Novocure (NVCR) R&D Day · Prof. Zvi Ram serves as the Chairman of the Department of Neurosurgery at Tel Aviv Medical Center in Israel. After completion of his neurosurgical residency

Novocure (NVCR) R&D Day

December 12, 2016

The St. Regis New York

© Novocure 2016 2

This presentation contains certain forward-looking statements with respect to the business of Novocure and certain of its plans and objectives, including with

respect to the development and commercialization of its lead product candidate, Optune, for a number of oncology indications. These forward-looking statements

can be identified in this presentation by the fact that they do not relate only to historical or current facts. Forward-looking statements often use words “expect”,

“intend”, “anticipate”, “plan”, “may”, “should”, “would”, “could” or other words of similar meaning. These statements are based on assumptions and assessments made

by Novocure in light of industry experience and perception of historical trends, current conditions, expected future developments and other appropriate factors. By

their nature, forward-looking statements involve risk and uncertainty, and Novocure's performance and financial results could differ materially from those expressed

or implied in these forward-looking statements due to general financial, economic, regulatory and political conditions as well as more specific risks and

uncertainties facing Novocure such as those set forth in its Annual Report on Form 10-K filed on March 1, 2016, or in subsequent quarterly filings with the U.S.

Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual

results may vary materially from those described in this presentation. Novocure assumes no obligation to update or correct the information contained in this

presentation, whether as a result of new information, future events or otherwise, except to the extent legally required.

The statements contained in this presentation are made as at the date of this presentation, unless some other time is specified in relation to them, and service of

this presentation shall not give rise to any implication that there has been no change in the facts set out in this presentation since such date. Nothing contained in

this presentation shall be deemed to be a forecast, projection or estimate of the future financial performance of Novocure, except where expressly stated.

As of the date of this presentation, Optune is only FDA-approved for glioblastoma, or GBM, and its approval for other indications is not certain. Novocure can

provide no assurances regarding market acceptance of Optune or its successful commercialization, and can provide no assurances regarding the company’s results

of operations or financial condition in the future. This presentation is for informational purposes only and may not be relied upon in connection with the purchase

or sale of any security.

forward-looking statements

opening remarks William Doyle

Executive Chairman

© Novocure 2016 4

agenda 12:00 – 1:00 p.m. ROUNDTABLE LUNCH WITH MANAGEMENT AND GUESTS

1:00 – 1:05 p.m. Opening remarks William Doyle Novocure

1:05 – 1:25 p.m. Intro to TTFields and preclinical overview Eilon Kirson, MD, PhD Novocure

1:25 – 1:50 p.m. Glioblastoma Zvi Ram, MD Tel Aviv Sourasky Medical Center

1:50 – 2:05 p.m. Brain metastases Vinai Gondi, MD Northwestern Medicine Proton Center

2:05 – 2:15 p.m. Non-small cell lung cancer Eilon Kirson, MD, PhD Novocure

2:15 – 2:30 p.m. BREAK

2:30 – 2:55 p.m. Pancreatic cancer Daniel D. Von Hoff, MD Translational Genomics Research Institute

2:55 – 3:10 p.m. Ovarian cancer Eilon Kirson, MD, PhD Novocure

3:10 – 3:25 p.m. Mesothelioma Uri Weinberg, MD, PhD Novocure

3:25 – 3:40 p.m. What’s next for Tumor Treating Fields Eilon Kirson, MD, PhD Novocure

3:40 – 3:55 p.m. Novocure Engineering Mike Ambrogi Novocure

3:55 p.m. Closing comments William Doyle Novocure

© Novocure 2016 5

Novocure speakers

Eilon Kirson, MD, PhD Chief Science Officer and Head of Research & Development

William Doyle Executive Chairman

Mike Ambrogi Chief Operating Officer

Uri Weinberg, MD, PhD Vice President of Research & Development

© Novocure 2016 6

expert participants Zvi Ram, MD

Prof. Zvi Ram serves as the Chairman of the Department of Neurosurgery at Tel Aviv Medical Center in Israel. After completion of his neurosurgical residency at Sheba Medical Center in Israel in 1991, Prof. Ram had joined the Surgical Neurology Branch at the National Institutes of Health in Bethesda, MD, where he led a variety of basic and clinical research projects, including paving the way and leading the first gene therapy trial for patients with brain tumors, as well as other innovative approaches for brain tumor therapy. Upon his return to Israel in 1994, Prof. Ram has launched an active clinical and academic career with emphasis on brain tumor therapy, pituitary surgery, and technology development projects with various companies, including the development and implementation of intraoperative MRI technology, High-Intensity Focused MRI-guided ultrasound for tumor ablation, spectroscopic brain mapping, novel drug distribution systems, and the use and modeling of convection-enhanced drug delivery systems and other innovative therapeutic approach for brain tumor. Prof. Ram has chaired the Tumor Section of the European Association of Neurosurgical Societies (EANS), is a member of the Executive Steering Committees and lead PI for several pharmaceuticals companies conducting multicenter international phase III clinical studies, Scientific advisor for biothechnology groups, and a member of editorial boards and reviewer for leading scientific journals in his areas of expertise. Prof. Ram's main clinical interests include surgery for complex brain tumors, including performance of Awake Craniotomies with intra-operative cortical mapping and white matter tracking when tumors are within or near functional brain regions, resection of pituitary tumors and complex benign tumors of the brain.

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expert participants Vinai Gondi, MD

Dr. Vinai Gondi is Director of Research at the Northwestern Medicine Chicago Proton Center and Director of CNS Radiation Oncology at the Northwestern Medicine Cancer Center Warrenville in Chicago, IL. He is an internationally recognized expert on the management of metastatic and primary brain tumors. His research focuses on technological advances such as proton therapy, intensity-modulated radiotherapy, and tumor-treating fields, to improve therapeutic efficacy and optimize overall quality of life of brain tumor patients. He serves as Principal Investigator on several cooperative NCI-sponsored clinical trials, including RTOG 0933, NRG CC001, NRG CC003, and NRG BN001, and serves as a member of the NRG Oncology Brain Tumor Core Committee. He has published over 35 peer-reviewed publications in such top-tiered journals as Journal of Clinical Oncology, Nature Reviews Neurology, JAMA Oncology, and International Journal of Radiation Oncology, Biology and Physics. He has presented his research at multiple international meetings, including three plenary presentations, and his research has been supported by funding from the NCI. He was instrumental in developing the METIS pivotal phase III trial for lung cancer patients with brain metastases.

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expert participants Daniel D. Von Hoff, MD, FACP Daniel D. Von Hoff, M.D., F.A.C.P. is currently Physician in Chief, Distinguished Professor Translational Research Division at TGen (Translational Genomics Research Institute) in Phoenix, Arizona. He is also Chief Scientific Officer for HonorHealth Clinical Research Institute and is the Medical Director of Research at McKesson Specialty Healthcare and the Scientific Medical Officer for US Oncology Research and leader of the Translation Oncology Program (TOP) specializing in phase I clinical trials done in the US Oncology Research network. He also holds an appointment as Professor of Medicine, Mayo Clinic, Scottsdale, AZ. Dr. Von Hoff’s major interest is in the development of new anticancer agents, both in the clinic and in the laboratory. He and his colleagues were involved in the beginning of the development of many of the agents we now use routinely, including: mitoxantrone, fludarabine, paclitaxel, docetaxel, gemcitabine, irinotecan, nelarabine, capecitabine, lapatinib, vismodegibm nab-paclitaxel, nal-IRI, and others. At present, he and his colleagues are concentrating on the development of molecularly targeted therapies particularly for patients with advanced pancreatic cancer. Dr. Von Hoff has published more than 690 papers, 140 book chapters and over 1400 abstracts. Dr. Von Hoff received the 2010 David A. Karnofsky Memorial Award from the American Society of Clinical Oncology for his outstanding contributions to cancer research leading to significant improvement in patient care. Dr. Von Hoff was appointed to President Bush’s National Cancer Advisory Board in 2004-2010. Dr. Von Hoff is the past President of the American Association for Cancer Research (the world’s largest cancer research organization), a Fellow of the American College of Physicians, and a member and past board member of the American Society of Clinical Oncology. He is a founder of ILEX™ Oncology, Inc. (acquired by Genzyme after Ilex had 2 agents, alemtuzumab and clofarabine approved by the FDA for patients with leukemia). Dr. Von Hoff is founder and the Editor Emeritus of Investigational New Drugs – The Journal of New Anticancer Agents; and, past Editor-in-Chief of Molecular Cancer Therapeutics. He is a co-founder of the AACR/ASCO Methods in Clinical Cancer Research Workshop. Dr. Von Hoff is the leader of the SU2C Pancreatic Dream Team. He is also proud to have been a mentor and teacher for multiple medical students, medical oncology fellows, graduate students, and post-doctoral fellows.

introduction to TTFields and preclinical overview Eilon Kirson, MD, PhD

Chief Science Officer and Head of R&D

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VALIDATED ANTI-CANCER MODALITY

tumor treating fields

SURGERY RADIATION PHARMACOLOGICAL TREATMENTS

TUMOR TREATING FIELDS (TTFIELDS)

• Most frequently employed therapy

• Reduces size of a tumor prior to initiation of additional therapies

• Kills cells when delivered at high doses

• Injures healthy tissues with numerous potential toxic side effects

• Includes chemotherapy, targeted therapies and immuno-oncology

• Limited by potential side effects

• Resistance can develop over time

• Low-intensity, alternating electric fields

• Mild side effect profile • No cumulative toxicity • Can be used in combination

with other treatment modalities

USED AS MONOTHERAPIES OR IN COMBINATION TO TREAT SOLID TUMORS

© Novocure 2016

Contractile ring mislocalization

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multi-pronged mechanism of action

1. Adapted from Giladi M., et al. Sci Rep, 2015; Dec 11; 518043. doi:10.1038/srep18046 2. Porat Y, et al. (2014 November) Triflupromazine, an Approved Antipsychotic Drug, Enhances Tumor Treating Fields Treatment Effi cacy In Vitro. Poster session presented at the Society for NeuroOncology. Miami, FL. 3. Voloshin, T., et al. Int. J. Cancer, 2016; 139: 2850–2858. doi:10.1002/ijc.30406

MITOTIC SPINDLE DAMAGE1,2

CHROMOSOME MIS-SEGREGATION3

CHROMOSOME MISALIGNMENT1

ABNORMAL CHROMOSOMAL SEGREGATION1 NSCLC

Ovarian Ovarian

NSCLC

© Novocure 2016

Normal Intestine

~50 kHz

Pancreatic Cancer

150 kHz

NSCLC

150 kHz

Ovarian Cancer

200 kHz

GBM

200 kHz

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TREATMENT DOES NOT HARM NORMAL CELL GROWTH

frequency tuned to specific cell types

EFFECTS ON CELLS ARE FREQUENCY SPECIFIC AND INVERSELY RELATED TO CELL SIZE

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TTFIELDS DELIVERY DESIGNED FOR HOME USE

• Battery or wall-powered electric field generator

• Single-use transducer arrays replaced 2–3 times/week

• Should be used at least 18 hours/day

• Mild side-effect profile, no known systemic toxicity

non-invasive, portable medical device

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REGIONAL TREATMENT ENABLES PERSONALIZATION

individualized anti-cancer modality

1. Miranda PC, Mekonnen A, Salvador R, Basser PJ. Physics in medicine and biology. 2014;59(15):4137-4147. doi:10.1088/0031-9155/59/15/4137 2. Wenger C, Salvador R, Basser PJ, Miranda PC. Int J Radiat Oncol. 2016; 94(5): 1137-1143. doi:10.1016/j.ijrobp.2015.11.042 3. Chaudhry A, Benson L, Varshaver M, et al. World J Surg Oncol. 2015;13:316. doi:10.1186/s12957‐015‐0722‐3 4. NovoTAL User Manual QSD‐QR‐700 Revision 1.4. Novocure January 2015.

The effect of a tumor with a necrotic core on the magnitude of the electric field, for the AP arrays (left) and LR arrays (right). The direction of the electric field in and around the tumor is shown in the insets. Values greater than 3.5 V/cm are shown in dark red.1-4

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15+ years of preclinical research • Deep understanding of the underlying mechanism of TTFields

• Continuing investment in mechanism of action substantiation and applications

© Novocure 2016

TTFields shown to reduce human glioma cell migration and invasion properties

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IBIDI CULTURE INSERT TO ASSESS WOUND HEALING1

1. Schneiderman, R.S. et al. (2016, April). Tumor Treating Fields (TTFields) Reduce Migration and Invasion Properties of Human Glioma Cancer Cells in Vitro. Poster session presented at the American Association for Cancer Research. New Orleans, LA.

TIME LAPSE MICROSCOPY SYSTEM1

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TTFIELDS INHIBITED MIGRATION OF GLIOMA CELLS IN SCRATCH WOUND ASSAYS IN VITRO

Schneiderman, R.S. et al. (2016, Apri l). Tumor Treating Fields (TTFields) Reduce Migration and Invasion Properties of Human Glioma Cancer Cells in Vitro. Poster session presented at the American Association for Cancer Research. New Orleans, LA.

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TTFIELDS INHIBITED GLIOMA CANCER CELL INVASIVE POTENTIAL IN VITRO

• TTFields’ frequency effect on glioma cell invasion is different from its peak antimitotic frequency

• TTFields’ inhibition of glioma cell migration in scratch wound assays is dependent upon electric

field direction

Schneiderman, R.S. et al. (2016, Apri l). Tumor Treating Fields (TTFields) Reduce Migration and Invasion Properties of Human Glioma Cancer Cells in Vitro. Poster session presented at the American Association for Cancer Research. New Orleans, LA.

© Novocure 2016

TTFields shown to induce autophagy in certain human cancer cell lines

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TTFIELDS APPLICATION TO U87 GLIOMA CELL LINE LED TO INCREASE IN CELLULAR GRANULARITY

Porat, Y. et al. (2016, Apri l). Alternating Electric Fields (TTFields) Induce Autophagy in Human Cancer Cell Lines. Poster session presented at the American Association for Cancer Research. New Orleans, LA.

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ELECTRON MICROGRAPHS REVEALED INCREASED LEVELS OF AUTOPHAGOSOME-LIKE STRUCTURES

IN U87 GLIOMA CELLS TREATED WITH TTFIELDS


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TTFIELDS UP-REGULATED AUTOGPHAGY IN U87 GLIOMA CELLS, REFLECTED BY INCREASED LC3-II LEVELS

A

D B

C Time dependent accumulation of LC3 on autophagosomal membranes following TTFields application (24 hours and 48 hours) is demonstrated by fluorescent microscopy of cells stained with anti-LC3 antibody (green) and DAPI DNA stain (blue) (Figure A). Original magnifications: x40. Image analysis shows significantly higher levels of LC3 signal per cell following treatment at 48 hours (Figure B). Immunoblot reveals increased levels of the LC3-derived autophagosomal marker LC3-II, in the presence of chloroquine, indicating the enhancement of autophagic flux during application of TTFields. (Mean ± SEM; *P < .05, ***P < .001 from control group, student’s t-test) (Figure C-D).


© Novocure 2016

TTFields shown to interfere with DNA damage response

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TTFIELDS INTERFERED WITH DAMAGE REPAIR OF IONIZING RADIATION-INDUCED DNA

DOUBLE STRAND REPAIR BY HOMOLOGOUS RECOMBINATION Control

TTFields IR + TTFields

IR

Giladi M., et al. (2015, October) Tumor Treating Fields (TTFields) Sensitize Glioma Tumor Cells to Radiation Therapy by Delaying DNA Damage Repair Through Homologous Recombination. Poster session presented at the Annual Meeting of the American Society for Radiation Oncology, San Antonio, TX.

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TTFIELDS PLUS IONIZING RADIATION TRIGGERED MULTI-NUCLEATION AND MITOTIC

ABNORMALITIES IN GLIOBLASTOMA CELLS

Ho Kim, E., Jin Kim, Y., Sook Song, H. et al. Oncotarget , 2016; 7(38), 62267-62279. doi:10.18632/oncotarget.11407

© Novocure 2016

TTFields are complementary to certain other anti-cancer therapies

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Chen DS, et al. Immunity. 2013; 39(1):1-10. doi: 10.1016/j.immuni.2013.07.012

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TTFIELDS DID NOT INHIBIT DEGRANULATION, CYTOKINE SECRETION OR ACTIVATION-

MARKER PRESENTATION IN ACTIVATED T-CELLS

Diamant, G.. et al. (2016, November). Evaluating the in-vitro effects of tumor treating fields on T cell responses. Poster session presented at the Society of NeuroOncology, Phoenix, AZ.

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In a mouse model of Lewis Lung carcinoma, combination of TTFields and

anti-PD-1 led to significant decrease in tumor volume compared to control

mice and to mice treated with anti-PD-1 alone after 1 week of treatment

• TTFields did not adversely affect immune cell infiltration into tumors

- TTFields applied to CD45+ cells did not inhibit immune function

- CD45+ and specifically CD11b+/CD11c+ and CD11b+/F4/80+ cells

from tumor in the combined treatment group exhibited higher tumor

infiltration and elevated PD-L1 expression compared to control groups

• Combining TTFields with anti-PD-1 may achieve tumor control by further

enhancing antitumor immunity

Giladi, M. et al. (2016, May). Alternating Electric Fields (TTFields) Induce Immunogenic Cell Death Resulting in Enhanced Antitumor Efficacy When Combined With Anti-PD-1 Therapy. Poster session presented at the Annual Meeting of the American Association of Immunologists, Seattle, WA.

TTFIELDS IN COMBINATION WITH ANTI-PD1 WERE THERAPEUTICALLY EFFECTIVE IN VIVO

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broad applicability to solid tumors

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ongoing clinical trials

PRE-CLINICAL

PHASE 2 PILOT

PHASE 3 PIVOTAL EXPECTED NEXT MILESTONE

INDICATIONS

Brain Metastases METIS trial last patient in 2019

NSCLC LUNAR first patient in 2017

Pancreatic Cancer phase three pivotal trial first patient in 2017

Ovarian Cancer finalization of phase three pivotal trial design

Mesothelioma STELLAR trial last patient in 2017

glioblastoma multiforme (GBM) Zvi Ram, MD

Tel Aviv Sourasky Medical Center

EF-14 Trial Investigator

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GLIOBLASTOMA

• Most common and most aggressive primary malignant brain tumor in adults1

• Located generally in the cerebral hemispheres of the brain, but may be found

anywhere in the brain or spinal cord

• One of a group of tumors referred to as gliomas

- Develop from the lineage of star-shaped glial cells, called astrocytes, that

are the “glue-like” support cells in the central nervous system

- Classified as a Grade IV astrocytoma by WHO2

• Because GBM can grow very rapidly, symptoms usually caused by increased

pressure in the brain

- Can include headache, nausea, vomiting, drowsiness or seizures

- Depending on tumor location, can include other symptoms like weakness

on one side of the body, memory and/or speech difficulties, visual changes

disease state and clinical presentation

1. Ostrom QT, Gittleman H, Jordan X, et al. Neuro-Oncology. 2016;18v1-v75. doi:10.1093/neuonc/now207 2. Louis D. N,, Ohgaki H,, Wiestler O.D, et al. Acta Neuropathologica. 2007;114(2):97-109. doi:10.1007/s00401-007-0243-4

© Novocure 2016

Europe2

GBM estimated incidence of 22,000 cases annually

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GLIOBLASTOMA

epidemiology

• Incidence of GBM is approximately 3.2 per 100,000 people1

• GBM incidence increases in frequency with age and affects men more than women

• GBM represents 14.9% of all primary brain tumors and about 60-75% of all astrocytomas

1. Ostrom QT, Gittleman H, Jordan X, et al. Neuro-Oncology. 2016;18v1-v75. doi:10.1093/neuonc/now207 2. Europe defined as all countries where Optune has CE mark approval 3. Etsuko Nomura, Akiko Ioka, and Hideaki Tsukuma. J Clin. Oncol. (2011) 41 (2): 291-294. doi:10.1093/jjco/hyq204

United States1 GBM incidence of 12,500 cases annually

Japan3 GBM incidence of 1,500 cases annually

© Novocure 2016

newly diagnosed

GBM

maximal debulking surgery / biopsy

radiation therapy (RT) +

temozolomide (TMZ)

TMZ (6 cycles)

MRI q2m until progression

second line chemotherapy

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GLIOBLASTOMA

• Since approval of temozolomide in 2005, standard of care for newly diagnosed GBM

has been the Stupp protocol pioneered by Dr. Roger Stupp1

• Standard treatment includes

- Maximal debulking surgery, if feasible

- Biopsy alone or subtotal resection, if maximal safe surgical resection not feasible

- Radiation therapy (45-70 Gray) with concomitant low-dose temozolomide (TMZ)

- Post radiation, high dose temozolomide (TMZ) given for five days every 28 days

prior standard of care: the Stupp protocol

1. Stupp R, Mason WP, van den Bent MJ, et al. N Engl J of Med 2005; 352:987-996

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MONOTHERAPY TREATMENT FOR RECURRENT GBM

EF-11 phase 3 pivotal trial overall survival TTFIELDS

(n=120) CHEMOTHERAPY

(n=117)

Median OS, months 6.6 6.0

HR and p value HR=0.86, p=0.27

4-year survival 8% 0%

n = 13 n = 85

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PRiDe overall survival MEDIAN OS MONTHS

PRiDe TTFields1 9.6

EF-11 TTFields2 6.6

EF-11 Physician Choice Chemo2 6.0

The Patient Registry Dataset (PRiDe) is a post-marketing registry of all recurrent GBM patients who received Optune in a real-world, clinical practice setting in the United States between 2011 and 2013 1. Mrugala MM, Engelhard HH, Dinh Tran D, et al. Semin Oncol. 2014;41(5)(suppl 6):S4-S13. doi: 10.1053/j.seminoncol.2014.09.010 2. Stupp R, Wong ET, Kanner AA, et al. Eur J Cancer. 2012;48(14):2192-2202. doi: 10.1016/j.ejca.2012.04.011

LOG-RANK (MANTEL-COX) TEST1

p value 0.0003

PRIDE VS EF-11 TTFIELDS1

HR 0.66

95% Cl 0.50-0.86

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PRiDe overall survival by recurrence MEDIAN OS MONTHS

1st recurrence 20.0

2nd recurrence 8.5

3rd-5th recurrence 4.9

LOG-RANK (MANTEL-COX) TEST1

Chi square 24.88

df 2

P value <0.0001

The Patient Registry Dataset (PRiDe) is a post-marketing registry of all recurrent GBM patients who received Optune in a real-world, clinical practice setting in the United States between 2011 and 2013 1. Mrugala MM, Engelhard HH, Dinh Tran D, et al. Semin Oncol. 2014;41(5)(suppl 6):S4-S13. doi: 10.1053/j.seminoncol.2014.09.010

1ST VS 2ND RECURRENCE

HR 0.6

95% Cl 0.4–0.9

P value 0.0271

1ST VS 3RD-5TH RECURRENCE

HR 0.3

95% Cl 0.2–0.5

P value <0.0001

1.0

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COMBINATION THERAPY FOR NEWLY DIAGNOSED GBM

EF-14 phase 3 pivotal trial initiated in 2009 A prospective, multicenter trial of TTFields together with temozolomide compared to temozolomide alone

in patients with newly diagnosed GBM

• 83 centers; 695 newly diagnosed GBM patients randomized 2:1 (TTFields plus TMZ vs TMZ alone)

• Treated until second progression or 24 months

• Pre-specified interim analysis 18 months after enrollment of the 315th patient

• Endpoints:

• Primary endpoint — progression-free survival (PFS) (intent to treat)

• Secondary endpoint — overall survival (OS) (as treated)

Novocure, Ltd. Effect of NovoTTF-100A Together With Temozolomide in Newly Diagnosed Glioblastoma Multiforme (GBM) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT00916409. NLM Identifier: NCT00916409

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INCLUSION CRITERIA

• Pathologic evidence of GBM (WHO criteria)

• >18 years old

• Received maximal debulking surgery, radiation

therapy, and concomitant TMZ

• KPS >70

• Treatment start >4 weeks from surgery

• Treatment start between 4-7 weeks from last

dose of concomitant chemotherapy and

radiation therapy

• Life expectancy >3 months

EF-14 key inclusion and exclusion criteria EXCLUSION CRITERIA

• Progressive disease per Macdonald Criteria

• Active participation in another clinical trial

• Pregnant

• Significant comorbidities that would prevent

maintenance TMZ (thrombocytopenia,

neutropenia, hepatic or renal function

impairment)

• Infratentorial tumor

• Evidence of increased intracranial pressure

• TMZ hypersensitivity

Novocure, Ltd. Effect of NovoTTF-100A Together With Temozolomide in Newly Diagnosed Glioblastoma Multiforme (GBM) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT00916409. NLM Identifier: NCT00916409

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EF-14 key baseline characteristics INTENT-TO-TREAT POPULATION

CHARACTERISTICS

OPTUNE + TMZ

(N=466)

TMZ ALONE

(N=229)

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 Partial resection Biopsy

53 34 13

53 34 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) 0 (0-0)

Baseline characteristics were well balanced between the two treatment arms1,2

ITT, intent-to-treat; TMZ, temozolomide; KPS, Karnofsky Performance Score; SD, standard deviation. 1. Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at the Society of NeuroOncology 21st Annual Meeting; November 17-20, 2016; Scottsdale, AZ. 2. Stupp R, et al; on behalf of EF-14 trial investigators. SNO Abstract LTBK-01. Neuro-Oncology. 2016. In press.

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© Novocure 2016


EF-14 key baseline characteristics (cont’d)

*Defined as 75% during the first 3 months of treatment. ITT, intent-to-treat; TMZ, temozolomide; MGMT, O6-methylguanine-DNA methyltransferase; IDH1, isocitrate dehydrogenase 1. 1. Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: SNO 21st Annual Meeting; November 17-20, 2016; Scottsdale, AZ. 2. Stupp R, et al; on behalf of EF-14 trial investigators. SNO Abstract LTBK-01. Neuro-Oncology. 2016. In press.

INTENT-TO-TREAT POPULATION

MOLECULAR PROFILES, %,

OPTUNE + TMZ

(N=466)

TMZ ALONE

(N=229)

MGMT status Tissue available and tested Methylated

82 35 54 10

81 42 51 7

Unmethylated Insufficient for testing

IDH1 R132 mutation status Tissue available and tested

56

52

Positive 7 5 Medications, %

Antiepileptics 44 41 Corticosteroids 29 28

Adherence to Optune,* % 75 -

Baseline characteristics were well balanced between the two treatment arms1,2

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© Novocure 2016

OPTUNE + TMZ (N=437)

N (%)

TMZ ALONE (N=207)

N (%) SYSTEM ORGAN CLASS GRADE 3 GRADE 4 GRADE 3 GRADE 4

Blood and lymphatic system disorders Leukopenia Lymphopenia Neutropenia Thrombocytopenia

9 2 3 2 6

4 0 1 1 3

9 <1 3 1 4

2 0 0 <1 1

Gastrointestinal disorders 5 <1 3 <1 General disorders and administration site conditions

Fatigue Asthenia Gait disturbance

9 4 3 2

<1 0 0 0

6 3 1 1

0 0 0 0

Infections and infestations 7 <1 4 1 Procedural complications

Fall Medical device site reaction

5 2 2

0 0 0

3 1 0

0 0 0

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EF-14 incidence of grade 3/4 adverse events

NOTES • Incidence of grade 3/4

adverse events seen in ≥2 % of patients

• Most common (≥10%) AEs involving Optune in combination with TMZ were thrombocytopenia, nausea, constipation, vomiting, fatigue, medical device site reaction, headache, convulsions, and depression.1,2

TMZ, temozolomide. 1. Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: SNO 21st Annual Meeting; November 17-20, 2016; Scottsdale, AZ. 2. Novocure Data on File OPT-103.

© Novocure 2016

OPTUNE + TMZ (N=437)

N (%)

TMZ ALONE (N=207)

N (%) SYSTEM ORGAN CLASS GRADE 3 GRADE 4 GRADE 3 GRADE 4

Metabolism and nutrient disorders Hyperglycemia

2 <1

1 1

5 2

0 0

Musculoskeletal and connective tissue disorders 4 <1 4 0 Nervous system disorders

Aphasia Brain edema Convulsion Headache Hemiparesis Neurological decompensation

21 2 2 5 3 4 2

3 0 <1 1 0 0 0

18 1 2 6 2 2 1

2 0 <1 <1 0 0 0

Psychiatric disorders 3 1 3 0 Renal and urinary disorders 1 0 2 0 Respiratory disorders Pulmonary embolism

2 <1

4 3

3 <1

2 2

Vascular disorders Hypertension

4 2

0 0

2 <1

0 0

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EF-14 incidence of grade 3/4 adverse events

TMZ, temozolomide. 1. Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: SNO 21st Annual Meeting; November 17-20, 2016; Scottsdale, AZ. 2. Novocure Data on File OPT-103.

NOTES • Incidence of grade 3/4

adverse events seen in ≥2 % of patients

• Most common (≥10%) AEs involving Optune in combination with TMZ were thrombocytopenia, nausea, constipation, vomiting, fatigue, medical device site reaction, headache, convulsions, and depression.1,2

© Novocure 2016 44


• EF-14 protocol prespecified one interim analysis to occur when the first 315 patients completed

18 months of follow-up1,2

• The primary endpoint of progression-free survival (PFS) was to be analyzed in the ITT population

and the secondary endpoint of overall survival (OS) was to be analyzed in the PP population

EF-14 interim analysis

INTERIM ANALYSIS

Population 315 patients

18 months of follow-up from enrollment of the 315th patient

PFS* (ITT) P=0.0139 required for trial to meet the primary endpoint

of a significantly higher PFS in the Optune + TMZ arm

OS (PP) P=0.0060 required to meet the powered secondary end point;

tested only if PFS was positive

*The central MRI review was based on an independent, blinded radiological review. PFS, progression-free survival; ITT, intent-to-treat; OS, overall survival; PP, per protocol. 1. Optune Instructions for Use. Novocure 2016. 2. Stupp R, et al. JAMA. 2015;314(23):2535-2543. doi: doi:10.1001/jama.2015.16669

© Novocure 2016

EF-14 INTERIM ANALYSIS

EF-14 enrollment and treatment

TMZ, temozolomide. 1. Optune Instructions for Use. Novocure 2016. 2. Stupp R, et al. JAMA. 2015;314(23):2535-2543. doi: doi:10.1001/jama.2015.16669

intent-to-treat population (ITT)

per-protocol population (PP)

randomization1,2

n=315

Optune + TMZ n=210

received any treatment n=203

TMZ n=105

started 2nd cycle TMZ n=95

no major protocol violations n=84

started 2nd cycle Optune + TMZ n=196

no major protocol violations n=196

received any

treatment n=101

45

© Novocure 2016 46

EF-14 INTERIM ANALYSIS: INTENT-TO-TREAT POPULATION

EF-14 progression free survival OPTUNE + TMZ

(n=210)1,2 TMZ ALONE

(n=105) 1,2 Median PFS from randomization, mo 7.2 4.0

95% CI, mo 5.9-8.2 3.0-4.3

Stratified log-rank p=0.0013

HR (95% CI) 0.621 (0.468-0.823)

Median PFS from diagnosis, mo

11.0 7.8

*Both interim and long-term analyses are protocol pre-specified.3,4

TMZ, temozolomide; ITT, intent-to-treat; PFS, progression-free survival; CI, confidence interval; HR, hazard ratio. 1. Optune Instructions for Use. Novocure 2016.

© Novocure 2016 47

EF-14 INTERIM ANALYSIS: AS-TREATED POPULATION

EF-14 overall survival OPTUNE + TMZ


(n=84) 1,2 Median OS from randomization, mo

20.5 15.6

95% CI, mo 16.6-24.9 12.9-18.5

Stratified log-rank p=0.0042

HR (95% CI) 0.666 (0.495-0.898)

Median OS from diagnosis, mo

24.4 19.4

2-year OS 48% 32%

*Both interim and long-term analyses are protocol pre-specified.3,4

TMZ, temozolomide; PP, per protocol; OS, overall survival; CI, confidence interval; HR, hazard ratio. 1. Optune Instructions for Use. Novocure 2016. 2. Novocure Data on File OPT-103. 3. Stupp R, et al. SNO Abstract LTBK-01. Neuro-Oncology. 2016. In press. 4. Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: SNO 21st

Annual Meeting; November 17-20, 2016; Scottsdale, AZ.

© Novocure 2016 48

EF-14 INTERIM ANALYSIS: INTENT-TO-TREAT POPULATION

• Quality of life was not adversely affected by the continuous use of TTFields1

• Activities of daily living did not decline when TTFields were added to temozolomide therapy

• Cognitive function did not decline when TTFields were added to temozolomide therapy

quality of life maintained

1. Zhu J.J. et. al. Quality of Life, Cognitive Function and Functional Status in the EF-14 Trial: a Prospective, Multi-Center Trial of Tumor Treating Fields Together With Temozolomide (TMZ) Compared to TMZ Alone in Patients With Newly Diagnosed GBM, SNO presentation, (Friday, Nov. 20, 2015, 2:40-2:50 p.m., concurrent session 2A – clinical trials phase II/III, abstract: 0761)

© Novocure 2016 49

EF-14 INTERIM ANALYSIS: MAINTAINING TTFIELDS AFTER FIRST RECURRENCE

TTFields with chemo versus chemo alone

TTFIELDS + CHEMOTHERAPY

(N=144)

CHEMOTHERAPY ALONE (N=60)

Median OS, mo1 11.8 9.2

Stratified log-rank1 p=0.0489

HR (95% CI) 1 0.695 1. Kesari S. and Ram Z.; on Behalf of EF-14 Trial Investigators .Neuro-Oncology. 2015;17(Suppl

5):v14. doi:10.1093/neuonc/nov205.19

© Novocure 2016 50

EF-14 INTERIM ANALYSIS: MAINTAINING TTFIELDS AFTER FIRST RECURRENCE

TTFields with bevacizumab versus bev. alone

TTFIELDS + BEVACIZUMAB

(N=79)

BEVACIZUMAB ALONE (N=30)

Median OS, mo1 11.8 9.0

Stratified log-rank1 p=0.0428

HR (95% CI) 1 0.606

55% of patients received bevacizumab (with or without chemo) as their second-line

treatment choice

1. Kesari S. and Ram Z.; on Behalf of EF-14 Trial Investigators .Neuro-Oncology. 2015;17(Suppl 5):v14. doi:10.1093/neuonc/nov205.19

© Novocure 2016

randomization1,2

EF-14 LONG-TERM ANALYSIS

EF-14 enrollment and treatment

*26 patients crossed over at the time of FDA approval of crossover. TMZ, temozolomide. 1. Stupp R, et al. JAMA. 2015;314(23):2535-2543. doi: doi:10.1001/jama.2015.16669 2. Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: SNO 21st Annual Meeting; November 17-20, 2016; Scottsdale, AZ.

n=695

interim analysis

Optune + TMZ n=210

TMZ n=105

Optune + TMZ n=466

TMZ n=229

long-term analysis*

51

© Novocure 2016

EF-14 LONG-TERM ANALYSIS: INTENT-TO-TREAT POPULATION

EF-14 progression free survival OPTUNE + TMZ


(n=229) 1,2 Median PFS from randomization, mo 6.7 4.0

95% CI, mo 6.1-8.1 3.8-4.3

Stratified log-rank p<0.0001

HR2 (95% CI) 0.63 (0.52-0.76)

Median PFS from diagnosis, mo

11.2 7.8

*Both interim and long-term analyses are protocol prespecified.1,2

TMZ, temozolomide; ITT, intent-to-treat; PFS, progression-free survival; CI confidence interval; HR, hazard ratio. 1. Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: SNO 21st Annual

Meeting; November 17-20, 2016; Scottsdale, AZ. 2. Stupp R, et al; on behalf of EF-14 trial investigators. SNO Abstract LTBK-01. Neuro-

Oncology. 2016. In press.

52

© Novocure 2016 53

EF-14 LONG-TERM ANALYSIS: INTENT-TO-TREAT POPULATION

EF-14 overall survival OPTUNE + TMZ

(n=466) 1,2 TMZ ALONE

(n=229) 1,2 Median OS from randomization, mo 20.8 16.0

95% CI, mo 19.0-22.6 13.9-18.2

Stratified log-rank p<0.0006

HR (95% CI) 0.65 (0.54-0.79)

Median OS from diagnosis, mo

24.5 19.8

*Both interim and long-term analyses are protocol prespecified.1,2

TMZ, temozolomide; ITT, intent-to-treat; OS, overall survival; CI, confidence interval; HR, hazard ratio. 1. Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: SNO 21st

Annual Meeting; November 17-20, 2016; Scottsdale, AZ. 2. Stupp R, et al; on behalf of EF-14 trial investigators. SNO Abstract LTBK-01. Neuro-

Oncology. 2016. In press. 3. Novocure Data on File OPT-118.

© Novocure 2016 54


EF-14 subgroup analysis SUBGROUP NO. OF PATIENTS (%) HAZARD RATIO

MEDIAN SURVIVAL (MONTHS) OPTUNE + TMZ1 TMZ ALONE1

Overall 695 (100) 20.8 16 MGMT (central) Unmethylated 303 (44) 17.3 13.9 Methylated 213 (31) 29.7 21.2 Resection Biopsy 89 (13) 14.7 11.6 Partial 234 (34) 21.4 15.1 Gross total 372 (53) 22.6 18.5 Age <50 y 194 (28) 24.4 19.9 50+ y 501 (72) 19.8 15.3 KPS 90-100 457 (67) 22.7 17.8 <80 228 (33) 14.7 11 Sex Female 222 (32) 24.4 18.5 Male 473 (68) 19 15.5

OPTUNE + TMZ BETTER TMZ ALONE BETTER

0 0.25 0.5 0.75 1.25 1.5 1.75 2.00 1 TMZ, temozolomide; MGMT, O6-methylguanine-DNA methyltransferase; KPS, Karnofsky Performance Score. 1. Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: SNO 21st Annual

Meeting; November 17-20, 2016; Scottsdale, AZ.

© Novocure 2016


70% IMPROVEMENT IN SURVIVAL WITH TTFIELDS + TMZ (17%) VERSUS TMZ ALONE (10%) AT 4 YEARS (P=0.028)1,2

EF-14 long-term survival rates

TMZ, temozolomide; ITT, intent-to-treat. 1. Stupp R, et al; on behalf of EF-14 trial investigators. [SNO Abstract LTBK-01]. Neuro-Oncology. 2016. In press. 2. Stupp R, et al; on behalf of EF-14 trial investigators. Slides presented at: SNO 21st Annual Meeting; November 17-20, 2016; Scottsdale, AZ.

55

© Novocure 2016


consistency across EF-14 analyses PFS, progression-free survival; OS, overall survival; TMZ, temozolomide; ITT, intent-to-treat; PP, per protocol. 1. Optune Instructions for Use. Novocure 2016. 2. Novocure Data on File OPT-103. 3. Stupp R, et al; on behalf of EF-14 trial

investigators. Slides presented at: SNO 21st Annual Meeting; November 17-20, 2016; Scottsdale, AZ.

4. Stupp R, et al; on behalf of EF-14 trial investigators. SNO Abstract LTBK-01. Neuro-Oncology. 2016. In press.

56

© Novocure 2016 57


• EF-14 long-term analysis confirms conclusions of interim analysis

• TTFields are safe and can be combined with TMZ chemotherapy

• Toxicity is limited to local skin irritation and cutaneous reactions

• Adjuvant therapy with TTFields significantly prolongs progression-free and

overall survival in patients with newly diagnosed GBM

EF-14 summary

brain metastases Vinai Gondi, MD

Northwestern Medicine Proton Center

METIS Principal Investigator

© Novocure 2016 59

BRAIN METASTASES

disease state and clinical presentation • Most common form of brain cancer, exceeding the number of primary brain

tumors by at least fourfold1 and occurring in roughly 15% of all cancer patients2

• Brain metastases most frequently arise from lung, breast, skin, colorectal and kidney cancers1

• Blood-brain barrier (BBB) critical to role of metastases - Certain primary neoplasms able to damage BBB, allowing spread into brain - Once these have crossed into brain, BBB repairs itself and the metastasis is

protected from many chemotherapies • Symptoms usually caused by increased pressure in the brain

- Can include headache, seizures, nausea, vomiting, or drowsiness - Depending on tumor location, can also include other focal neurological

defects such as weakness on one side of the body, visual changes, motor dysfunction, cognitive dysfunction, or sensory changes

1. Goetz P, Ebinu JO, Roberge D, Zadeh G. Intl J of Surg Onc. 2012;2012:493426. doi:10.1155/2012/493426. 2. Bashour S.I., William W.N., Patel S., Rao G., Strom E., McAleer M.F., Guha-Thakurta N., Conrad C. and Ibrahim N.K., Chapter 1 - Brain Metastasis from Solid Tumors, In Brain Metastases from

Primary Tumors, edited by M.A. Hayat,, Academic Press, San Diego, 2015, Pages 3-29, ISBN 9780128014196, doi:10.1016/B978-0-12-801419-6.00001-X.

© Novocure 2016 60

BRAIN METASTASES

epidemiology

United States 1 Brain metastases estimated incidence of 98,000-170,000 cases annually

Europe

Brain metastases estimated incidence of 75,000 cases annually Japan

Brain metastases estimated incidence of 13,000 cases annually

• Exact global incidence unknown, with estimates varying widely

• Occur in roughly 15% of cancer patients, though autopsy analyses have indicated higher incidence2

1. Goetz P, Ebinu JO, Roberge D, Zadeh G. Intl J of Surg Onc. 2012;2012:493426. doi:10.1155/2012/493426. 2. Bashour S.I., William W.N., Patel S., Rao G., Strom E., McAleer M.F., Guha-Thakurta N., Conrad C. and Ibrahim N.K., Chapter 1 - Brain Metastasis from Solid Tumors, In Brain Metastases from Primary Tumors, edited by M.A. Hayat,,

Academic Press, San Diego, 2015, Pages 3-29, ISBN 9780128014196, doi:10.1016/B978-0-12-801419-6.00001-X.

© Novocure 2016 61

BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER (NSCLC)

• Approximately 7.4% of NSCLC patients will have brain metastases at

presentation and 25-30% will develop brain metastases during the course

of their disease1

• Survival impacted by factors such as age, number of brain metastases,

patient health status, presence of extracranial metastases, and presence of

targetable mutations1,2

- Median time to intracranial (IC) failure is approximately 7-9 months3

- Median OS is approximately 7-13 months3

current prognosis

1. Owen S, Souhami L. Frontiers in Oncology. 2014;4:248. doi:10.3389/fonc.2014.00248 2. Sperduto, P. et al. JAMA Oncol. (2016) 2016 Nov 17. doi: 10.1001/jamaoncol.2016.3834. [Epub ahead of print] 3. See additional references next slide.

© Novocure 2016 62

BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER

references for time to IC failure and OS AUTHOR YEAR JOURNAL HISTOLOGY

OVERALL SURVIVAL, MO

% 1 YEAR SURVIVAL

MEDIAN TIME TO IC FAILURE

Williams et al. 1998 J Neurooncol NSCLC 7.9 - -

Li et al. 2000 Int J Cancer NSCLC 9.3 - 6.9

Maor et al. 2000 Int J Cancer NSCLC 7 - -

Regine et al. 2002 Int J Radiat Oncol Biol Phys NA 9 36% -

Pollock et al. 2002 J Neurooncol NSCLC, Breast, Melanoma, renal 15.5 63% 8

Flannery et al. 2003 Lung Cancer NSCLC 8.6 - -

Rades et al. 2007 Cancer NSCLC - 45% -

Kim et al. 2008 Cancer NSCLC 6.5 - -

Mariya et al 2010 J Rad Res NSCLC 9 38% 9

Marko et al. 2011 J Neurooncol NSCLC 8.2 - -

Kelly et al. 2012 Int J Radiat Oncol Biol Phys NA - - 7.4

Xu et al. 2013 World Neurosurg NSCLC 8 - -

Xu et al. 2013 Clin Transl Oncol NSCLC 12.6 - -

Smith et al. 2014 J Neurosurgery NSCLC, Melanoma, Breast, Other 13.2 52% -

Median 8.4 42% 7.7 Hazard rate 0.08252 0.08161

© Novocure 2016

newly diagnosed brain metastases

stereotactic radiosurgery (SRS)

monthly follow-up with supportive care

MRI q2m

whole-brain radiotherapy (WBRT)

63


• Due to failure of most chemotherapies to cross BBB, treatment of brain metastases

has been largely confined to supportive care with surgery and radiation therapy


- Surgical resection, usually limited to single metastasis

- Stereotactic radiosurgery (SRS), to deliver a single high dose of irradiation

- Post SRS, supportive care given during watchful waiting

- Whole-brain radiotherapy (WBRT), usually utilized as salvage therapy due to

detrimental neurocognitive effects

current standard of care

1. Owen S, Souhami L. Frontiers in Oncology. 2014;4:248. doi:10.3389/fonc.2014.00248

© Novocure 2016 64


• TTFields shown to be effective and safe in glioblastoma patients (phase 3 pivotal EF-

14 trial in GBM)1

• Believe the device can be applied to other intracranial solid tumors

• In-vitro data has shown NSCLC sensitivity to TTFields at 150kHz2

• TTFields have been to shown to prevent metastatic seeding in-vivo3

• Phase 2 pilot data in primary NSCLC (EF-15) showed potential efficacy4

• TTFields at 150kHz were safe in a pilot trial of NSCLC brain metastasis patients (EF-

21/COMET) and have been shown not to harm cognitive function of GBM patients5

when used in combination with temozolomide

rationale for testing TTFields in brain mets

1. Stupp R, et al. JAMA. 2015;314(23):2535-2543. doi: doi:10.1001/jama.2015.16669 2. Pless M, Weinberg U, Betticher D, Giladi M, von Moos R, Schneiderman R, et al. Cancer Res 2012;72(8 (Suppl. 1)). p. abstract 4607. doi: 10.1158/1538-7445.AM2012-4607 3. Kirson, E.D., Giladi, M., Gurvich, Z. et al. Clin Exp Metastasis. 2009; 26: 633-640. doi: 10.1007/s10585-009-9262-y 4. Pless M, et al. Lung Cancer. 2013;81(3):445-50. doi: 10.1016/j.lungcan.2013.06.025 5. Zhu J.J. et al. Quality of Life, Cognitive Function and Functional Status in the EF-14 Trial: a Prospective, Multi-Center Trial of Tumor Treating Fields Together With Temozolomide (TMZ) Compared to TMZ Alone in Patients With Newly

Diagnosed GBM, SNO presentation, (Friday, Nov. 20, 2015, 2:40-2:50 p.m., concurrent session 2A – clinical trials phase II/III, abstract: 0761)

© Novocure 2016 65


METIS phase 3 pivotal trial initiated in 2016 A prospective, randomized controlled, multicenter trial testing efficacy, safety and neurocognitive outcomes

of TTFields at 150 kHz following stereotactic radiosurgery in advanced non-small cell lung cancer patients

with 1-10 brain metastases

• 270 patients internationally, randomized 1:1 (TTFields vs supportive care)

• Twelve month follow-up after final patient enrollment

• Endpoints:

• Primary endpoint — time to first cerebral progression

• Secondary endpoints include neurocognitive failure, overall survival, radiological response rate

Novocure, Ltd. Effect of TTFields (150 kHz) in Non-small Cell Lung Cancer (NSCLC) Patients With 1-10 Brain Metastases Following Radiosurgery (METIS) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT02831959. NLM Identifier: NCT02831959

© Novocure 2016 66


INCLUSION CRITERIA

• New diagnosis of brain metastases from histologically

confirmed metastatic NSCLC

• ≥ 18 years old

• Life expectancy ≥ 3 months

• KPS ≥70

• GPA ≥ 2.0

• 1 inoperable brain metastasis or 2-10 brain lesions,

confirmed by MRI

• At least 1 measurable lesion per RANO-BM

• Receiving optimal therapy for extracranial disease

• Prior clinical trial enrollment allowed, as long as no

brain directed therapy included

key inclusion and exclusion criteria EXCLUSION CRITERIA

• Somatic tumor mutations for which targeted agents

are available

• Single, operable brain metastasis

• Significant edema with risk of brain herniation

• Midline shift > 10mm

• Intractable seizures

• Infratentorial or leptomeningeal metastases

• Previously treated recurrent brain metastases or prior

surgical resection for newly diagnosed brain

metastases

• Severe comorbidities

• Implantable electronic medical devices

• Pregnant Novocure, Ltd. Effect of TTFields (150 kHz) in Non-small Cell Lung Cancer (NSCLC) Patients With 1-10 Brain Metastases Following Radiosurgery (METIS) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT02831959. NLM Identifier: NCT02831959

© Novocure 2016 67


clinical milestones and next steps

Enrolled in October 2016

Expected in 2019 Expected 12 months following last patient enrollment

First patient in Last patient in Data

NEXT STEPS

• Continued expansion of investigator and investigating site footprint

• Last patient enrollment expected in 2019

• Data presentation expected to be twelve months following LPI

non-small cell lung cancer Eilon Kirson, MD, PhD


Actor portrayal

© Novocure 2016 69

NON-SMALL CELL LUNG CANCER

• Lung cancer is the most common cancer type worldwide1

• Smoking is the major risk factor for non-small cell lung cancer2

• 80-85% of all lung cancers are non-small cell (NSCLC)2

- Majority of NSCLC cases (40%) are adenocarcinomas, arising

from the cells that normally secrete substances such as mucus

- Squamous cells carcinomas (25-30% of NSCLCs) arise from flat cells lining the inner airways near the central lungs

- Large cell carcinomas (10-15% of NSCLCs) appear in any part of the lung and tend to spread quickly

• Only a minority of NSCLC patients present with localized disease

• Symptoms include trouble breathing, coughing that does not abate, coughing up blood, chest pain, hoarseness, infection, wheezing

disease state and clinical presentation

1. WHO (2016) GLOBOCAN 2012: Estimated Cancer Incidence, Mortality, and Prevalence Worldwide in 2012, Lyon, France (accessed December 2016) 2. Lung Cancer – Non-Small Cell Detailed Guide. Atlanta: American Cancer Society, 2016. 3. SEER Cancer Statistics Factsheets: Lung and Bronchus Cancer. National Cancer Institute. Bethesda, MD (accessed December 2016)

© Novocure 2016 70

NON-SMALL CELL LUNG CANCER

epidemiology

United States 1 NSCLC incidence of 185,000 cases annually

Europe 2 NSCLC incidence of 350,000 cases annually

Japan 3 NSCLC incidence of 80,000 cases annually

1. SEER Cancer Statistics Factsheets: Lung and Bronchus Cancer. National Cancer Institute. Bethesda, MD (accessed December 2016) 2. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JWW, Comber H, Forman D, Bray F. Eur J Cancer. 2013;49(6):1374-403. doi: 10.1016/j.ejca.2012.12.027 3. WHO (2016) GLOBOCAN 2012: Estimated Cancer Incidence, Mortality, and Prevalence Worldwide in 2012, Lyon, France (accessed December 2016)

• Incidence of NSCLC is approximately 16 per 100,000 people, varying widely on a geographic basis3

• Regional incidence variations directly reflect smoking prevalence

© Novocure 2016 71

ADVANCED NON-SMALL CELL LUNG CANCER

• Heterogeneity of patient demographics, tissue involvement and disease

staging at presentation require personalized approaches

• Stage IIIB-IV defined as being locally advanced within the lungs or

metastatic to lymph nodes and distant organs1

• Surgical resection usually only feasible for stage I-IIIA NSCLC patients2

• Prognosis for stage IIIB-IV remains poor, despite active research

• Median progression-free survival (PFS) is approximately 3-4 months3,4

• Median overall survival (OS) is approximately 13 months4

current prognosis

1. Lung Cancer – Non-Small Cell Detailed Guide. Atlanta: American Cancer Society, 2016. 2. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Mayo Clinic proceedings Mayo Clinic. 2008;83(5):584-594. doi: 10.4065/83.5.584 3. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. J Clin Oncol 2004;22(9):1589–97. doi: 10.1200/JCO.2004.08.163 4. Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, et al. Lancet 2009;374(9699): 1432–40. doi: 10.1016/S0140-6736(09)61497-5

© Novocure 2016

Stage IIIB or IV NSCLC

radiation therapy (RT) + cisplatin/carboplatin

platinum-based doublet

CT q2m until progression

second or third line chemotherapy

72

SECOND LINE TREATMENT FOR ADVANCED NON-SMALL CELL LUNG CANCER

• Since 1991, radiation with a combination of platinum-based chemotherapy has been the first-

line standard of care for locally advanced or metastatic NSCLC 1


- Radiation therapy with concomitant platinum-based chemo (cisplatin/carboplatin)

- Post-radiation, chemotherapy doublets may include docetaxel, gemcitabine, paclitaxel, and

vinorelbine with platinum-based agents

- At recurrence, second line treatment may include pemetrexed, docetaxel or immunotherapies

evolving standard of care

1. Le Chevalier T, et al. J Natl Cancer Inst. 1991;83(6):417-23. doi: 10.1093/jnci/83.6.417 2. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Mayo Clinic proceedings Mayo Clinic. 2008;83(5):584-594. doi: 10.4065/83.5.584

© Novocure 2016 73


torso array placement

Bomzon, Z. et al. (2015 August) Modelling Tumor Treating Fields (TTFields) for the treatment of lung tumors. Poster session presented at the EMBC annual IEEE Engineering in Medicine and Biology Society. Milan, Italy.

DISTRIBUTION OF TTFIELDS AROUND THE LUNGS

© Novocure 2016 74


phase 2 pilot EF-15 trial A prospective, open label, single-arm, non-randomized, multicenter study of TTFields at 150 kHz to estimate

efficacy and determine safety together with pemetrexed in pretreated patients with locally advanced non-

small cell lung cancer versus historical controls

• 42 patients in Switzerland with locally advanced and/or metastatic non-small cell lung cancer

• Last patient enrolled May 2011 with six month follow-up

• Endpoints:

• Primary endpoint – severity and frequency of adverse events, as well as feasibility based on compliance

with TTFields therapy

• Secondary endpoints include progression free survival, overall survival, overall response rate

Novocure, Ltd. NovoTTF-100L in Combination With Pemetrexed (Alimta®) for Advanced Non-small Cell Lung Cancer In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT00749346. NLM Identifier: NCT00749346

© Novocure 2016 75


INCLUSION CRITERIA

• Histologically confirmed NSCLC

• Stage IV or IIIB disease with malignant pleural

effusion, also locally advanced NSCLC not otherwise

amenable to local treatment

• One line of prior chemotherapy

• Measurable disease



• ECOG score of 0-2

• Laboratory verification of adequate hemotologic,

renal and hepatic function upon entry

EF-15 key inclusion and exclusion criteria EXCLUSION CRITERIA

• Brain metastases or meningeal carcinomatosis

• Concurrent treatment with other experimental drugs

or participation in other clinical trials

• Pregnant

• Other serious concomitant illness, including

- Uncontrolled congestive heart failure or angina

pectoris

- History of myocardial infarction within 1 year

- Uncontrolled hypertension or arrhythmias

- Implanted pacemaker, defibrillator or deep brain

stimulation device

- History of neurologic or psychiatric disorders

Novocure, Ltd. NovoTTF-100L in Combination With Pemetrexed (Alimta®) for Advanced Non-small Cell Lung Cancer In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT00749346. NLM Identifier: NCT00749346

© Novocure 2016


EF-15 key baseline characteristics

1. Pless M, et al. Lung Cancer. 2013;81(3):445-50. doi: 10.1016/j.lungcan.2013.06.025

CHARACTERISTICS (N=42) NUMBER (%)1

Median age, years (range) 63 (44-78) Gender Male Female

26 (63%) 15 (37%)

ECOG performance status 0 or 1 2 unknown

31 (76%) 7 (17%) 3 (7%)

Disease stage, % IIIB (pleural effusion) IV

10 (24%) 31 (76%)

Histology Adenocarcinoma Squamous cell Large cell

32 (78%) 7 (17%) 2 (5%)

Past treatments Surgery Radiation

5 (12%)

10 (24%) Time since diagnosis, median 45.4 weeks Time since last chemotherapy, median 14.9 weeks

76

© Novocure 2016 77


EF-15 incidence of adverse events

1. Pless M, et al. Lung Cancer. 2013;81(3):445-50. doi: 10.1016/j.lungcan.2013.06.025

SYSTEM ORGAN CLASS

GRADE 3-4

N (%) 1

GRADE 1-2

N (%) 1

Constitutional Fatigue Asthenia Insomnia Night sweats Fever

1 (2%)

0 0 0 0

9 (22%) 2 (5%) 3 (7%) 3 (7%) 2 (5%)

Cardiovascular Arrhythmia

0

1 (2%)

Dermatology Rash/dermatitis/erythema Blister Pruritus Alopecia Ulceration

1 (2%)

0 0 0 0

10 (24%)

3 (7%) 2 (5%) 1 (2%) 1 (2%)

Infectious Urinary

2 (5%) 0

SYSTEM ORGAN CLASS

GRADE 3-4

N (%) 1

GRADE 1-2

N (%) 1

Gastrointestinal Anorexia Diarrhea Nausea Constipation Vomiting

2 (5%) 2 (5%)

0 0 0

3 (7%) 2 (5%) 3 (7%)

4 (10%) 3 (7%)

Neurological Dizziness Neuropathy

1 (2%) 0

1 (2%) 2 (5%)

Pain Thoracic/chest/rib Limb Abdominal Headache Electric pain Cervical pain

2 (5%)

0 0 0

1 (2%) 1 (2%)

3 (7%)

4 (10%) 3 (7%) 3 (7%)

0 0

Respiratory Dyspnea Cough

4 (10%)

0

8 (19%) 11 (27%)

© Novocure 2016 78


phase 2 pilot EF-15 trial results EFFICACY ENDPOINTS

TTFIELDS WITH PEMETREXED1

PEMETREXED-ALONE HISTORICAL

CONTROL2

Median in-field PFS 6.5 months n/a

Median PFS 5 months 2.9 months

Median OS 13.8 months 8.3 months

One-year survival rate 57% 29.7%

Partial response rate 14.6% 9.1% 1. Pless M, et al. Lung Cancer. 2013;81(3):445-50. doi: 10.1016/j.lungcan.2013.06.025 2. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. J Clin Oncol 2004;22(9):1589–97. doi: 10.1200/JCO.2004.08.163

© Novocure 2016 79


• Randomized pivotal trial, standard-of-care controlled

• 512 patients with second line NSCLC, all histologies

• Treatment groups:

• TTFields with PD-1 inhibitor or docetaxel (based on physician’s choice)

• PD-1 inhibitor or docetaxel (based on physician’s choice)

• Stratification factors:

• PD-1 inhibitor vs docetaxel

• Histology (squamous vs non-squamous)

• Endpoints:

• Primary – overall survival (OS) (Superiority)

• Secondary –

- OS of TTFields + docetaxel vs docetaxel alone (superiority)

- OS of TTFields + PD-1 inhibitor vs PD-1 inhibitor alone (superiority)

- OS of TTFields + docetaxel vs PD-1 inhibitor alone (non-inferiority)

planned LUNAR phase 3 pivotal trial

© Novocure 2016 80


• Intended to facilitate accrual as standard of care treatments are included on both arms,

regardless of reimbursement for PD-1 inhibitors

• Intended to enable data collection for different combinations with TTFields (immune therapy

and taxanes)

• Will not compete with first line PD-1 NSCLC trials

• If PD-1 inhibitors move to first line, have chance at superiority data with taxanes in second line

• If PD-1 inhibitors fail in first line:

- Two chances of success in second line:

• Superiority with PD-1 inhibitors

• Non-inferiority with taxanes compared to PD-1 inhibitors

- Plan to have data on TTFields with taxanes to support potentially moving TTFields to first line

(where standard of care includes taxanes)

LUNAR design considerations

© Novocure 2016 81


planned LUNAR inclusion and exclusion criteria INCLUSION CRITERIA



• Histologically confirmed unresectable, locally

advanced or metastatic NSCLC

• ECOG score of 0-1

• Assigned by physician to receive either docetaxel

or PD-1 inhibitor per standard of care

EXCLUSION CRITERIA

• Brain metastases or leptomeningeal spread

• Prior surgery or radiation in the lungs

• Severe comorbidities, including

- Hematological, hepatic or renal dysfunction

- Uncontrolled cardiovascular disease

- Symptomatic arrhythmia

- History of cerebrovascular accident

- Active infection

- History of psychiatric condition

• Concurrent experimental studies


• Pregnant or breast-feeding

© Novocure 2016 82



Expected 1H 2017 Expected 2-3 years following first patient enrolled

Expected 18 months following last patient enrollment


NEXT STEPS

• First patient enrollment anticipated in 1H 2017

break

pancreatic cancer

Daniel D. Von Hoff, MD

Translational Genomics Research Institute

World-renowned expert in pancreatic cancer

Actor portrayal

© Novocure 2016

why would a doc interested in pancreatic cancer drug dev. be interested in TTFields

85

• Glioblastoma

- Almost impossible to improve

survival

- TTFields did improve survival

• Pancreatic cancer is similarly

difficult

• A new and different approach;

new mechanisms of action are

always interesting

Image: Voloshin T, Munster M, Blatt R, et al. Int J of Cancer. 2016;139(12):2850-2858. doi:10.1002/ijc.30406

© Novocure 2016

in 2016, pancreatic cancer is still with us and it is still bad

86

• Currently the 4th leading cause of death from cancer in the U.S. (2nd leading cause

by 2030)1,2

• The worst survival rate of any cancer

• Latest 2016 estimates1

- 53,070 (27,670 men; 25,400 women) people diagnosed with the disease

- 41,780 (21,450 men; 20,330 women) people will die from the disease (114 people

a day)

- Kills >300,000 worldwide

• Incidence increasing 0.8% - 1% / year - mostly because we are an aging population

1. Siegel, R. L., Miller, K. D. and Jemal, A. CA: A Cancer Journal for Clinicians, 2016; 66: 7–30. doi:10.3322/caac.21332 2. Rahib L. et al. Cancer Res . 2014; 74 (11):2913-2921; doi: 10.1158/0008-5472.CAN-14-0155

© Novocure 2016

pancreatic cancer kills more than 300,000 individuals each year worldwide

87

© Novocure 2016 88

clinical staging of pancreatic cancer • Resectable (localized): med survival = 12-19 mo.

- No encasement of celiac axis or superior

mesenteric artery (SMA)

- Patent superior mesenteric – portal veins

- No extra pancreatic disease

• Locally advanced: med survival = 6-10 months

- Encasement of arteries

- Venous occlusion (SMV or portal)

- No extra pancreatic disease

• Metastatic: median survival 3-6 months (in past)

There is an unmet medical need for patients with locally advanced inoperable pancreatic cancer –

survival is still terrible

© Novocure 2016 90

ADVANCED PANCREATIC CANCER

current standard of care, but need to do better

1. Von Hoff, D.D. et al. N Engl J Med, 2013, 369:1691-1703. doi:10.1056/NEJMoa1304369

• Resectable

- Surgery followed by gemcitabine + capecitabine

• Locally Advanced

- No current standard

- Try to make operable chemotherapy with or without XRT

• Metastatic

- First line

• Nab-paclitaxel + gemcitabine

• Folfirinox (folinic acid) +5FU +irinotecan + oxaliplatin

- Second line

• Irinotecan liposome

© Novocure 2016 91


based on biology: abdominal array placement

DISTRIBUTION OF TTFIELDS AROUND THE PANCREAS

© Novocure 2016 92


phase 2 pilot PANOVA trial A prospective, open label, single-arm, non-randomized, multicenter study testing feasibility, safety and

preliminary efficacy of TTFields at 150 kHz together with gemcitabine or gemcitabine plus nab-paclitaxel in

patients with advanced pancreatic cancer versus historical controls

• 40 patients in Europe with locally advanced or metastatic pancreatic cancer

• First cohort (n=20) of TTFields at 150 kHz with gemcitabine

• Second cohort (n=20) of TTFields at 150 kHz with gemcitabine and nab-paclitaxel


• Endpoints:

• Primary endpoint – severity and frequency of adverse events, as well as feasibility based on compliance

with TTFields therapy


Novocure, Ltd. Safety Feasibility and Effect of TTFields (150 kHz) Concomitant With Gemcitabine or Concomitant With Gemcitabine Plus Nab-paclitaxel for Front-line Therapy of Advanced Pancreatic Adenocarcinoma (PANOVA) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT01971281. NLM Identifier: NCT01971281

© Novocure 2016 93


INCLUSION CRITERIA

• Histologically confirmed, unresectable locally

advanced or metastastatic pancreatic

adenocarcinoma

• >18 years old


• Measurable or assessable disease

• ECOG score 0-1

• Adequate bone marrow, liver, and kidney function

• No concurrent anti-tumor therapy beyond

gemcitabine or nab-paclitaxel

• At least 4 weeks recovery from surgery

• No prior chemotherapy or radiation

PANOVA key inclusion and exclusion criteria EXCLUSION CRITERIA

• Known brain metastases or meningeal

carcinomatosis

• Any other malignancy requiring anti-tumor treatment

in prior 3 years

• Significant comorbidity expected to affect prognosis

or ability to receive combined therapy


• Known allergies to medical adhesives, hydrogel,

gemcitabine or nab-paclitaxel

• Pregnant

Novocure, Ltd. Safety Feasibility and Effect of TTFields (150 kHz) Concomitant With Gemcitabine or Concomitant With Gemcitabine Plus Nab-paclitaxel for Front-line Therapy of Advanced Pancreatic Adenocarcinoma (PANOVA) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT01971281. NLM Identifier: NCT01971281

© Novocure 2016 94


phase 2 pilot PANOVA trial results

EFFICACY ENDPOINTS

FIRST COHORT1

TTFIELDS WITH GEMCITABINE

SECOND COHORT

TTFIELDS WITH NAB-PACLITAXEL PLUS

GEMCITABINE

Median PFS 8.3 months 12.7 months

Median OS 14.9 months Not yet reached

One-year survival rate 55% 72%

Partial response rate 30% 40%

Stable disease 30% 47%

1. Rivera, F. Gallego, J., Guillen C. et al. (2016 June) A pilot study of TTFields concomitant gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma. Poster session presented at ASCO GI. Chicago, IL.

For historical reference, see Von Hoff, D.D. et al. N Engl J Med, 2013, 369:1691-1703. doi:10.1056/NEJMoa1304369. Median PFS for gemcitabine-alone was 3.7 months; median OS for gemcitabine-alone was 6.7 months. Median PFS for

nab-paclitaxel plus gemcitabine was 5.5 months; median OS for nab-paclitaxel plus gemcitabine was 8.5 months.

• Only 1 case of severe skin irritation related to TTFields

• 4 patients experienced mild to moderate skin irritation

• 9 patients reported severe adverse events unrelated to TTFields therapy

© Novocure 2016 95


planned phase 3 pivotal pancreatic cancer trial • Protocol design in final stages of

development

• First line, locally advanced, non-

resectable, pancreatic cancer

• Patients randomized 1:1 (TTFields

plus nab-paclitaxel + gemcitabine vs

nab-paclitaxel + gemcitabine alone)

• Endpoints include

• Progression-free survival (PFS)

• Overall survival (OS)

• Incidence of down-staging to

resectability

© Novocure 2016 96



Expected 2H 2017 Expected 2 years following first patient enrolled



NEXT STEPS

• Presentation of second cohort data at medical conference targeted for Q2 2017

• Publication of PANOVA data targeted for 2017

ovarian cancer

Eilon Kirson, MD, PhD


Actor portrayal

© Novocure 2016 98

OVARIAN CANCER

disease state and clinical presentation • Accounts for ~3% of cancers among women, but causes more deaths

than any other cancer of the female reproductive system1

• Established risk factors include age and family history, with ~10% of cases occurring in women with BRCA1 and BRCA2 mutations2

• Approximately 85-90% of ovarian cancers arise from the epithelial cell

lining covering the outer surface of the ovary • Early tumors often cause no symptoms or can cause symptoms

similar to other diseases - Only 14.8% of cases are diagnosed at the local stage3

- Symptoms can include swelling or bloating, pelvic or abdominal

pressure, abdominal pain, trouble eating or feeling full quickly, and feeling the need to urinate often or urgently

1. Ovarian Cancer Detailed Guide. Atlanta: American Cancer Society, 2016 2. Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK. Mol Oncol. 2009;3(2):97-137. doi: 10.1016/j.molonc.2009.02.004. 3. SEER Cancer Statistics Factsheets: Ovarian Cancer. National Cancer Institute. Bethesda, MD (accessed December 2016)

© Novocure 2016 99

OVARIAN CANCER

epidemiology

United States 1 Ovarian cancer incidence of 22,000 cases annually

Europe 2

Ovarian cancer incidence of 65,000 cases annually Japan 3

Ovarian cancer incidence of 9,000 cases annually

• Incidence of ovarian cancer is approximately 11.9 per 100,000 women1

• Increases in frequency with age, with median age at time of diagnosis of 63 years old1

1. SEER Cancer Statistics Factsheets: Ovarian Cancer. National Cancer Institute. Bethesda, MD (accessed December 2016) 2. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JWW, Comber H, Forman D, Bray F. Eur J Cancer. 2013;49(6):1374-403. doi: 10.1016/j.ejca.2012.12.027 3. WHO (2016) GLOBOCAN 2012: Estimated Cancer Incidence, Mortality, and Prevalence Worldwide in 2012, Lyon, France (accessed December 2016)

© Novocure 2016 100

RECURRENT OVARIAN CANCER

• Approximately 80% of women with advanced ovarian cancer will have tumor

progression or, more commonly, recurrence1

• Platinum-free interval a strong predictor of treatment success1

- Classified as platinum-resistant if time to recurrence after completion of platinum-

based treatment is <6 months

- At first relapse, ~25% of patients have platinum-resistant cancer

- Almost all patients with recurrent disease ultimately develop resistance

• Platinum-resistant population has a very poor prognosis

- Median progression-free survival (PFS) after recurrence is approximately 3-4 months2

- Median overall survival (OS) after recurrence is approximately 13-14 months2

current prognosis

1. Luvero D, Milani A, Ledermann JA. Therapeutic Advances in Medical Oncology. 2014;6(5):229-239. doi:10.1177/1758834014544121 2. Pujade-Laurain E., et al. J of Clin Onc. 2014; 32(13): 1302-130. doi: 10.1200/JCO.2013.51.4489

© Novocure 2016

recurrent ovarian cancer

platinum-based chemotherapy +/-

paclitaxel

CT q3m until progression

third line chemotherapy

101


• Since 2003, weekly paclitaxel therapy has been the standard of care for patients with

platinum-resistant recurrent ovarian cancer1


- Platinum-based chemotherapy, used in combination with paclitaxel

- At platinum resistance, third-line chemo may include paclitaxel, topotecan, or

pegylated liposomal doxorubicin (PLD)


1. Luvero D, Milani A, Ledermann JA. Therapeutic Advances in Medical Oncology. 2014;6(5):229-239. doi:10.1177/1758834014544121



pelvic array placement

Voloshin, T., et al. (2016), Alternating electric fields (TTFields) in combination with paclitaxel are therapeutically effective against ovarian cancer cells in vitro and in vivo. Int. J. Cancer, 139: 2850–2858. doi:10.1002/ijc.30406

DISTRIBUTION OF TTFIELDS AROUND THE OVARIES



phase 2 pilot INNOVATE trial A prospective, open label, single-arm, non-randomized, multicenter study testing feasibility, safety,

toxicity and preliminary efficacy of TTFields at 200 kHz together with weekly paclitaxel in patients

with recurrent ovarian cancer versus historical controls

• 30 patients in Europe with recurrent ovarian cancer


• Endpoints:

• Primary endpoint — severity and frequency of adverse events, as well as premature

discontinuation of therapy due to skin toxicity


Novocure, Ltd. Safety, Feasibility and Effect of TTFields (200 kHz) Concomitant With Weekly Paclitaxel in Recurrent Ovarian Carcinoma (INNOVATE) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT02244502. NLM Identifier: NCT02244502



INCLUSION CRITERIA

• Histologically confirmed ovarian cancer

• Recurrent ovarian cancer with prior therapy

• >18 years old


• Measurable disease according to RECIST criteria

• ECOG score 0-1


• Adequate bone marrow, liver and renal functions

• No concurrent anti-tumor therapy beyond weekly

paclitaxel

INNOVATE key inclusion and exclusion criteria EXCLUSION CRITERIA

• Meningeal carcinomatosis or known brain mets

• Any other malignancy requiring anti-tumor treatment

in prior 3 years

• Chemotherapy or radiotherapy within 4 weeks prior

to treatment start

• Pregnant or breast feeding

• Significant comorbidities that would prevent

combined therapy (uncontrolled cardiovascular

disease, arrhythmia, infection, psychiatric)

• Implantable electronic medical device

• Grade ≥2 peripheral neuropathy

• Pregnant or breast feeding

Novocure, Ltd. Safety, Feasibility and Effect of TTFields (200 kHz) Concomitant With Weekly Paclitaxel in Recurrent Ovarian Carcinoma (INNOVATE) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT02244502. NLM Identifier: NCT02244502

© Novocure 2016

EFFICACY ENDPOINTS

TTFIELDS WITH PACLITAXEL

PACLITAXEL-ALONE HISTORICAL

CONTROL1

Median PFS 8.9 months 3.9 months*

Median OS Not yet reached 13.2 months

One-year survival rate 61%

105


phase 2 pilot INNOVATE trial results

1. Pujade-Laurain E., et al. J of Clin Onc. 2015; 33(32): 3836-3838. doi: 10.1200/jco.2015.63.1408 * Median PFS reflects the weekly paclitaxel subgroup; Median PFS for all chemotherapies was 3.4 months

• 15 patients experienced mild to moderate skin irritation

• 2 cases of severe skin irritation due to TTFields were reported

• 13 patients reported severe adverse events unrelated to TTFields therapy



clinical milestones and next steps NEXT STEPS

• Presentation of INNOVATE data at medical conference targeted for Q2 2017

• Publication of INNOVATE data targeted for 2017

• Phase 3 pivotal trial design in recurrent ovarian cancer in development

mesothelioma Uri Weinberg, MD, PhD

Vice President of Research & Development

Actor portrayal


MALIGNANT PLEURAL MESOTHELIOMA

disease state and clinical presentation • Rare thoracic solid cancer strongly linked to asbestos exposure1

• Incidence increasing in countries where asbestos still in use2 • Long latency period of at least 20-30 years following exposure2

• Tumors arise from the mesothelial lining of the pleural cavity, and belong to three main histological subtypes: epithelioid (50%), sarcomatoid (10%) or mixed (30-40%)3

• Typical presentation is in older patients with advanced clinical stage and other medical comorbidities - Symptoms can include cough, dyspnea, chest wall pain, pleural

effusion, hoarseness, fatigue, weight loss, excessive sweating, fever, or swelling of the face and arms

- Epithelioid histology responds better to treatments and is associated with better prognosis2

1 Robinson B.M. Ann Cardiothorac Surg. 2012; 1(4): 491–496. doi: 10.3978/j.issn.2225-319X.2012.11.04 2 Ai J. and Stevenson J.P. Oncologist. 2014; 19(9): 975–984. doi: 10.1634/theoncologist.2014-0122 3 Mesothelioma Cancer Detailed Guide. Atlanta: American Cancer Society, 2016.



epidemiology

United States 1 Mesothelioma incidence of 3,000 cases annually

Western Europe 2

Predicted peak incidence of 9,000 male deaths around the year 2018 Japan 3

Mesothelioma estimated incidence of 1,000 cases annually

• Incidence of mesothelioma varies markedly within and between countries3

• Highest annual rates of disease, ~30 cases per 1,000,000, reported in Australia and Great Britain

• With the exception of the U.S., incidence continues to increase worldwide

• Risk is greater in men, resulting from exposure to workplace asbestos and other inhaled silicates 1 SEER Cancer Statistics Review, 1975-2010. Available at http://seer.cancer.gov/csr/1975_2010/. Updated June 14, 2013. 2 Peto J, Decarli A, La Vecchia C, Levi F, Negri E. Br J Cancer 1999;79:666 –72. doi: 10.1038/sj.bjc.6690105 3 Robinson B.M. Ann Cardiothorac Surg. 2012; 1(4): 491–496. doi: 10.3978/j.issn.2225-319X.2012.11.04

http://seer.cancer.gov/csr/1975_2010/



• Malignant pleural mesothelioma generally involves local spread on one

side of the chest

- Stage I-III may be resectable, depending on spread and tissue subtype1

- However, unresectable disease generally involves extensive growth, with

regional lymph node spread and ipsilateral lung tissue involvement

• Given advanced age of patients, comorbidities, and limited treatment

effectiveness, prognosis for malignant pleural mesothelioma remains poor

- Median progression-free survival (PFS) is approximately 6 months2

- Median overall survival (OS) is approximately 12 months2

current prognosis

1 Mesothelioma Cancer Detailed Guide. Atlanta: American Cancer Society, 2016. 2 Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. J Clin Oncol. 2003;21:2636–2644. doi: 10.1200/JCO.2003.11.136

© Novocure 2016

newly diagnosed malignant

pleural mesothelioma

surgical resection/

biopsy

pemetrexed + cisplatin/carboplatin

CT q6w until progression

second line chemotherapy

111


• Since 2003, pemetrexed plus platinum-based therapy (cisplatin or carboplatin) has

been the standard of care for patients with malignant pleural mesothelioma1-3


- Surgical resection, feasible for only a minority of patients

- First-line chemotherapy of pemetrexed plus carboplatin or cisplatin

- Second-line chemotherapies, including oxaliplatin, gemcitabine or vinorelbine


1 Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. J Clin Oncol. 2003;21:2636–2644. doi: 10.1200/JCO.2003.11.136 2 Santoro A, O'Brien ME, Stahel RA, et al. J Thorac Oncol. 2008; 3(7):756-63. doi: 10.1097/JTO.0b013e31817c73d6 3 Ai J. and Stevenson J.P. Oncologist. 2014; 19(9): 975–984. doi: 10.1634/theoncologist.2014-0122


FIRST LINE TREATMENT OF MALIGNANT PLEURAL MESOTHELIOMA

phase 2 pilot STELLAR trial A prospective, open label, single-arm, non-randomized, multicenter study testing safety and

preliminary efficacy of TTFields at 150 kHz together with pemetrexed and cisplatin or carboplatin in

patients with previously untreated malignant pleural mesothelioma versus historical controls

• 80 patients in Europe with unresectable, previously untreated malignant mesothelioma

• Actively recruiting patients since February 2015

• Twelve month follow-up after final patient enrollment

• Endpoints:

• Primary endpoint — overall survival (OS)

• Secondary endpoints — progression free survival (PFS), response rate, treatment-emergent

toxicity

Novocure, Ltd. Safety and Efficacy of TTFields (150 kHz) Concomitant With Pemetrexed and Cisplatin or Carboplatin in Malignant Pleural Mesothelioma (STELLAR) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT02397928. NLM Identifier: NCT02397928



INCLUSION CRITERIA

• Pathologic evidence of malignant pleural

mesothelioma (MPM)

• > 1 evaluable lesion according to RECIST

• ECOG performance status of 0-1

• >18 years old

• Not candidate for curative treatment (surgery or

radiotherapy)



• Required contraceptive use, if applicable

STELLAR key inclusion and exclusion criteria EXCLUSION CRITERIA

• Candidate for curative intent

• Previous chemotherapy or radiation

• Prior malignancy requiring anti-tumor treatment

• Significant comorbidities, esp. liver function

impairment, renal impairment, coagulopathy,

thrombocytopenia, neutropenia or anemia

• Factors affecting prognosis or compliance,

(uncontrolled cardiovascular disease, arrhythmia,

active infection, or psychiatric condition)

• Untreated brain metastases

• Implanted electronic medical devices

• Pregnant

Novocure, Ltd. Safety and Efficacy of TTFields (150 kHz) Concomitant With Pemetrexed and Cisplatin or Carboplatin in Malignant Pleural Mesothelioma (STELLAR) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Dec]. Available from: https://clinicaltrials.gov/ct2/show/NCT02397928. NLM Identifier: NCT02397928



STELLAR key baseline characteristics CHARACTERISTICS (N=42) NUMBER (%)1

Median age, years (range) 67 (43-78)

Gender Male Female

34 (81%) 8 (19%)

ECOG performance status 0 1

27 (64%) 15 (36%)

Caucasian race 42 (100%)

Histology Epithelioid Biphasic Sarcomatoid Unspecified

25 (59%) 5 (12%) 2 (5%)

10 (24%)

Disease stage Stage ≤III Stage IV

36 (86%) 6 (14%)

Past smoker 22 (52%)

1. Cerasoli, G.L. International Association for the Study of Lung Cancer. OA22.01 – STELLAR – Interim Results of a Phase 2 Trial of TTFields with Chemotherapy for First Line Treatment of Malignant Mesothelioma. Oral Session: Novel Trials and Biomarkers in Malignant Pleural Mesothelioma. Wednesday, Dec. 7, 2016, 2:20 p.m. CET



STELLAR incidence of adverse events

1. Cerasoli, G.L. International Association for the Study of Lung Cancer. OA22.01 – STELLAR – Interim Results of a Phase 2 Trial of TTFields with Chemotherapy for First Line Treatment of Malignant Mesothelioma. Oral Session: Novel Trials and Biomarkers in Malignant Pleural Mesothelioma. Wednesday, Dec. 7, 2016, 2:20 p.m. CET

SYSTEM ORGAN CLASS

GRADE 3-4

N (%)1

ALL GRADES

N (%) 1

Hematological disorders Anemia Leukopenia Neutropenia (non-febrile) Thrombocytopenia

11 (26%) 6 (14%) 3 (7%)

6 (14%) 2 (4%)

22 (52%)

General & administration site conditions Fatigue Pain

2 (5%) 1 (2%) 1 (2%)

14 (33%)

Hepatobiliary disorders Hepatoxicity

1 (2%) 1 (2%)

2 (5%)

Respiratory, thoracic & mediastinal disorders Dyspnea

1 (2%) 1 (2%)

7 (17%)

Skin and subcutaneous tissue disorders

Rash

Skin irritation

2 (5%) 1 (2%) 1 (2%)

23 (55%)

SYSTEM ORGAN CLASS

GRADE 3-4

N (%) 1

ALL GRADES

N (%) 1

Gastrointestinal disorders 0 14 (33%) Infections and infestations 0 6 (14%) Injury, poisoning and procedural 0 1 (2%) Metabolism and nutrition 0 2 (5%)

Musculoskeletal and connective tissue 0 2 (5%) Nervous system 0 2 (5%) Psychiatric disorders 0 1 (2%) Renal and urinary disorders 0 1 (2%) Vascular disorders 0 3 (7%)



phase 2 pilot STELLAR trial results

EFFICACY ENDPOINTS

TTFIELDS WITH PEMETREXED AND

CISPLATIN OR CARBOPLATIN1

PEMETREXED AND CISPLATIN-ALONE

HISTORICAL CONTROL2

Median PFS 7.3 months 5.7 months

Median OS Not yet reached 12.1 months

One-year survival rate 79.7% 50.3% Interim data presented at IASLC in December 2016 with a cutoff date of July 12, 2016 1. Cerasoli, G.L. International Association for the Study of Lung Cancer. OA22.01 – STELLAR – Interim Results of a Phase 2 Trial of TTFields with Chemotherapy for First Line Treatment of Malignant

Mesothelioma. Oral Session: Novel Trials and Biomarkers in Malignant Pleural Mesothelioma. Wednesday, Dec. 7, 2016, 2:20 p.m. CET 1 Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. J Clin Oncol. 2003;21:2636–2644. doi: 10.1200/JCO.2003.11.136



phase 2 pilot STELLAR trial results PROGRESSION-FREE SURVIVAL (N=42) OVERALL SURVIVAL (N=42)




Enrolled in February 2015

54 of 80 patients enrolled

Expected in 2017



NEXT STEPS

• Last patient enrollment anticipated in 2017

• Following last patient enrollment, 12 month follow up with data presentation

expected in 2018

what’s next for TTFields Eilon Kirson, MD, PhD


© Novocure 2016

• Incidence of approximately 39,000 new cases in US annually1

• Standard-of-care treatments include

- Surgery, ablation (chemical/thermal/microwave/cryoablation)

- Arterially directed therapies (embolization)

- EBRT

- Sorafenib

• Significant unmet medical need

- Most cases diagnosed at advanced stage

- Median OS only 6-20 months with five-year survival rate of 17.5%1

• TTFields intensity in the liver and surrounding tissues especially high (>3 V/cm)

• Hepatocellular carcinoma cells are sensitive to TTFields in-vitro (200 kHz)

• Loco-regional therapies have led to improved outcomes

unresectable hepatocellular carcinoma

1. SEER Cancer Statistics Factsheets: Liver and Intrahepatic Bile Duct Cancer. National Cancer Institute. Bethesda, MD, (accessed December 2016)

120


• Incidence of approximately 26,000 new cases in the US annually

• Standard-of-care treatments include

- Surgery

- Radiation therapy

- 5-FU/Capecitabine + cisplatin/oxaliplatin OR paclitaxel/docetaxel + cisplatin/carboplatin

• Significant unmet medical need worldwide

- In Asian countries, incidence can be up to 10 fold higher than in the US (South Korea)

- Majority of patients diagnosed as having advanced disease

- Median OS only 5-8 months with five-year survival rates of 20-30%1

• TTFields intensity in the gastric/esophageal regions is very high (>3 V/cm)

• Gastric cancer cells sensitive to TTFields in-vitro (150 kHz)

• Loco-regional control may lower morbidity and lead to prolonged disease control

advanced gastric cancer

1. SEER Cancer Statistics Factsheets: Stomach Cancer. National Cancer Institute. Bethesda, MD (accessed December 2016).

© Novocure 2016

• Term “brain stem glioma” is a generic description referring to any tumor of glial origin

arising in the brain stem, inclusive of the midbrain, pons, and medulla

• Two predominant histologies:

- Diffuse (infiltrating) astrocytomas centered in the pons, also called diffuse intrinsic

pontine glioma (DIPG)

- Pilocytic astrocytomas, which occur throughout the brain stem

• Incidence:

- Approximately 300 to 400 pediatric brain stem tumors diagnosed annually in the U.S.1

- DIPG accounts for approximately 75% to 80% of pediatric brain stem tumors1

- Most children with DIPG are diagnosed between the ages of 5 and 10 years1

- Focal pilocytic astrocytomas in the brain stem occur less frequently1

pediatric brain stem glioma

1. Warren KE. Frontiers in Oncology. 2012;2:205. doi:10.3389/fonc.2012.00205.

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POTENTIAL APPLICATION FOR BOTH ADULTS AND PEDIATRICS

brain stem glioma

© Novocure 2016

breast cancer prevention in BRCA1/2 women

124

© Novocure 2016

prophylactic breast cancer therapy

125

Novocure engineering Mike Ambrogi

Chief Operating Officer


second generation Optune system • Received FDA approval of PMA supplement on July 13, 2016

• Half the size and weight of the first generation Optune system, weighing 2.7 pounds

• Anecdotal reports suggest improved patient compliance and acceptance


tan transducer arrays • Developing less conspicuous

transducer array color in

response to patient requests

• In final stages of

development, with targeted

release in 2017 (pending

regulatory approval)

Actor portrayal


second generation transducer arrays • Developing streamlined transducer array with goal of minimizing impact of wires

• Designed to improve overall aesthetics of the array through the use of new materials


the connected patient • Using secure infrastructure,

planning mobile platform

intended to improve patient

communications

• Initial goal of collecting device

data for compliance reporting

and diagnostics

closing comments

William Doyle

Executive Chairman

Documents

Novocure (NVCR) R&D Day · Prof. Zvi Ram serves as the Chairman of the Department of Neurosurgery at Tel Aviv Medical Center in Israel. After completion of his neurosurgical residency