Contractor Advisory Committee for Tumor Treating Fields … · 2019. 3. 6. · • Tumor Treating Fields – common scientific name in the literature – TTFields – TTF – TTFields

Contractor Advisory Committee for Tumor Treating Fields Therapy (TTFT)

March 6, 2019

1

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

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

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

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

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, 2019. https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/default.htm

6

Medicare standards for local coverage determinations (LCD)

Medicare Program Integrity Manual, Chapter 13, section 13.5.3. Rev 863, 02-12-19. Accessed March 2, 2019.

7

• 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.”

Agenda




8

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

9

Substantial research demonstrates the effects of forces on tubulin proteins and the mitotic spindle

1. Dogterom M et al. Science. 1997; 278: 856-60. 2. Search of Medline Database using “force” and “tubulin” for all fields. March 2, 2019. 3. Heidemann SR, McIntosh JR. Nature. 1980 Jul 31;286(5772):517-9. 4. Brouhard GJ, Rice LM. Nat Rev Mol Cell Biol. 2018 July ; 19(7): 451–463.

10

Biophysics literature reports clear thresholds of force required to halt spindle formation Dogterom M et al. Science. 1997; 278: 856-60

473 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.”

2018 “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.”

Like gravity and magnetic fields, electric fields exert forces at a distance

11

Earth

ELECTRIC FIELDS exert forces on charges & polarized molecules

Charged Plates

GRAVITATIONAL FIELDS MAGNETIC FIELDS

Magnet

exert forces on masses exert forces on ferromagnetic materials like iron

uniform field

Electric fields exert forces on charged tubulin proteins, disrupting mitosis

1. Fishkind DJ et al. J Cell Sci. 1996; 109: 2041-1. 2. Gagliardi LJ. Phys Rev E Stat Nonlin Phys. 2002; 66:011901. 3. Pohl AH. Dielectrophoresis. Cambridge, UK: Cambridge University Press; 1978. 4. Kirson ED, et al. Cancer Res. 2004;64(9):3288-3295. 5. Giladi M., et al. Sci Rep. 2015 Dec 11;5:18046. 12

Polar (charged) tubulin dimer proteins orient in direction of electric fields

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

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. 2015 Dec 11;5:18046. 2. Kim EH, et al. Oncotarget. 2016; 7:38 2. Additional data on file with Novocure. 13

CONTROL TUMOR TREATING FIELDS

Tumor Treating Fields Therapy delivery system

14

2.7 lbs, portable Tumor Treating Fields generator Sterile, single-use transducer array replaced every 3-4 days

TRANSDUCER ARRAY ELECTRIC FIELD GENERATOR

Independent research confirms TTFields system delivers effective electric field dose to cranium

Electric field intensity (V/cm) models confirm dose deposition in target regions

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):4137-47. 2. Wenger C, et al. Phys Med Biol. 2015;60(18):7339-57. 3. Wenger C, et al. Int J Radiat Oncol Biol Phys. 2016 Apr 1;94(5):1137-43. 4. Timmons JJ et al. Phys Med Biol. 2017;62(21):8264-82. 5. Korshoej AR, et al. PLoS One. 2018;13(8):e0201957. 6. Korshoej AR, et al. PLoS One. 2017;12(6):e0179214.

15

Field intensity (V/cm) Field intensity (V/cm)

Anterior and posterior arrays active Left and right arrays active

Significant and growing body of external research elucidating the mechanism of action for TTFields

1. Kim EH, et al. Oncotarget. 2016;7(38):62267-62279. 2. Kim EH, et al. Oncotarget. 2016;7(40):65125-65136. 3. Joy Y, et al. Cell Death Discov. 2018 Oct 3;4:46. 4. Chang E, et al J Neurooncol. 2017;134(2):259-68. 5. Chang E, et al. Cell Death Discov. 2018 Dec 5;4:113. 6. Korshoej AR, et al PLoS One. 2018;13(8):e0201957. 7. Korshoej AR, et al PLoS One. 2017;12(6):e0179214. 8. Kessler AF, et al. Cell Death Discov. 2018 Jul 16;4:12. 16

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

30+ academic centers performing bench and animal research on TTFields

External authors produce the majority of the peer-reviewed research on Tumor Treating Fields

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

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

05

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Before2015

2015 2016 2017 2018 2019

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Company research External authors only

Agenda




18

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

19

TTFields development timeline

20

2003

First-in-man study

2004 2006 2011 2018

TTFields Category 1 in NCCN Guidelines® for newly diagnosed GBM

2000

Company founded

2017

EF-07 pilot trial in GBM begins

2009 2015

EF-11 pivotal trial in recurrent GBM begins

EF-14 pivotal trial in newly diagnosed GBM begins

Optune FDA approval in recurrent GBM

Optune FDA approval in newly diagnosed GBM

EF-14 pivotal trial in newly diagnosed GBM positive final long-term analysis results published

In 2018, 40% of eligible patients received a prescription for TTFields

669

1,607

2,344

3,102

3,741

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

2014 2015 2016 2017 2018

New prescriptions written for Tumor Treating Fields in the U.S. by year

1. Novocure. 2018 Annual Report on Form 10-K. www.sec.gov; accessed March 1, 2019. 2. Novocure. 2015 Annual Report on Form 10-K. www.sec.gov; accessed March 1, 2019. 3. Ostrom QT et al. Neuro-Oncol, 2018 Oct 1;20(suppl_4):iv1-iv86. 4. Eligible population estimated based on EF-14 enrollment screening data, reported in Stupp R, et al. JAMA. 2017;318(23):2306-2316. 21

Glioblastoma statistics 13,800 patients diagnosed annually 9,300 patients eligible for TTFields 40% of eligible patients received a prescription in 2018

http://www.sec.gov/http://www.sec.gov/

Prescriber base has increased steadily since 2015 FDA approval for newly diagnosed GBM

172

345

641

887

1,109

0

200

400

600

800

1,000

1,200

2014 2015 2016 2017 2018

Unique prescribers in the U.S. by year

Novocure data requested by CAC panel. Segments based on volume of prescriptions written. 22

2018 Rx Volume by Segment 50% neuro-oncologists 31% radiation oncologists 15% medical oncologists 4% neurosurgeons

TTFields has achieved general acceptance in the medical community throughout the United States

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

Regional acceptance

39 to 42% of eligible patients receiving a prescription for Optune in East, Central, and West regions

Prescriptions from

50 states + Washington D.C. and Puerto Rico

TTFields has achieved general acceptance in the medical community throughout the United States

Novocure data requested by CAC panel. Novocure 2018 data.

24

Prescription distribution

48% of prescriptions from community practices; 52% from academic practices

Certified prescribers at

59 of the 62 NCI-designated cancer centers

Novocure supplies Optune directly to patients

1. Medicare Claims Processing Manual, Chapter 17 – Drugs and Biologicals, Section 20.1.2; (Rev. 4204, 01-17-19). Accessed March 2, 2019; described the payment methodology of ASP plus 6%, currently subject to a 2% sequestration reduction; and 42 C.F.R. § 405 2. 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, www.medpac.gov, accessed March 3, 2019. 3. Polite BN et al, Journal of Oncology Practice 2014 10:6, 357-362 4. Novocure data on file from propriretary market survey of oncology practice reimbursement rates with managed care payers for infusion drugss. 25

Infused oncology drugs

4 to 40% of the product revenue is received by the physician practice

Optune

0% of the product revenue is received by the physician practice

http://www.medpac.gov/

TTFields for newly diagnosed GBM is covered by essentially every commercial payer, including every national payer

BCBSA: Blue Cross Blue Shield Association. All statements related to healthcare payer coverage are specific to glioblastoma. 1. Novocure. 2018 Annual Report on Form 10-K. www.sec.gov; accessed March 1, 2019. 26

85 HEALTHCARE PAYERS IN THE UNITED STATES HAVE ISSUED POSITIVE COVERAGE POLICIES

243 MILLION AMERICANS COVERED UNDER PRIVATE HEALTH PLANS

5+ ALL FIVE OF THE LARGEST COMMERCIAL PAYERS AND THE BCBSA COVER TTFIELDS

2 THE PARENT CORPORATIONS OF CGS AND NORIDIAN, THE MEDICARE MACS ORGANIZING THIS PANEL, BOTH COVER TTFIELDS

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

Agenda




27

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

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, www.hhs.gov, accessed March 2, 2019. 2. Reardon DA. J Clin Oncol. 2006 Mar 10;24(8):1253-65.

29

http://www.hhs.gov/

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

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-v75. 2. Curran WJ, et al. J Natl Cancer Inst.1993;85(9):704-710. 3. Lamborn KR, et al. Neuro Oncol. 2004;6(3):227-235. 4. Hegi ME, et al. N Engl J Med. 2005;352(10):997-1003. 5. Verhaak RGW, et al. Cancer Cell. 2010;17(1):98-110. 6. Wilson TA, et al. Surg Neurol Int. 2014;5:64. 31

FDA-approved therapies for glioblastoma

GBM, glioblastoma multiforme; TMZ, temozolomide.1. BiCNU [package insert]: Bristol-Myers Squibb Co, 2011. 2. US NLM. Drug record: carmustine. US NLM website. http://livertox.nih.gov/Carmustine.htm. Accessed January 31, 2018. 3. Gliadel Wafer [package insert]: Eisai Inc; 2013. 4. FDA. Drug approval package. Gliadel wafer. Published July 8, 2003. www.accessdata.fda.gov/drugsatfda_docs/nda/2003/20-637s016_Gliadel.cfm. Accessed January 31, 2018. 5. Temodar [package insert]: Merck & Co, Inc; 2015. 6. NCI/NIH. FDA approval for temozolomide. NCI website. http://www.cancer.gov/about-cancer/treatment/drugs/fda-temozolomide. Accessed January 31, 2018. 7. Avastin [package insert]: Genentech, Inc; 2015. 8. NCI/NIH. FDA approval for bevacizumab. NCI website. https://www.cancer.gov/about-cancer/treatment/drugs/fda-bevacizumab#Anchor-Glioblastoma. Accessed January 31, 2018. 9. Optune Instructions for Use. Novocure 2016.

32

1977 1996

Carmustine Injection Palliative Therapy

Carmustine Polymer Wafers Recurrent GBM

2003

Carmustine Polymer Wafers Newly Diagnosed GBM

2005

TMZ Newly Diagnosed and Maintenance

2009

Bevacizumab Recurrent GBM

2011

Optune Recurrent GBM

2015

Optune + TMZ Newly Diagnosed GBM

2018

FDA approved expanded label for Optune to include final long term analysis Newly Diagnosed GBM

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), 1034–1043.

33

The results of the EF-14 Randomized Control Trial (n=695) have been reported in multiple JAMA publications

1. Stupp R, et al. JAMA. 2015;314(23):2535-2543. 2. Stupp R, et al. JAMA. 2017;318(23):2306-2316. 3. Taphoorn MJB, et al. JAMA Oncol. 2018;4(4):495-504.

34

December 15, 2015

December 17, 2017

February 1, 2018

EF-14: phase 3 pivotal trial design

*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):2306-2316. 2. Stupp R, et al. JAMA. 2017;318(23 suppl 1):S1-S213. 35

Stratification by: 1. Resection (biopsy vs partial vs gross total) 2. MGMT promoter methylation status

Primary endpoint: PFS Powered secondary endpoint: OS Additional secondary endpoints: PFS6, 1-y/2-y survival, ORR, safety, QoL

Newly diagnosed

GBM n=695

Biopsy/ debulking

Radiation +

TMZ

2L chemotherapy, surgery, SRS, or

combination

TMZ × 6 cycles

1st progression

Optune ≥18 h/day + TMZ

× 6 cycles

Optune + 2L chemotherapy, surgery, SRS, or

combination*

2nd progression or

24 months

Enrollment window

(4-7 weeks after

RT + TMZ)

R A N D O M I Z E D

2:1

EF-14 Protocol: “Central MRI review will be performed by a neuro-radiologist blinded to the treatment group of each patient.”

Characteristics Median age, years (range) 56 (19-83) 57 (19-80) Female sex, % 32 31 Median KPS (range) 90 (60-100) 90 (70-100) Extent of resection, %

Gross total resection 53 54 Partial resection 34 33 Biopsy 13 13

Median time from diagnosis to randomization, mo (range) 3.8 (1.7-6.2) 3.7 (1.4-6.3)

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)

EF-14: key baseline characteristics

ITT, intent-to-treat; TMZ, temozolomide; KPS, Karnofsky Performance Score; SD, standard deviation. 1. Stupp R, et al. JAMA. 2017;318(23):2306-2316.

36

Baseline characteristics were well balanced between the two treatment arms

ITT Population TMZ Alone (n=229)

Optune + TMZ (n=466)

Molecular Profiles, % MGMT status

Tissue available and tested 83 81 Methylated 36 42 Unmethylated 54 51 Insufficient for testing 10 7

IDH1 R132H mutation status Tissue available and tested 56 52 Positive 7 5

Medications, % Antiepileptics 44 41 Corticosteroids 29 28 Average daily usage of TTFields*, % 75

EF-14: key baseline characteristics (cont’d)

*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):2306-2316. 37

ITT Population

Baseline characteristics were well balanced between the two treatment arms

TMZ Alone (n=229)


EF-14: Progression-Free Survival (ITT)

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):2306-2316. 2. 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

At the time of the final survival analysis, PFS was reported out to 30 months.

ITT Population

Median PFS from randomization, mo 6.7 4.0

95% CI, mo 6.1-8.1 3.8-4.4

Stratified log-rank P

EF-14: Overall Survival (ITT)

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):2306-2316. 2. 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

ITT Population

Median OS from randomization, mo 20.9 16.0

95% CI, mo 19.3-22.7 14.0-18.4

Stratified log-rank P

EF-14 safety summary: incidence of grade 3/4 adverse events in ≥5% of patients

*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):2306-2316. 2. Optune Instructions for Use. 40

Grade 3-4 Events, No. (%) of Patients

≥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)

TMZ Alone (n=216)


Safety Population

EF-14 overall survival: magnitude of benefit was comparable to Stupp/EORTC trial in 2005 for temozolomide

TMZ, temozolomide; RT, radiation therapy; CI, confidence interval. 1. Stupp R, et al. N Engl J Med 2005;352:987-96. 2. Stupp R, et al. Lancet Oncol 2009; 10:459-66. 3. Stupp R, et al. JAMA. 2017;318(23):2306-2316 41

Hazard ratio 0.63 0.63 (95% CI) (0.52 – 0.75) (0.53 – 0.76) 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%

RT alone vs. TMZ+RT TMZ alone vs. Optune+TMZ

The EF-14 control arm survival was consistent with prior trials, specifically the RTOG-0525 trial randomized post RT

TMZ, temozolomide. 1. Stupp R, et al. JAMA. 2017;318(23):2306-2316. 2. 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. 2013 Nov 10;31(32):4085-91. 42

From randomization Median 16.0 16.6

95% CI 14.0-18.4

Two year survival Median 30.7% 34.2%

95% CI 25-38

From registration Median 19.8 18.9

95% CI 17.6-22.1

Overall Survival (months) Control arm of

RTOG0525 (n=411)

Control arm of EF-14

(n=266)

National Comprehensive Cancer Network® (NCCN®) Category 1* Adjuvant Treatment Recommendations for Newly Diagnosed GBM

43

Postoperative Newly diagnosed GBMAge ≤70 years, KPS ≥60

MGMTpromoter unmethylatedor indeterminate

Standard brain RT + concurrent TMZ and adjuvant TMZ + alternating electric field therapy (Optune)†,‡,§ORStandard brain RT + concurrent TMZ and adjuvant TMZ†,‡

MGMTpromoter methylated

Standard brain RT + concurrent TMZ‖ and adjuvant TMZ‖ + alternating electric field therapy (Optune)†,‡,§ORStandard 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.1.2018. ©2018 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.

National Comprehensive Cancer Network® (NCCN®) Category 1* Adjuvant Treatment Recommendations for Newly Diagnosed GBM (cont’d)

*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.1.2018. ©2018 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

Postoperative Newly diagnosed GBMAge >70 years, KPS ≥60

MGMTpromoter unmethylatedor indeterminate

MGMTpromoter methylated

Hypofractionated brain RT + concurrent and adjuvant TMZ†,‡ORStandard RT + concurrent TMZ and adjuvant TMZ + alternating electric field therapy (Optune)†,‡,§

Standard RT + concurrent TMZ‖ and adjuvant TMZ‖ + alternating electric field therapy (Optune)†,‡,§

Agenda




45

46

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

EF-14 trial subgroup analysis for overall survival

TMZ, temozolomide; MGMT, O-6-methylguanine-DNA methyltransferase; KPS, Karnofsky Performance Score. 1. Stupp R, et al. JAMA. 2017;318(23):2306-2316.

47

Subgroup No. of Patients (%) Hazard Ratio

Median Survival (months) Optune +

TMZ TMZ

Alone Overall 695 (100) 20.9 16.0 MGMT (central) Unmethylated 304 (44) 16.9 14.7 Methylated 214 (31) 31.6 21.2 Resection Biopsy 89 (13) 16.5 11.6 Partial 234 (34) 21.4 15.1 Gross total 372 (54) 22.6 18.5 Age

Understanding dose and measuring dose-response in EF-14

48

In vitro evidence of mechanism of action: field frequency must be titrated to tumor cell size

• Multiple cancer cell lines were exposed to TTFields at various frequencies (50–500 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):10151-10157. 49

500 400 300 200 100 0 0

20

40

60

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100

120

Frequency (kHz)

Rel

ativ

e C

ell N

umbe

r (%

of C

ontr

ol)

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)

In vitro evidence of mechanism of action: time-dependent effects of TTFields (more is better)

0.05 >*P >0.01, 0.01 >†P >0.001, ‡P

In vitro evidence of mechanism of action: increased force (field intensity, V/cm) = increased kill rate

• 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

TTFields, Tumor Treating Fields; NSCLC, non–small cell lung carcinoma. Adapted from: Kirson ED, et al. PNAS. 2007;104(24):10151-10157.

51

2 1 0 0

20

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3 TTFields Intensity (V/cm)

Rel

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Optimal frequency (kHz) 100: Mouse melanoma (B16F1) 150: Human breast carcinoma (MDA-MB-231) 200: Rat glioma (F-98) 200: Human NSCLC (H1299)

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): 1137-1143

52

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. Ballo1, Noa Urman2, Gitit Lavy-Shahaf2, Ze’ev Bomzon2 and Steven Toms3

1West Cancer Center Center, Memphis Tennessee; 2Novocure Ltd, Haifa, Israel; 3Warren Alpert Medical School of Brown University

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.

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/cm3)

Higher TTFields intensity (≥1.0 Volts/cm) and power density (≥1.1 mW/cm3) are associated with improved overall survival and independent of compliance

LMiFI (V/cm)

0.1

1.0

Prob

abili

ty o

f sur

viva

l 0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

6 0 12 18 24 30 36 42 48 Overall survival (months)

1:

Summary:

• 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.

Dose Density = Power Density X Compliance

1.0

6 0 12 18 24 30 36 42 48 Overall survival (months)

Prob

abili

ty o

f sur

viva

l

1: LMiPD

Increased dose correlated with increased survival

58

16

21

23

25

37

TMZ alone

lower energy*

higher energy* and2 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 1110 - 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. 2017 Dec 19;318(23):2306-2316.

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

Agenda




60

61

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

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 – Physical functioning – Cognitive functioning

• 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):495-504. 2. Novocure announces CE mark and first patient use of second generation Optune system [news release]. St Helier, NJ: Business Wire; October 5, 2015. https://www.businesswire.com/news/home/20151005005560/en/ Novocure-Announces-CE-Mark-Patient-Generation-Optune. Accessed February 15, 2018. 62

– Role functioning – Social functioning – Emotional functioning

– Itchy skin – Pain – Weakness of legs

EF-14: Deterioration-Free Survival (DFS)

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):495-504. 63

Subgroup Hazard Ratio

Median (months) Optune +

TMZ TMZ

Alone Progression-Free Survival 6.7 4.0 Deterioration-Free Survival (DFS)

Global health status 4.8 3.3 Physical functioning 5.1 3.7 Cognitive functioning 4.4 3.6 Role functioning 4.3 3.8 Social functioning 4.5 3.9 Emotional functioning 5.3 3.9 Pain 5.6 3.6 Itchy skin 3.9 4.0 Weakness of legs 5.6 3.9

Optune + TMZ Better TMZ Alone Better

1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0

DFS was significantly longer with Optune + TMZ vs TMZ alone for global health status, physical and emotional functioning, pain, and weakness of legs

Substantial and growing body of peer-reviewed evidence supports clinical adoption of TTFields

• 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

12 10

17

26 28

39

05

1015202530354045

Before2014

2014 2015 2016 2017 2018

Clinical publications on Tumor Treating Fields by year

Original clinical research Review articles Clinical case studies

TTFields has achieved “general acceptance” in the medical community based on gold standard clinical data

All healthcare payer coverage data is specific to glioblastoma. 1. Stupp R, et al. JAMA. 2017;318(23):2306-2316. 2. Novocure. 2018 Annual Report on Form 10-K. www.sec.gov; accessed March 1, 2019. 65

243 MILLION AMERICANS COVERED FOR TTFIELDS TREATMENT BY 85 COMMERCIAL PAYERS

1,109 UNIQUE PRESCRIBERS IN ALL 50 STATES, D.C. AND PUERTO RICO USED TTFIELDS IN 2018

59 OF THE 62 NCI-DESIGNATED CANCER CENTERS OFFER TTFIELDS FOR GLIOBLASTOMA

1 NCCN CATEGORY 1 RECOMMENDATION FOR TTFIELDS IN NEWLY DIAGNOSED GLIOBLASTOMA

0.63 PFS AND OS HAZARD RATIO IN THE EF-14 TRIAL (N=695), THE LARGEST SUCCESFUL PHASE 3 TRIAL IN GBM

40% OF ELIGIBLE GLIOBLASTOMA PATIENTS ARE PRESCRIBED TTFIELDS

Agenda




66

Living with GBM and Thriving with Optune

67

TTFields Peer Reviewed Publications

Alexiades N, McKhann GM. A Shock to the System: Tumor-Treating Fields Plus Temozolomide for Glioblastoma. Neurosurgery. 2018 May 1;82(5):E115-E116. doi: 10.1093/neuros/nyy044. Alphandery, E. Glioblastoma Treatments: An Account of Recent Industrial Developments. Front Pharmacol. 2018 Sep 13;9:879. doi: 10.3389/fphar.2018.00879. 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. 2018 Dec;34(5):454-464. doi: 10.1016/j.soncn.2018.10.007. 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): 141–144. 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. 2017 Aug;42:172-175. doi: 10.1016/j.jocn.2017.04.002. Epub 2017 Apr 17. Benson L. Tumor Treating Fields Technology: Alternating Electric Field Therapy for the Treatment of Solid Tumors. Semin Oncol Nurs. 2018 Apr 6. pii: S0749-2081(18)30018-4. doi: 10.1016/j.soncn.2018.03.005 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;2015:6888-6891. 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. 2018 Mar;43(3):176-179. doi: 10.1097/RLU.0000000000001942. Branter J, Basu S, Smith S. Tumour treating fields in a combinational therapeutic approach. Oncotarget. 2018 Nov 27;9(93):36631-36644. doi: 10.18632/oncotarget.26344. 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. 2018 Feb;41(2):191-196. doi: 10.1097/COC.0000000000000395. 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.

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. 2018 Jul;45(9):1626-1635. doi: 10.1007/s00259-018-3992-5. 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. 2016 Jul; 8(7): e675. doi: 10.7759/cureus.675. Chang A. Tumor-Treating Fields: Nursing Implications for an Emerging Technology. Clin J Oncol Nurs. 2017 Jun 1;21(3):302-304. doi: 10.1188/17.CJON.302-304. 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:10.1038/s41420-018-0130-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. 2017 Jul 5. doi: 10.1007/s11060-017-2534-5. 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;36:120-124. Cloughesy T and Lassman A. NovoTTF: where to go from here? Neuro Oncol. 2017 May 1;19(5):605-608. doi: 10.1093/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. 2016 Aug; 18(8): 1033–1034. doi: 10.1093/neuonc/now138. Davies AM, Weinberg U, Palti Y. Tumor treating fields: a new frontier in cancer therapy. Ann N Y Acad Sci. 2013 Jul;1291:86-95. doi: 10.1111/nyas.12112. Epub 2013 May 9. Davis ME. Tumor treating fields - an emerging cancer treatment modality. Clin J Oncol Nurs. 2013 Aug 1;17(4):441-3. Davis ME. Glioblastoma: Overview of Disease and Treatment. Clin J Oncol Nurs. 2016 Oct 1;20(5 Suppl):S2-8. doi: 10.1188/16.CJON.S1.2-8.

Domingo-Musibay E, Galanis E. What next for newly diagnosed glioblastoma? Future Oncol. 2015;11(24):3273-83. 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. 2018 Dec; 2018(12): omy095. doi: 10.1093/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. 2014 Apr 5;6(1):109-15. Kim EH, Song HS, Yoo SH, Yoon M. Tumor treating fields inhibit glioblastoma cell migration, invasion and angiogenesis. Oncotarget. 2016; 7:65125-65136 Fonkem E, Wong ET. NovoTTF-100A: a new treatment modality for recurrent glioblastoma. Expert Rev Neurother. 2012;12(8):895-899. 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): e0125269. 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. 2017 Dec 29;12(1):206. doi: 10.1186/s13014-017-0941-6. Giladi M, Porat Y,Blatt A,Wasserman Y, Kirson ED, Dekel E ,Palti Y. Microbial Growth Inhibition by Alternating Electric Fields. Antimicrob Agents Chemother. 2008 Oct;52(10):3517-22. 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: 18046. 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. 2014 Jan-Feb;14(1):54-63. Gourd E. Tumour-treating fields complement glioblastoma treatment. Lancet Oncol. 2018 Mar;19(3):e145. doi: 10.1016/S1470-2045(18)30088-3. 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. 2017 May 3. doi: 10.1007/s00381-017-3431-0.

Gutin PH, Wong ET. Noninvasive application of alternating electric fields in glioblastoma: a fourth cancer treatment modality. Am Soc Clin Oncol Educ Book. 2012 : 126–131. doi: 10.14694/EdBook_AM.2012.32.126. Guzauskas G, Salzberg M, Wang B. Estimated lifetime survival benefit of tumor treating fields and temozolomide for newly diagnosed glioblastoma patients. CNS Oncol. 2018 Jul 1;7(3):CNS23. doi: 10.2217/cns-2018-0010. Epub 2018 Aug 20. Lia M. Halasz, MD; Timur Mitin, MD, PhD. Tumor-Treating Fields: Answering the Concern About Quality of Life. JAMA Oncol. 2018 Apr 1;4(4):504-505. doi: 10.1001/jamaoncol.2017.5062. Heymach J, Krilov L, Alberg A, Baxter N, Chang SM, Corcoran R, Dale W, DeMichele A, Magid Diefenbach CS, Epstein AS, Gillison ML, Graham DL, Jones J, Ko AH, Lopez AM, Maki RG, Rodriguez-Galindo C, Schilsky RL, Sznol M, Westin SN, Burstein H. Clinical Cancer Advances 2018: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol. 2018 Apr 1;36(10):1020-1044. doi: 10.1200/JCO.2017.77.0446. Hottinger AF, Pacheco P, Stupp R. Tumor treating fields: a novel treatment modality and its use in brain tumors. Neuro Oncol. 2016 Oct;18(10):1338-49. Inui T, Amitani H, Kubo K, et al. Case Report: A Non-small Cell Lung Cancer Patient Treated with GcMAF, Sonodynamic Therapy and Tumor Treating Fields. Anticancer Res. 2016 Jul; 36(7): 813-4. Jalali R. Commentary on 19th annual scientific meeting of the Society for Neuro-Oncology. Indian J Med Paediatr Oncol. 2015;36(1):63-65. Jimenez H, Blackman C, Lesser G, Debinski W, Chan M, Sharma S, Watabe K, Lo HW, Thomas A, Godwin D, Blackstock W, Mudry A, Posey J, O'Connor R, Brezovich I, Bonin K, Kim-Shapiro D, Barbault A, Pasche B. Use of non-ionizing electromagnetic fields for the treatment of cancer. Front Biosci (Landmark Ed). 2018 Jan 1;23:284-297. Jo Y, Hwang S, Jin YB, Sung J, Jeong YK, Baek JH, Cho J, Kim EH, Yoon M. Selective toxicity of tumor treating fields to melanoma: an in vitro and in vivo study. Cell Death Dis. 2018; 5(46). Jo Y, Kim EH, Sai S, Kim JS, Cho J, Kim H, Baek J, Kim J, Hwang S, Yoon M. Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy. Int J Mol Sci. 2018, 19(11), 3684; doi:10.3390/ijms19113684. Kamiya-Matsuoka C, Gilbert M. Treating recurrent glioblastoma: An Update. CNS Oncol. 2015;4(2):91-104. Kanner AA, Wong ET, Villano JL, Ram Z; on behalf of EF-11 Investigators. Post hoc analysis of intention-to-treat population in phase 3 comparison of NovoTTF-100A™ System versus best physician’s choice chemotherapy. Semin Oncol. 2014;41(5)(suppl 6):S25-S34. Karanam NK, Srinivasan K, Ding L, Sishc B, Saha D, Story MD.Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. Cell Death Dis. 2017 Mar 30;8(3):e2711. doi: 10.1038/cddis.2017.136

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Contractor Advisory Committee for�Tumor Treating Fields Therapy (TTFT)AgendaParticipantsDefinitions and abbreviationsRequested coverage for Tumor Treating FieldsFDA premarket approval (PMA) backgroundMedicare standards for local coverage determinations (LCD) AgendaHow confident are you that scientific evidence supports mitotic spindle disruption and cellular apoptosis as the mechanism of action of TTFT?Substantial research demonstrates the effects of forces on tubulin proteins and the mitotic spindleLike gravity and magnetic fields, electric fields exert forces at a distanceElectric fields exert forces on charged tubulin proteins, disrupting mitosisMitotic spindle disruption by electric fields has been observed in every cancer cell line testedTumor Treating Fields Therapy delivery systemIndependent research confirms TTFields system delivers effective electric field dose to craniumSignificant and growing body of external research elucidating the mechanism of action for TTFieldsExternal authors produce the majority of the peer-reviewed research on Tumor Treating FieldsAgendaHow confident are you that TTFT is generally accepted by the medical community for newly diagnosed GBM?TTFields development timelineIn 2018, 40% of eligible patients received a prescription �for TTFieldsPrescriber base has increased steadily since 2015 FDA approval for newly diagnosed GBMTTFields has achieved general acceptance in the medical community throughout the United StatesTTFields has achieved general acceptance in the medical community throughout the United StatesNovocure supplies Optune directly to patientsTTFields for newly diagnosed GBM is covered by essentially every commercial payer, including every national payerAgendaHow 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?Medicare-eligible population definitionReview of clinical data for TTFT in �newly diagnosed GBMGlioblastomaFDA-approved therapies for glioblastomaThe success of the EF-14 trial for TTFields provided a much needed advance in clinical outcomes in glioblastomaThe results of the EF-14 Randomized Control Trial (n=695) have been reported in multiple JAMA publicationsEF-14: phase 3 pivotal trial designEF-14: key baseline characteristicsEF-14: key baseline characteristics (cont’d)EF-14: Progression-Free Survival (ITT)EF-14: Overall Survival (ITT)EF-14 safety summary: incidence of grade 3/4 adverse events in 5% of patientsEF-14 overall survival: magnitude of benefit was comparable to Stupp/EORTC trial in 2005 for temozolomideThe EF-14 control arm survival was consistent with prior trials, specifically the RTOG-0525 trial randomized post RTNational Comprehensive Cancer Network® (NCCN®) Category 1* Adjuvant Treatment Recommendations for Newly Diagnosed GBMNational Comprehensive Cancer Network® (NCCN®) Category 1* Adjuvant Treatment Recommendations for Newly Diagnosed GBM (cont’d)AgendaSlide Number 46EF-14 trial subgroup analysis for overall survivalUnderstanding dose and measuring �dose-response in EF-14In vitro evidence of mechanism of action:�field frequency must be titrated to tumor cell sizeIn vitro evidence of mechanism of action:�time-dependent effects of TTFields (more is better)In vitro evidence of mechanism of action:�increased force (field intensity, V/cm) = increased kill ratePersonalizing the array layout: changing the layout changes field distribution and resulting dose delivered to tumor��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��BackgroundMethods:�Step 1: Contouring of tumor on MRI�Step 2: Head model creation & Transducer �placement�Slide Number 56Summary:��Increased dose correlated with increased survivalTTFields in practice at the West Cancer CenterAgendaSlide Number 61EF-14: health-related quality of life evaluationEF-14: Deterioration-Free Survival (DFS)Substantial and growing body of peer-reviewed evidence supports clinical adoption of TTFieldsTTFields has achieved “general acceptance” in the medical community based on gold standard clinical dataAgendaLiving with GBM and �Thriving with Optune

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Contractor Advisory Committee for Tumor Treating Fields … · 2019. 3. 6. · • Tumor Treating Fields – common scientific name in the literature – TTFields – TTF – TTFields