Contractor Advisory Committee for Tumor Treating Fields Therapy (TTFT) March 6, 2019

Transcription

1 Contractor Advisory Committee for Tumor Treating Fields Therapy (TTFT) March 6,

2 Agenda Introductions and background Answering the scientific questions Mechanism of action General acceptance by medical community Net positive health outcomes Predictors of success Additional supporting evidence Patient perspective 2

3 Participants Bill Doyle Executive Chairman, Novocure Matthew Ballo, M.D. Professor of Radiation Oncology, University of Tennessee Health Science Center Medical Director, Radiation Oncology, West Cancer Center Steve W. Tumor Treating Fields patient Adrian Kinzel, M.D. Vice President and Medical Director, Novocure 3

4 Definitions and abbreviations Tumor Treating Fields common scientific name in the literature TTFields TTF TTFields treatment or TTF treatment Tumor Treatment Field Therapy (TTFT) Medicare/MAC name for the therapy Optune Brand name for the TTFields delivery device for glioblastoma patients Formerly known as the NovoTTF-100A device EF-14 Trial Randomized control trial (n=695) for TTFields in newly diagnosed glioblastoma Glioblastoma GBM Glioblastoma multiforme, older name based on a previous WHO classification 4

5 Requested coverage for Tumor Treating Fields Medicare coverage requested: TTFT with temozolomide (TMZ) is covered for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery and completion of radiation therapy together with concomitant standard of care chemotherapy. Requested coverage matches the FDA pre-market approval (PMA) indication for use: Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery and completion of radiation therapy together with concomitant standard of care chemotherapy. 5

6 FDA premarket approval (PMA) background PMA is the most stringent type of device marketing application required by FDA. Class III devices are those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury. PMA approval is based on a determination by FDA that the PMA contains sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s). U.S. Food and Drug Administration (FDA). Premarket Approval (PMA) webpage. Accessed March 2,

7 Medicare standards for local coverage determinations (LCD) General acceptance standard for LCDs In conducting a review, MACs [Medicare Administrative Contractors] shall use the available evidence of general acceptance by the medical community, such as published original research in peer-reviewed medical journals, systematic reviews and meta-analyses, evidence-based consensus statements and clinical guidelines. Medicare Program Integrity Manual, Chapter 13, section Rev 863, Accessed March 2,

8 Agenda Introductions and background Answering the scientific questions Mechanism of action General acceptance by medical community Net positive health outcomes Predictors of success Additional supporting evidence Patient perspective 8

9 How confident are you that scientific evidence supports mitotic spindle disruption and cellular apoptosis as the mechanism of action of TTFT? 9

10 Substantial research demonstrates the effects of forces on tubulin proteins and the mitotic spindle Biophysics literature reports clear thresholds of force required to halt spindle formation Dogterom M et al. Science. 1997; 278: publications in Medline Database on the biophysics of mechanical forces and tubulin function 1980 Many models for the mechanism of [microtubules] MT-mediated transport and mitosis postulate an important role for MT polarity because a symmetric fibre could not generate force in one direction along its surface Dynamic microtubules can also engage in mechanical processes, such as exerting forces by pushing or pulling against a load [microtubule-associated proteins] and forces can modulate microtubule growth and shrinkage. 1. Dogterom M et al. Science. 1997; 278: Search of Medline Database using force and tubulin for all fields. March 2, Heidemann SR, McIntosh JR. Nature Jul 31;286(5772): Brouhard GJ, Rice LM. Nat Rev Mol Cell Biol July ; 19(7):

11 Like gravity and magnetic fields, electric fields exert forces at a distance GRAVITATIONAL FIELDS exert forces on masses MAGNETIC FIELDS exert forces on ferromagnetic materials like iron ELECTRIC FIELDS exert forces on charges & polarized molecules Earth Magnet uniform field Charged Plates 11

12 Electric fields exert forces on charged tubulin proteins, disrupting mitosis Polar (charged) tubulin dimer proteins orient in direction of electric fields 1. Fishkind DJ et al. J Cell Sci. 1996; 109: Gagliardi LJ. Phys Rev E Stat Nonlin Phys. 2002; 66: Pohl AH. Dielectrophoresis. Cambridge, UK: Cambridge University Press; Kirson ED, et al. Cancer Res. 2004;64(9): Giladi M., et al. Sci Rep Dec 11;5:

13 Mitotic spindle disruption by electric fields has been observed in every cancer cell line tested Mitotic spindle disruption in fluorescence images of A549 cells exposed to TTFields CONTROL TUMOR TREATING FIELDS A549 cells in lung tissue were treated with Tumor Treating Fields for 24 hours. Tubulin fluorescence images were inverted and pseudocolored so that increasing fluorescence intensity is indicated from blue to red (scale bar represent arbitrary units). Dashed lines define the region between the two spindle poles (white) and overall tubulin fluorescence within the cell (Red). 1. Giladi M., et al. Sci Rep Dec 11;5: Kim EH, et al. Oncotarget. 2016; 7:38 2. Additional data on file with Novocure. 13

14 Tumor Treating Fields Therapy delivery system TRANSDUCER ARRAY Sterile, single-use transducer array replaced every 3-4 days ELECTRIC FIELD GENERATOR 2.7 lbs, portable Tumor Treating Fields generator 14

15 Independent research confirms TTFields system delivers effective electric field dose to cranium Electric field intensity (V/cm) models confirm dose deposition in target regions Anterior and posterior arrays active Left and right arrays active Field intensity (V/cm) Field intensity (V/cm) Electric field distribution within the brain was calculated using the finite element method to solve the quasistatic approximation of the Maxwell s equations. The model estimates field distribution with consideration for established measurements of permitivity (σ) and conductivity (εr) for critical tissue (e.g., skull, white matter, tumor, etc.).1. Miranda PC, et al. Phys Med Biol. 2014;59(15): Wenger C, et al. Phys Med Biol. 2015;60(18): Wenger C, et al. Int J Radiat Oncol Biol Phys Apr 1;94(5): Timmons JJ et al. Phys Med Biol. 2017;62(21): Korshoej AR, et al. PLoS One. 2018;13(8):e Korshoej AR, et al. PLoS One. 2017;12(6):e

16 Significant and growing body of external research elucidating the mechanism of action for TTFields 30+ academic centers performing bench and animal research on TTFields Recently published external research Korea University Comprehensive revalidation of MOA in vitro and in vivo Stanford University Effect of combinations with selected systemic agents and recent research on cell membrane permeability under TTFields University of Würzburg Synergism with checkpoint inhibitors UT Southwestern Effects of TTFields with ionizing radiation. Identifying a reduction in the DNA repair mechanisms and downregulation of BRCA1 Aarhus University and Max Planck Institute for Biological Cybernetics Advanced techniques to personalize electric field maps and maximize field intensity using alternative array layouts 1. Kim EH, et al. Oncotarget. 2016;7(38): Kim EH, et al. Oncotarget. 2016;7(40): Joy Y, et al. Cell Death Discov Oct 3;4: Chang E, et al J Neurooncol. 2017;134(2): Chang E, et al. Cell Death Discov Dec 5;4: Korshoej AR, et al PLoS One. 2018;13(8):e Korshoej AR, et al PLoS One. 2017;12(6):e Kessler AF, et al. Cell Death Discov Jul 16;4:12. 16

17 External authors produce the majority of the peer-reviewed research on Tumor Treating Fields Company research External authors only Cumulative number of publications Before CAC bibliography does not contain an up-to-date list of relevant external research on effect of electric fields on tubulin or the science of TTFields Refer to bibliography annex for complete list of citations; totals do not include general scientific publications studying the effect of force and biophysical mechanics on mitotic spindle formation; 23 of the external publications were performed entirely independent of Novocure and 7 publications were run independently while relying on a pre-clinical system provided by Novocure. 17

18 Agenda Introductions and background Answering the scientific questions Mechanism of action General acceptance by medical community Net positive health outcomes Predictors of success Additional supporting evidence Patient perspective 18

19 How confident are you that TTFT is generally accepted by the medical community for newly diagnosed GBM? 19

20 TTFields development timeline Company founded EF-07 pilot trial in GBM begins EF-14 pivotal trial in newly diagnosed GBM begins Optune FDA approval in newly diagnosed GBM TTFields Category 1 in NCCN Guidelines for newly diagnosed GBM First-inman study EF-11 pivotal trial in recurrent GBM begins Optune FDA approval in recurrent GBM EF-14 pivotal trial in newly diagnosed GBM positive final long-term analysis results published 20

21 In 2018, 40% of eligible patients received a prescription for TTFields 4,000 3,500 3,000 2,500 2,000 1,500 1, New prescriptions written for Tumor Treating Fields in the U.S. by year 669 1,607 2,344 3,102 3, Glioblastoma statistics 13,800 patients diagnosed annually 9,300 patients eligible for TTFields 40% of eligible patients received a prescription in Novocure Annual Report on Form 10-K. accessed March 1, Novocure Annual Report on Form 10-K. accessed March 1, Ostrom QT et al. Neuro-Oncol, 2018 Oct 1;20(suppl_4):iv1-iv Eligible population estimated based on EF-14 enrollment screening data, reported in Stupp R, et al. JAMA. 2017;318(23):

22 Prescriber base has increased steadily since 2015 FDA approval for newly diagnosed GBM 1,200 1,000 Unique prescribers in the U.S. by year 887 1, Rx Volume by Segment 50% neuro-oncologists % radiation oncologists % medical oncologists 4% neurosurgeons Novocure data requested by CAC panel. Segments based on volume of prescriptions written. 22

23 TTFields has achieved general acceptance in the medical community throughout the United States Prescriptions from 50 states + Washington D.C. and Puerto Rico Regional acceptance 39 to 42% of eligible patients receiving a prescription for Optune in East, Central, and West regions Novocure data requested by CAC panel. Novocure estimate based on total 2018 prescription volume as a proportion of eligible patient population. 1. Ostrom QT et al. Neuro-Oncol, 2018 Oct 1;20(suppl_4):iv1-iv86. 23

24 TTFields has achieved general acceptance in the medical community throughout the United States Prescription distribution 48% of prescriptions from community practices; 52% from academic practices Certified prescribers at 59 of the 62 NCI-designated cancer centers Novocure data requested by CAC panel. Novocure 2018 data. 24

25 Novocure supplies Optune directly to patients Optune 0% of the product revenue is received by the physician practice Infused oncology drugs 4 to 40% of the product revenue is received by the physician practice 1. Medicare Claims Processing Manual, Chapter 17 Drugs and Biologicals, Section ; (Rev. 4204, ). Accessed March 2, 2019; described the payment methodology of ASP plus 6%, currently subject to a 2% sequestration reduction; and 42 C.F.R Hospitals designated as 340B hospitals are eligible to secure discounts from drug manufacturers of approximately 23%. In turn, these hospitals are still able to charged a full contract price for patients with private / commercial insurance, resulting in a substantial margin. Source: Medicare Payment Advisory Committee, May 2015 Report to Congress, accessed March 3, Polite BN et al, Journal of Oncology Practice :6, Novocure data on file from propriretary market survey of oncology practice reimbursement rates with managed care payers for infusion drugss. 25

26 TTFields for newly diagnosed GBM is covered by essentially every commercial payer, including every national payer 2 THE PARENT CORPORATIONS OF CGS AND NORIDIAN, THE MEDICARE MACS ORGANIZING THIS PANEL, BOTH COVER TTFIELDS 85 HEALTHCARE PAYERS IN THE UNITED STATES HAVE ISSUED POSITIVE COVERAGE POLICIES 5+ ALL FIVE OF THE LARGEST COMMERCIAL PAYERS AND THE BCBSA COVER TTFIELDS 243 MILLION AMERICANS COVERED UNDER PRIVATE HEALTH PLANS Medicare s current negative LCD is: Non-conforming with U.S. payers Out of step with reimbursement decisions by other major governments around the world Putting Medicare beneficiaries at risk for inequitable access to oncology care* *Novocure has to date provided Optune to Medicare beneficiaries BCBSA: Blue Cross Blue Shield Association. All statements related to healthcare payer coverage are specific to glioblastoma. 1. Novocure Annual Report on Form 10-K. accessed March 1,

27 Agenda Introductions and background Answering the scientific questions Mechanism of action General acceptance by medical community Net positive health outcomes Predictors of success Additional supporting evidence Patient perspective 27

28 How confident are you that there is sufficient evidence to determine that TTFT for newly diagnosed GBM can provide net positive health outcomes in the Medicare-eligible population? 28

29 Medicare-eligible population definition Medicare eligibility Over age 65; or End-stage renal disease; or Permanently disabled regardless of age Glioblastoma often leads to debilitating side-effects, rendering patients unable to function independently 1. Department of Health and Human Services, accessed March 2, Reardon DA. J Clin Oncol Mar 10;24(8):

30 Review of clinical data for TTFT in newly diagnosed GBM Matthew Ballo, M.D. Professor of Radiation Oncology, University of Tennessee Health Science Center, Medical Director, Radiation Oncology, West Cancer Center 30

31 Glioblastoma Most prevalent and aggressive central nervous system cancer in adults Disease prognosis depends on Age Extent of surgical resection Tumor location Genetics Functional status Treatment options are limited and survival can be measured in months without aggressive treatment 1. Ostrom QT, et al. Neuro Oncol. 2016;18(suppl 5):v1-v Curran WJ, et al. J Natl Cancer Inst.1993;85(9): Lamborn KR, et al. Neuro Oncol. 2004;6(3): Hegi ME, et al. N Engl J Med. 2005;352(10): Verhaak RGW, et al. Cancer Cell. 2010;17(1): Wilson TA, et al. Surg Neurol Int. 2014;5:64. 31

32 FDA-approved therapies for glioblastoma Carmustine Injection Palliative Therapy Carmustine Polymer Wafers Newly Diagnosed GBM TMZ Newly Diagnosed and Maintenance Optune + TMZ Newly Diagnosed GBM FDA approved expanded label for Optune to include final long term analysis Newly Diagnosed GBM Carmustine Polymer Wafers Recurrent GBM Bevacizumab Recurrent GBM Optune Recurrent GBM GBM, glioblastoma multiforme; TMZ, temozolomide.1. BiCNU [package insert]: Bristol-Myers Squibb Co, US NLM. Drug record: carmustine. US NLM website. Accessed January 31, Gliadel Wafer [package insert]: Eisai Inc; FDA. Drug approval package. Gliadel wafer. Published July 8, Accessed January 31, Temodar [package insert]: Merck & Co, Inc; NCI/NIH. FDA approval for temozolomide. NCI website. Accessed January 31, Avastin [package insert]: Genentech, Inc; NCI/NIH. FDA approval for bevacizumab. NCI website. Accessed January 31, Optune Instructions for Use. Novocure

33 The success of the EF-14 trial for TTFields provided a much needed advance in clinical outcomes in glioblastoma Venderbeek AM, et al. Neuro-oncology. 2018; 20(8),

34 The results of the EF-14 Randomized Control Trial (n=695) have been reported in multiple JAMA publications December 15, 2015 December 17, 2017 February 1, Stupp R, et al. JAMA. 2015;314(23): Stupp R, et al. JAMA. 2017;318(23): Taphoorn MJB, et al. JAMA Oncol. 2018;4(4):

35 EF-14: phase 3 pivotal trial design Newly diagnosed GBM n=695 Biopsy/ debulking Radiation + TMZ Enrollment window (4-7 weeks after RT + TMZ) R A N D O M I Z E D 2:1 Optune 18 h/day + TMZ 6 cycles TMZ 6 cycles 1st progression Optune + 2L chemotherapy, surgery, SRS, or combination* 2L chemotherapy, surgery, SRS, or combination 2nd progression or 24 months Primary endpoint: PFS Powered secondary endpoint: OS Additional secondary endpoints: PFS6, 1-y/2-y survival, ORR, safety, QoL Stratification by: 1. Resection (biopsy vs partial vs gross total) 2. MGMT promoter methylation status EF-14 Protocol: Central MRI review will be performed by a neuro-radiologist blinded to the treatment group of each patient. *Treatment with Optune was continued for 24 months or until second progression, whichever occurred first unless prohibited by the patient s clinical condition.1,2 GBM, glioblastoma multiforme; TMZ, temozolomide; RT, radiation therapy; 2L, second-line; SRS, stereotactic radiosurgery; PFS, progression-free survival; OS, overall survival; PFS6, the percentage of patients alive and progression-free at 6 months; ORR, objective response rate; QoL, quality of life; MGMT, O6-methylguanine-DNA methyltransferase. 1. Stupp R, et al. JAMA. 2017;318(23): Stupp R, et al. JAMA. 2017;318(23 suppl 1):S1-S

36 EF-14: key baseline characteristics ITT Population Optune + TMZ (n=466) TMZ Alone (n=229) Characteristics Median age, years (range) 56 (19-83) 57 (19-80) Female sex, % Median KPS (range) 90 (60-100) 90 (70-100) Extent of resection, % Gross total resection Partial resection Biopsy Median time from diagnosis to randomization, mo (range) 3.8 ( ) 3.7 ( ) Duration of therapy with TMZ, mo Median (range) 6 (0-51) 5 (0-33) Duration of therapy with Optune, mo Median (range) 8.2 (0-82) Baseline characteristics were well balanced between the two treatment arms ITT, intent-to-treat; TMZ, temozolomide; KPS, Karnofsky Performance Score; SD, standard deviation. 1. Stupp R, et al. JAMA. 2017;318(23):

37 EF-14: key baseline characteristics (cont d) ITT Population Optune + TMZ (n=466) TMZ Alone (n=229) Molecular Profiles, % MGMT status Tissue available and tested Methylated Unmethylated Insufficient for testing 10 7 IDH1 R132H mutation status Tissue available and tested Positive 7 5 Medications, % Antiepileptics Corticosteroids Average daily usage of TTFields*, % 75 Baseline characteristics were well balanced between the two treatment arms *Defined as use of Optune 75% of the time, or 18 hours per day, in the first 3 months of treatment. ITT, intent-to-treat; TMZ, temozolomide; MGMT, O6- methylguanine-dna methyltransferase; IDH1, isocitrate dehydrogenase 1.Stupp R, et al. JAMA. 2017;318(23):

38 EF-14: Progression-Free Survival (ITT) Fraction Survival Optune + TMZ TMZ alone ITT Population At the time of the final survival analysis, PFS was reported out to 30 months. Optune + TMZ (n=466) TMZ Alone (n=229) Median PFS from randomization, mo % CI, mo Stratified log-rank P <0.001 HR (95% CI) 0.63 ( ) Median PFS from diagnosis, mo Progression-Free Survival (months) ITT, intent to treat; TMZ, temozolomide; PFS, progression-free survival; CI, confidence interval; HR, hazard ratio. 1. Stupp R, et al. JAMA. 2017;318(23): Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. 38

39 EF-14: Overall Survival (ITT) Fraction Survival Optune + TMZ TMZ alone ITT Population Optune + TMZ (n=466) TMZ Alone (n=229) Median OS from randomization, mo % CI, mo Stratified log-rank P <0.001 HR (95% CI) 0.63 ( ) Median OS from diagnosis, mo year OS 43% 31% Overall Survival (months) ITT, intent to treat; TMZ, temozolomide; CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival. 1. Stupp R, et al. JAMA. 2017;318(23): Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. 39

40 EF-14 safety summary: incidence of grade 3/4 adverse events in 5% of patients Safety Population Grade 3-4 Events, No. (%) of Patients Optune + TMZ (n=456) TMZ Alone (n=216) 1 Adverse event 218 (48) 94 (44) Blood and lymphatic system disorder* 59 (13) 23 (11) Thrombocytopenia 39 (9) 11 (5) Gastrointestinal disorders 23 (5) 8 (4) Asthenia, fatigue, and gait disturbance 42 (9) 13 (6) Infections 32 (7) 10 (5) Injury, poisoning, and procedural complications (falls and medical device site reaction) 24 (5) 7 (3) Metabolism and nutrition disorders (anorexia, dehydration, and hyperglycemia) 16 (4) 10 (5) Musculoskeletal and connective tissue disorders 21 (5) 9 (4) Nervous system disorders 109 (24) 43 (20) Seizures 26 (6) 13 (6) Respiratory, thoracic, and mediastinal disorders (pulmonary embolism, dyspnea, and aspiration pneumonia) 24 (5) 11 (5) *The numerically slightly higher incidence of hematological toxicity, fatigue, and some other adverse effects are due to the longer treatment duration and observation time in the experimental group. The differences disappear when data are normalized to treatment duration. TMZ, temozolomide. 1. Stupp R, et al. JAMA. 2017;318(23): Optune Instructions for Use. 40

41 EF-14 overall survival: magnitude of benefit was comparable to Stupp/EORTC trial in 2005 for temozolomide RT alone vs. TMZ+RT TMZ alone vs. Optune+TMZ Hazard ratio (95% CI) ( ) ( ) Median survival 12.1 months 14.6 months 16.0 months 20.9 months Δ 2.5 months Δ 4.9 months Two-year survival rate 10% 27% 31% 43% Δ 17% Δ 12% Five-year survival rate 2% 10% 5% 13% Δ 8% Δ 8% TMZ, temozolomide; RT, radiation therapy; CI, confidence interval. 1. Stupp R, et al. N Engl J Med 2005;352: Stupp R, et al. Lancet Oncol 2009; 10: Stupp R, et al. JAMA. 2017;318(23):

42 The EF-14 control arm survival was consistent with prior trials, specifically the RTOG-0525 trial randomized post RT Overall Survival (months) From randomization Median 95% CI Two year survival Median 95% CI From registration Median 95% CI Control arm of EF-14 (n=266) % 34.2% Control arm of RTOG0525 (n=411) TMZ, temozolomide. 1. Stupp R, et al. JAMA. 2017;318(23): Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. 3. Gilbert MR, et al. J Clin Oncol Nov 10;31(32):

43 National Comprehensive Cancer Network (NCCN ) Category 1* Adjuvant Treatment Recommendations for Newly Diagnosed GBM MGMT promoter methylated Postoperative Newly diagnosed GBM Age 70 years, KPS 60 Standard brain RT + concurrent TMZ and adjuvant TMZ + alternating electric field therapy (Optune),, OR Standard brain RT + concurrent TMZ and adjuvant TMZ, MGMT promoter unmethylated or indeterminate Standard brain RT + concurrent TMZ and adjuvant TMZ + alternating electric field therapy (Optune),, OR Standard brain RT + concurrent TMZ and adjuvant TMZ,, *There is uniform NCCN consensus for this recommendation based on high-level evidence (Category 1). Combination of agents may lead to increased toxicity or radiographic changes. Benefit of treatment with TMZ for GBM beyond 6 months is unknown. Alternating electric field therapy is only indicated for patients with supratentorial disease. Clinical benefit from TMZ is likely to be lower in patients whose tumors lack MGMT promoter methylation. Note: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is preferred for eligible patients. See the NCCN Guidelines for Central Nervous System Cancers for the complete list of adjuvant treatment recommendations for newly diagnosed glioblastoma. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. GBM, glioblastoma; KPS, Karnofsky Performance Score; MGMT, O6-methylguanine-DNA methyltransferase; RT, radiation therapy; TMZ, temozolomide. Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Central Nervous System Cancers. V National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. 43

44 National Comprehensive Cancer Network (NCCN ) Category 1* Adjuvant Treatment Recommendations for Newly Diagnosed GBM (cont d) MGMT promoter methylated Postoperative Newly diagnosed GBM Age >70 years, KPS 60 Hypofractionated brain RT + concurrent and adjuvant TMZ, OR Standard RT + concurrent TMZ and adjuvant TMZ + alternating electric field therapy (Optune),, MGMT promoter unmethylated or indeterminate Standard RT + concurrent TMZ and adjuvant TMZ + alternating electric field therapy (Optune),, *There is uniform NCCN consensus for this recommendation based on high-level evidence (Category 1). Combination of agents may lead to increased toxicity or radiographic changes. Benefit of treatment with TMZ for GBM beyond 6 months is unknown. Alternating electric field therapy is only indicated for patients with supratentorial disease. Clinical benefit from TMZ is likely to be lower in patients whose tumors lack MGMT promoter methylation. Note: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is preferred for eligible patients. See the NCCN Guidelines for Central Nervous System Cancers for the complete list of adjuvant treatment recommendations for newly diagnosed glioblastoma. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. GBM, glioblastoma; KPS, Karnofsky Performance Score; MGMT, O6-methylguanine-DNA methyltransferase; RT, radiation therapy; TMZ, temozolomide. Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Central Nervous System Cancers. V National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. 44

45 Agenda Introductions and background Answering the scientific questions Mechanism of action General acceptance by medical community Net positive health outcomes Predictors of success Additional supporting evidence Patient perspective 45

46 How confident are you that the available evidence demonstrates adequate predictors of success in Medicare-eligible population? 46

47 EF-14 trial subgroup analysis for overall survival Median Survival (months) Subgroup No. of Patients (%) Hazard Ratio Optune + TMZ TMZ Alone Overall 695 (100) MGMT (central) Unmethylated 304 (44) Methylated 214 (31) Resection Biopsy 89 (13) Partial 234 (34) Gross total 372 (54) Age <65 y 561 (81) y 134 (19) KPS (66) (33) Sex Female 222 (32) Male 473 (68) Optune + TMZ Better TMZ Alone Better TMZ, temozolomide; MGMT, O-6-methylguanine-DNA methyltransferase; KPS, Karnofsky Performance Score. 1. Stupp R, et al. JAMA. 2017;318(23):

48 Understanding dose and measuring dose-response in EF-14 48

49 In vitro evidence of mechanism of action: field frequency must be titrated to tumor cell size Relative Cell Number (% of Control) Relative Change in Cell Number After 24 Hours of Treatment at Different Frequencies Optimal frequency (khz) 100: Mouse melanoma (B16F1) 150: Human breast carcinoma (MDA-MB-231) 200: Rat glioma (F-98) 200: Human NSCLC (H1299) Frequency (khz) Multiple cancer cell lines were exposed to TTFields at various frequencies ( khz) Inhibition of cellular proliferation by TTFields was frequency dependent Optimal frequency was inversely proportional to cell size Smaller cells were inhibited at higher frequencies Larger cells were inhibited at lower frequencies The optimal frequency for inhibiting GBM cells was 200 khz TTFields, Tumor Treating Fields; NSCLC, non small cell lung carcinoma; GBM, glioblastoma multiforme. Adapted from: Kirson ED, et al. PNAS. 2007;104(24):

50 In vitro evidence of mechanism of action: time-dependent effects of TTFields (more is better) U-87 MG A-172 U-118 MG F-98 Number of Cells (% of control) st 2nd 3rd * * Time (Hours) Number of Cells (% of control) st 2nd 3rd Time (Hours) Number of Cells (% of control) st 2nd 3rd 4th 5th Time (Hours) Number of Cells (% of control) st 2nd 3rd Time (Hours) Glioma Cell Line Doubling Time (hours) Number of Cells Following TTFields Application (%) 1st Cell Cycle 2nd Cell Cycle 3rd Cell Cycle U-87 MG A U-118 MG F >*P >0.01, 0.01 > P >0.001, P < Adapted from Schneiderman RS, et al. Poster presented at: 2015 Society for NeuroOncology (SNO) Annual Meeting; November 19-22, 2015; San Antonio, TX. Poster no ATPS

51 In vitro evidence of mechanism of action: increased force (field intensity, V/cm) = increased kill rate Relative Cell Number (% of Control) TTFields Intensity (V/cm) 3 Multiple cancer cell lines subjected to TTFields at various electric field intensities Inhibition of cellular proliferation by TTFields is dose dependent Effective inhibition of cell culture growth seen at intensities >1.0 V/cm Optimal frequency (khz) 100: Mouse melanoma (B16F1) 150: Human breast carcinoma (MDA-MB-231) 200: Rat glioma (F-98) 200: Human NSCLC (H1299) TTFields, Tumor Treating Fields; NSCLC, non small cell lung carcinoma. Adapted from: Kirson ED, et al. PNAS. 2007;104(24):

52 Personalizing the array layout: changing the layout changes field distribution and resulting dose delivered to tumor Field strength within a tumor did not correlate with its size and shape Field strength always increased when the arrays were adapted to the tumor's location Compared with a default layout, the largest increase in field strength was 184% The highest average field strength induced in a tumor was 2.21 V/cm Wenger C, et al. Int J Radiat Oncol. 2016; 94(5):

53 Correlation of TTFields dose density and survival outcomes in newly diagnosed glioblastoma: A numerical simulation-based analysis of patient data from the EF-14 randomized trial Matthew T. Ballo 1, Noa Urman 2, Gitit Lavy-Shahaf 2, Ze ev Bomzon 2 and Steven Toms 3 1 West Cancer Center Center, Memphis Tennessee; 2 Novocure Ltd, Haifa, Israel; 3 Warren Alpert Medical School of Brown University

54 Background Rationale: Preclinical investigations have defined a relationship between TTFields antimitotic effects and exposure time (in hours), frequency (in khz) and field intensity (in V/cm). The randomized clinical phase III trial (EF-14) of TTFields in Glioblastoma showed improved overall survival. The overall survival benefit was associated with the degree of TTFields compliance (% monthly use). Hypothesis: Overall survival and Progression free survival are higher in patients who receive higher doses of TTFields at the tumor bed.

55 Methods: Step 1: Contouring of tumor on MRI Step 2: Head model creation & Transducer placement Step 3: Intensity Distribution calculation Assign electric properties to model tissue types Calculate 3D electric field distribution numerically (Finite Difference Method). Analyze Field distribution by gross tumor volumes & peritumoral boundary zones (3mm around GTV and Resection cavity) Patient data EF-14 TTFields txt arm: N=466 Treatment duration >2 mths: n=379 Sufficient MRI quality: n=340 Total number for analysis: 340 patients Local Minimum Field Intensity (LMiFI) : The lower of the two field intensities delivered to each point (Volts/cm) Local Minimum Power Density (LMiPD): The lower of the two power densities delivered to each point (milliwatts/cm 3 )

56 Probability of survival LMiFI (V/cm) 1: <1.00 (V/cm) 2: 1.00 (V/cm) Probability of survival LMiPD (mw/cm 3 ) 1: <1.10 (mw/cm 3 ) 2: 1.10 (mw/cm 3 ) Hazard ratio = ( ) Log rank p= Hazard ratio = ( ) Log rank p= Overall survival (months) Overall survival (months) Median Subjects Event Censored survival 95% CI 1: <1.00 (V/cm) , : 1.00 (V/cm) , Median Subjects Event Censored survival 95% CI 1: <1.10 (mw/cm3) , : 1.10 (mw/cm3) , Higher TTFields intensity ( 1.0 Volts/cm) and power density ( 1.1 mw/cm 3 ) are associated with improved overall survival and independent of compliance

57 Summary: Dose Density = Power Density X Compliance Higher TTFields intensity ( 1.0 Volts/cm) and power density ( 1.1 mw/cm3) are associated with improved overall survival and independent of compliance. Calculating, visualizing and manipulating TTFields dose distributions to maximize TTFields dose in the tumor bed is expected to improve patient outcome further. A new term, Dose Density, expresses the two most important variables associated with TTFields use and Overall Survival as a single variable. Probability of survival Log rank p= : LMiPD<1.1 (V/cm) and <75% 2: LMiPD<1.1 (V/cm) and 75-85% 3: LMiPD<1.1 (V/cm) and % 4: LMiPD 1.1 (V/cm) and <75% 5: LMiPD 1.1 (V/cm) and 75-85% 6: LMiPD 1.1 (V/cm) and % Overall survival (months)

58 Increased dose correlated with increased survival Overall Survival by dose in newly diagnosed GBM higher energy* and hours/day higher energy* and hours/day higher energy* and <18 hours/day lower energy* TMZ alone median overall survival, months 16 n= months 23 n=42 3 n= n=44 2 months months months 37 n=36 1 months TMZ, temozolomide; CI; confidence interval. Dose density defined as a factor of both power loss density and monthly usage of therapy. * Higher energy defined as power loss densities greater than or equal to 1.1 mw/cm 3. Lower energy defined as power loss densities less than1.1 mw/cm % CI 21-48; 23 events, 13 censored 2 95% CI 18-39; 29 events, 15 censored 3 95% CI 19-44; 24 events, 18 censored 4 95% CI 17-24; 153 events, 42 censored Post-hoc analysis of EF-14 treatment arm patient data. Of the 466 EF-14 treatment arm patients, the analysis reviewed 317 patients with treatment duration >2 months and sufficient MRI quality. Ballo MT, Bomzon Z, Urman N, Lavy-Shahaf G, Toms SA. American Society for Radiation Oncology (ASTRO) 2018 Annual Meeting. Poster Presentation Correlation of TTFields Dose Density and Survival Outcomes in Newly Diagnosed Glioblastoma: A Numerical Simulation-Based Analysis of Patient Data from the EF-14 Randomized Trial. Poster Presentation 1110: Tuesday, Oct. 23, 2018, 4:57 p.m. CDT. Stupp, R., et al. JAMA Dec 19;318(23):

59 TTFields in practice at the West Cancer Center Multidisciplinary approach Neurosurgery Radiation oncology Medical/Neuro oncology Consistent education of patient by treatment team throughout care Offered as national and institutional standard of care for newly diagnosed GBM 59

60 Agenda Introductions and background Answering the scientific questions Mechanism of action General acceptance by medical community Net positive health outcomes Predictors of success Additional supporting evidence Patient perspective 60

61 How confident are you that there are no significant evidence gaps that may impact positive health outcomes in the Medicare-eligible population? 61

62 EF-14: health-related quality of life evaluation Quality of life (QoL) was a predefined secondary endpoint in the EF-14 clinical trial EORTC QLQ-C30 and QLQ-BN20 questionnaires were completed at baseline and every 3 months thereafter, up to 12 months Nine scales and items were preselected based on relevance for patients with glioblastoma and the hypothesized effects of Optune on patients QoL Global health status Role functioning Itchy skin Physical functioning Social functioning Pain Cognitive functioning Emotional functioning Weakness of legs Patients were using first generation Optune, which when compared with the second generation device is twice the size and weight QoL, quality of life; EORTC, European Organisation for Research and Treatment of Cancer; QLQ-C30, Quality of Life Core Questionnaire-C30; QLQ-BN20, Quality of Life Questionnaire for Brain Neoplasms. 1. Taphoorn MJB, et al. JAMA Oncol. 2018;4(4): Novocure announces CE mark and first patient use of second generation Optune system [news release]. St Helier, NJ: Business Wire; October 5, Novocure-Announces-CE-Mark-Patient-Generation-Optune. Accessed February 15,

63 EF-14: Deterioration-Free Survival (DFS) Median (months) Subgroup Hazard Ratio Optune + TMZ TMZ Alone Progression-Free Survival Deterioration-Free Survival (DFS) Global health status Physical functioning Cognitive functioning Role functioning Social functioning Emotional functioning Pain Itchy skin Weakness of legs Optune + TMZ Better TMZ Alone Better DFS was significantly longer with Optune + TMZ vs TMZ alone for global health status, physical and emotional functioning, pain, and weakness of legs DFS: Time to >10-point deterioration in scores from baseline without a subsequent 10-point improvement in scores compared with baseline; progressive disease; or death in the absence of a previous definitive deterioration before the next assessment. TMZ, temozolomide; DFS, deterioration-free survival. 1. Taphoorn MJB, et al. JAMA Oncol. 2018;4(4):

64 Substantial and growing body of peer-reviewed evidence supports clinical adoption of TTFields Before 2014 Clinical publications on Tumor Treating Fields by year Original clinical research Review articles Clinical case studies 132 peer reviewed publications of clinical data on TTFields over the past 11 years in Medline Database Bibliography provided to the CAC panel is incomplete Bibliography provided to CAC; available through Medline Database. 64

65 TTFields has achieved general acceptance in the medical community based on gold standard clinical data 0.63 PFS AND OS HAZARD RATIO IN THE EF-14 TRIAL (N=695), THE LARGEST SUCCESFUL PHASE 3 TRIAL IN GBM 1 NCCN CATEGORY 1 RECOMMENDATION FOR TTFIELDS IN NEWLY DIAGNOSED GLIOBLASTOMA 59 OF THE 62 NCI-DESIGNATED CANCER CENTERS OFFER TTFIELDS FOR GLIOBLASTOMA 40% OF ELIGIBLE GLIOBLASTOMA PATIENTS ARE PRESCRIBED TTFIELDS 1,109 UNIQUE PRESCRIBERS IN ALL 50 STATES, D.C. AND PUERTO RICO USED TTFIELDS IN MILLION AMERICANS COVERED FOR TTFIELDS TREATMENT BY 85 COMMERCIAL PAYERS All healthcare payer coverage data is specific to glioblastoma. 1. Stupp R, et al. JAMA. 2017;318(23): Novocure Annual Report on Form 10-K. accessed March 1,

66 Agenda Introductions and background Answering the scientific questions Mechanism of action General acceptance by medical community Net positive health outcomes Predictors of success Additional supporting evidence Patient perspective 66

67 Living with GBM and Thriving with Optune 67

68 TTFields Peer Reviewed Publications Alexiades N, McKhann GM. A Shock to the System: Tumor-Treating Fields Plus Temozolomide for Glioblastoma. Neurosurgery May 1;82(5):E115-E116. doi: /neuros/nyy044. Alphandery, E. Glioblastoma Treatments: An Account of Recent Industrial Developments. Front Pharmacol Sep 13;9:879. doi: /fphar Ansstas G, Tran D. Treatment with Tumor-Treating Fields Therapy and Pulse Dose Bevacizumab in Patients with Bevacizumab-Refractory Recurrent Glioblastoma: A Case Series. Case Rep Neurol 2016;8:1 9. Anthony P, McArdle S, McHugh M. Tumor Treating Fields: Adjuvant Treatment for High-grade Gliomas. Semin Oncol Nurs Dec;34(5): doi: /j.soncn Epub 2018 Nov 7. Bądziul D, Banaś-Ząbczyk A, Tabarkiewicz J. An overview of the preclinical and clinical studies of the effects of tumor treating fields on malignant glioma cells. Eur J Clin Exp Med. 2017; 15 (2): Bender E, Kozak K, Howard S, Hayes L, Bayouth J, Robins HI. The effect of OptuneTM Tumor Treating Fields transducer arrays on skin radiation dose during radiotherapy. J Clin Neurosci Aug;42: doi: /j.jocn Epub 2017 Apr 17. Benson L. Tumor Treating Fields Technology: Alternating Electric Field Therapy for the Treatment of Solid Tumors. Semin Oncol Nurs Apr 6. pii: S (18) doi: /j.soncn Bomzon Z, Urman N, Wenger C, et al. Modelling Tumor Treating Fields for the treatment of lung-based tumors. Conf Proc IEEE Eng Med Biol Soc. 2015;2015: Bosnyák E, Barger GR, Michelhaugh SK, Robinette NL, Amit-Yousif A, Mittal S, Juhász C. Amino Acid PET Imaging of the Early Metabolic Response During Tumor-Treating Fields (TTFields) Therapy in Recurrent Glioblastoma. Clin Nucl Med Mar;43(3): doi: /RLU Branter J, Basu S, Smith S. Tumour treating fields in a combinational therapeutic approach. Oncotarget Nov 27;9(93): doi: /oncotarget Burri SH, Gondi V, Brown PD, Mehta MP.The Evolving Role of Tumor Treating Fields in Managing Glioblastoma: Guide for Oncologists. Am J Clin Oncol Feb;41(2): doi: /COC Butowski N, Wong ET, Mehta MP, Wilson LK. A roundtable discussion on the clinical challenges and options for the treatment of glioblastoma: introducing a novel modality, TTFields. Semin Oncol. 2013; 40 (6):S2-4. Castellví Q, Ginestà MM, Capellà G, Ivorra A. Tumor growth delay by adjuvant alternating electric fields which appears non-thermally mediated. Bioelectrochemistry. 2015;105:16-24.

69 Ceccon G, Lazaridis L, Stoffels G, Rapp M, Weber M, Blau T, Lohmann P, Kebir S, Herrmann K, Fink G R, Langen KJ, Glas M, Galldiks N. Use of FET PET in glioblastoma patients undergoing neurooncological treatment including tumour-treating fields: initial experience. Eur J Nucl Med Mol Imaging Jul;45(9): doi: /s Epub 2018 Mar 21. Chamberlain MC. Treatment of Patients With Newly Diagnosed GBM. JAMA. 2016;315(21):2348. Chan AK, Birk HS, Winkler EA, et al. Stability of Programmable Shunt Valve Settings with Simultaneous Use of the Optune Transducer Array: A Case Report. Cureus Jul; 8(7): e675. doi: /cureus.675. Chang A. Tumor-Treating Fields: Nursing Implications for an Emerging Technology. Clin J Oncol Nurs Jun 1;21(3): doi: /17.CJON Chang E, Patel CB, Pohling C, Young C, Song J, Flores TA, Zeng Y, Joubert L, Arami H, Natarajan A, Sinclair R, Gambhir SS. Tumor treating fields increases membrane permeability in glioblastoma cell. Cell Death Dis. 2018; 4:113, doi: /s x. Chang E, Pohling C, Beygui N, Patel CB, Rosenberg J, Ha DH, Gambhir SS. Synergistic inhibition of glioma cell proliferation by Withaferin A and tumor treating fields. J Neurooncol Jul 5. doi: /s Chaudhry A, Benson L, Varshaver M, et al. NovoTTF-100A System (Tumor Treating Fields) Transducer Array Layout Planning for Recurrent Glioblastoma: Results of a NovoTAL System User Study. World J Surg Oncol. 2015;13(1):316. Clark P, Gaal J, Strebe J, Pasch C, Deming A, Kuo J, Robins H.The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells. J Clin Neurosci. 2017;36: Cloughesy T and Lassman A. NovoTTF: where to go from here? Neuro Oncol May 1;19(5): doi: /neuonc/nox014. Connelly J, Hormigo A, Mohilie N, Hu J, Chaudhry A, Blondin N. Planning TTFields treatment using the NovoTAL system-clinical case series beyond the use of MRI contrast enhancement. BMC Cancer. 2016;16:842. D Schiff, D Schrag. Living in a material world: tumor-treating fields at the top of the charts. Neuro Oncol Aug; 18(8): doi: /neuonc/now138. Davies AM, Weinberg U, Palti Y. Tumor treating fields: a new frontier in cancer therapy. Ann N Y Acad Sci Jul;1291: doi: /nyas Epub 2013 May 9. Davis ME. Tumor treating fields - an emerging cancer treatment modality. Clin J Oncol Nurs Aug 1;17(4): Davis ME. Glioblastoma: Overview of Disease and Treatment. Clin J Oncol Nurs Oct 1;20(5 Suppl):S2-8. doi: /16.CJON.S1.2-8.

70 Domingo-Musibay E, Galanis E. What next for newly diagnosed glioblastoma? Future Oncol. 2015;11(24): Doyle SP, Gurbani SS, Ross AS, Rosen H, Barrett CD, Olson JJ, Shim H, Shu HK, Sengupta S. The role of erlotinib and the Optune device in a patient with an epidermal growth factor receptor viii amplified glioblastoma. Oxf Med Case Reports Dec; 2018(12): omy095. doi: /omcr/omy095 Elzinga G, Wong ET. Resolution of cystic enhancement to add-on tumor treating electric fields for recurrent glioblastoma after incomplete response to bevacizumab. Case Rep Neurol Apr 5;6(1): Kim EH, Song HS, Yoo SH, Yoon M. Tumor treating fields inhibit glioblastoma cell migration, invasion and angiogenesis. Oncotarget. 2016; 7: Fonkem E, Wong ET. NovoTTF-100A: a new treatment modality for recurrent glioblastoma. Expert Rev Neurother. 2012;12(8): Gera N, Yang A, Holtzman TS, Lee SX, Wong ET, Swanson KD. Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit. PLoS One. 2015; 10(5): e Giladi M, Munster M, Schneiderman RS, Voloshin T, Porat Y, Blat R, Zielinska-Chomej K, Hååg P, Bomzon Z, Kirson ED, Weinberg U, Viktorsson K, Lewensohn R, Palti Y.Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells. Radiat Oncol Dec 29;12(1):206. doi: /s Giladi M, Porat Y,Blatt A,Wasserman Y, Kirson ED, Dekel E,Palti Y. Microbial Growth Inhibition by Alternating Electric Fields. Antimicrob Agents Chemother Oct;52(10): Giladi M, Weinberg U, Schneiderman RS, et al. Alternating electric fields (Tumor Treating Fields Therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo. Semin Oncol. 2014;41(5)(suppl 6):S35-S41. Giladi M, Schneiderman RS, Voloshin T, et al. Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells. Sci Rep. 2015; 5: Giladi N, Schneiderman RS, Porat Y, et al. Mitotic disruption and reduced clonogenicity of pancreatic cancer cells in vitro and in vivo by tumor treating fields. Pancreatology Jan- Feb;14(1): Gourd E. Tumour-treating fields complement glioblastoma treatment. Lancet Oncol Mar;19(3):e145. doi: /S (18) Green AL, Mulcahy Levy JM, Vibhakar R, Hemenway M, Madden J, Foreman N, Dorris K. Tumor treating fields in pediatric high-grade glioma. Childs Nerv Syst May 3. doi: /s