.3 percent increase in lung function and a decrease in sweat chloride of 20.9 after two weeks of treatment. In the Phase 1 clinical trial of VX-659 in combination with ivacaftor and tezacaftor (VX- 661), participants in the study with a single F508del mutation who received the 120 mg dose of VX-659 had a 9.6 percent increase in lung function and decrease in sweat chloride of 41.6 after two weeks of treatment. Data from the trials, along with results from another study expected to begin later this year, will help Vertex decide which next-generation modulator candidate or candidates to move forward into Phase 3 studies in early /20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

252 18 1/20/2018 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]