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Item 1. Business

2021-02-25 compared with 2020-02-27 · 260 added, 244 removed, 324 unchanged (61% of the section changed)

We are a global oncology company with a proprietary platform technology called Tumor Treating Fields, the use of electric fields tuned to specific frequencies to disrupt solid tumor cancer cell division.

Our key priorities are to drive commercial adoption of Optune and NovoTTF-100L, our commercial Tumor Treating Fields delivery systems, and to advance clinical and product development programs intended to extend overall survival in some of the most aggressive forms of cancer.

We are a global oncology company with a proprietary platform technology called Tumor Treating Fields ("TTFields"), which are electric fields tuned to specific frequencies that disrupt cancer cell division.

Our key priorities are to drive commercial adoption of Optune and Optune Lua, our commercial TTFields delivery systems, and to advance clinical and product development programs intended to extend overall survival in some of the most aggressive forms of cancer.

Optune is approved by the U.S.

Food and Drug Administration ("FDA") under the Premarket Approval ("PMA") pathway for the treatment of adult patients with newly diagnosed GBM in combination with temozolomide, a chemotherapy drug, and for adult patients with GBM following confirmed recurrence after chemotherapy as monotherapy treatment.

Food and Drug Administration ("FDA") under the Premarket Approval ("PMA") pathway for the treatment of adult patients with newly diagnosed gioblastoma ("GBM") in combination with temozolomide, a chemotherapy drug, and for adult patients with GBM following confirmed recurrence after chemotherapy as monotherapy treatment.

We also have approval or a CE certificate to market Optune for the treatment of GBM in the European Union ("EU"), Japan and certain other countries.

NovoTTF-100L is approved by the FDA under the Humanitarian Device Exemption ("HDE") pathway to treat MPM in combination with standard chemotherapies.

We have submitted an application for CE certification to market NovoTTF-100L in the EU.

We market Optune in the U.S., Austria, Germany, Israel, Japan, Sweden and Switzerland, which we refer to as our "active markets," and we market NovoTTF-100L in the U.S.

With respect to GBM, our sales and marketing efforts are principally focused on driving adoption with both neuro-oncologists and radiation oncologists.

With respect to MPM, our commercial efforts are principally focused on generating awareness with radiation oncologists and on establishing a dialogue with third-party payers around access to NovoTTF-100L.

We market Optune in the U.S., Austria, Germany, Israel, Japan, Sweden and Switzerland, which we refer to as our "active markets." With respect to GBM, our sales and marketing efforts are principally focused on driving adoption with both neuro-oncologists and radiation oncologists.

We are expanding our commercial operations into France with an initial focus on developing key opinion leader relationships in GBM and establishing a path to reimbursement for our Products.

We believe the mechanism of action behind Tumor Treating Fields therapy may be broadly applicable to solid tumor cancers.

Currently, we are conducting phase 3 pivotal trials evaluating the use of Tumor Treating Fields in non-small-cell lung cancer ("NSCLC"), brain metastases from NSCLC ("brain metastases"), pancreatic cancer and ovarian cancer.

We are also conducting phase 2 pilot trials evaluating the use of Tumor Treating Fields in liver cancer and gastric cancer.

We anticipate expanding our clinical pipeline over time to study the safety and efficacy of Tumor Treating Fields for additional solid tumor indications.

We plan to initiate at least one additional randomized, well-controlled clinical trial in GBM in order to further advance the scientific evidence supporting the use of Optune in GBM and to gather additional information about Optune's optimal use.

The first trial planned will study the potential clinical benefit of initiating Optune concurrent with radiation therapy versus following radiation therapy.

Our therapy is delivered through a medical device and we have several product development programs underway intended to improve efficacy and usability for patients.

Optune Lua is approved by the FDA under the Humanitarian Device Exemption ("HDE") pathway to treat malignant pleural mesothelioma ("MPM") in combination with standard chemotherapies.

We have received CE certification to market Optune Lua (under the name " NovoTTF-100L ") in the EU and Switzerland.

We currently market Optune Lua in the U.S., and are evaluating plans to expand access to our therapy for MPM patients in other markets.

With respect to MPM, our commercial efforts are principally focused on generating awareness and on establishing a dialogue with third-party payers around access to Optune Lua.

We believe the mechanism of action behind TTFields therapy may be broadly applicable to solid tumor cancers.

Currently, we are conducting phase 3 pivotal trials evaluating the use of TTFields in brain metastases from non-small cell lung cancer ("brain metastases"), non-small cell lung cancer ("NSCLC"), ovarian cancer and pancreatic cancer.

In 2020, we enrolled our first patient in our global phase 4 TRIDENT trial to test the potential survival benefit of initiating Optune concurrent with radiation therapy versus following radiation therapy in patients with newly diagnosed GBM.

We are also conducting phase 2 pilot trials evaluating the use of TTFields in liver cancer and gastric cancer, as well as testing the potential incremental survival benefit of TTFields delivered using high-intensity arrays versus standard arrays.

We anticipate expanding our clinical pipeline over time to study the safety and efficacy of TTFields for additional solid tumor indications and combinations with other cancer treatment modalities.

In the second quarter of 2021, we plan to launch the KEYNOTE B36 trial ("KEYNOTE B36"), a phase 2 pilot trial to study TTFields with pembrolizumab in first-line NSCLC through our clinical trial collaboration with MSD (a tradename of Merck & Co., Inc.).

Our therapy is delivered through a medical device and we continue to advance our Products with the intention to extend survival and maintain quality of life for patients.

We have several product development programs underway that prioritize impact on both TTFields dose and patient ease of use.

Our intellectual property portfolio contains over 185 issued patents and numerous patent applications pending worldwide.

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("Zai") a license to commercialize Optune in China, Hong Kong, Macau and Taiwan ("Greater China") under a License and Collaboration Agreement (the "Zai Agreement").

The Zai Agreement also establishes a development partnership intended to accelerate the development of Tumor Treating Fields in multiple solid tumor cancer indications.

The Zai Agreement also establishes a development partnership intended to accelerate the development of TTFields in multiple solid tumor cancer indications.

For additional information, see Note 12 to the Consolidated Financial Statements.

Our ordinary shares are quoted on the NASDAQ Global Select Market under the symbol "NVCR." We were incorporated in the Bailiwick of Jersey in 2000.

Our principal operations are located in the U.S., Israel and Switzerland.

Tumor Treating Fields is a cancer therapy that uses electric fields tuned to specific frequencies to disrupt cell division, inhibiting tumor growth and causing affected cancer cells to die.

Our track record of fundamental scientific research extends across two decades and, in all of our preclinical research to date, Tumor Treating Fields has demonstrated a consistent anti-mitotic effect.

In our clinical research and commercial experience to date, Tumor Treating Fields has exhibited no systemic toxicity, with mild to moderate skin irritation being the most common side

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Tumor Treating Fields is intended principally for use in combination with other standard-of-care cancer treatments.

Recognizing what electric fields are and how they can be utilized for medical applications is essential to understanding Tumor Treating Fields.

An electric field is a field of force.

Electric fields surround all charged objects.

An electric field exerts forces on charged objects within it.

Tumor Treating Fields uses alternating electric fields specifically tuned to target cancer cells.

Once the electric fields enter the cancer cell, they attract and repel charged proteins during cancer cell division.

Tumor Treating Fields utilizes the natural electrical properties of dividing cancer cells.

While many intracellular molecules are slightly polarized or neutral, some are highly polarized and are strongly affected by Tumor Treating Fields.

For example, tubulin is a highly polarized cellular protein that must orient spatially to form the mitotic spindle, which segregates chromosomes into two daughter cells during mitosis.

Tumor Treating Fields exerts forces on tubulin, disrupting mitotic spindle formation and causing probable cell death.

Septin is another highly polarized molecule in cells that must orient spatially to form the contractile ring needed to split daughter cells during mitosis.

Tumor Treating Fields exerts forces on septin, leading to improper localization of the contractile ring.

This process causes membrane blebbing, a sign of cell damage that may result in cell death.

In addition to its anti-mitotic effect, Tumor Treating Fields has been shown to inhibit DNA damage repair, to induce autophagy, to reduce cell migration and invasion, to increase cell membrane permeability and disrupt the blood-brain barrier, and to induce immunogenic cell death.

Research is ongoing to enhance our understanding of the multi-pronged mechanism behind Tumor Treating Fields.

We provide independent researchers a preclinical laboratory bench system, known as inovitro™, and we grant funding to support basic and translational research on Tumor Treating Fields.

We believe Tumor Treating Fields causes minimal damage to healthy cells surrounding affected cancer cells.

Tumor Treating Fields does not stimulate or heat tissue and targets dividing cancer cells with specific characteristics, such as size.

Tumor Treating Fields is regionally delivered to the tumor site rather than systemically delivered throughout the body and, as a result, the parts of the body not covered by Tumor Treating Fields are generally not affected.

Our principal operations are located in Switzerland, the U.S.

When cancer develops, rapid and uncontrolled division of unhealthy cells occurs.

Electrically charged proteins within the cell are critical for cell division, making the rapidly dividing cancer cells vulnerable to electrical

interference.

TTFields therapy is a cancer treatment that uses electric fields tuned to specific frequencies to disrupt cancer cell division.

All cells are surrounded by a bilipid membrane, which separates the interior of the cell, or cytoplasm, from the space around it.

This membrane prevents low frequency electric fields from entering the cell.

TTFields, however, have a unique frequency range, between 100 to 500 kHz, enabling the electric fields to penetrate the cancer cell membrane.

As healthy cells differ from cancer cells in their division rate, geometry and electric properties, the frequency of TTFields can be tuned to specifically affect the cancer cells while leaving healthy cells mostly unaffected.

Whether cells are healthy or cancerous, cell division, or mitosis, is the same.

When mitosis starts, charged proteins within the cell, or microtubules, form the mitotic spindle.

The spindle is built on electric interaction between its building blocks.

During division, the mitotic spindle segregates the chromosomes, pulling them in opposite directions.

As the daughter cells begin to form, electrically polarized molecules migrate towards the midline to make up the mitotic cleavage furrow.

The furrow contracts and the two daughter cells separate.

TTFields can interfere with these conditions.

When TTFields are present in a dividing cancer cell, they cause the electrically charged proteins to align with the directional forces applied by the field, thus preventing the mitotic spindle from forming.

Electrical forces also interrupt the migration of key proteins to the cell midline, disrupting the formation of the mitotic cleavage furrow.

Interfering with these key processes disrupts mitosis and can lead to cell death.

Our track record of fundamental scientific research extends across two decades and, in all of our preclinical research to date, TTFields has demonstrated a consistent anti-mitotic effect.

Research is ongoing to further refine our understanding of the multi-pronged mechanism of action of TTFields.

In addition to its anti-mitotic effect, TTFields has been shown to inhibit DNA damage repair, to induce autophagy, to reduce cell migration and invasion, to increase cell membrane permeability and disrupt the blood-brain barrier, and to induce immunogenic cell death.

Beyond our internal research efforts, we provide independent researchers with preclinical laboratory bench systems, known as inovitro™ and inovivo™, and we grant funding to support basic and translational research on TTFields.

We also support independent research through our Investigator-Sponsored Trials and Preclinical Material Transfer Agreement programs in order to enhance our understanding of the optimal use of TTFields.

TTFields is intended principally for use in combination with other standard-of-care cancer treatments.

There is a growing body of evidence that supports TTFields' broad applicability with certain other cancer therapies, including radiation therapy, certain chemotherapies and certain immunotherapies.

In our clinical research and commercial experience to date, TTFields has exhibited no systemic toxicity, with mild to moderate skin irritation being the most common side effect.

Our technology

Treatment with Tumor Treating Fields is delivered through a portable medical device.

The complete delivery system, called Optune or NovoTTF-100L, includes a portable electric field generator, transducer arrays, rechargeable batteries and accessories.

Sterile, single-use transducer arrays are placed directly on the skin in the region surrounding the tumor and connected to the electric field generator to deliver therapy.

Transducer arrays are changed when hair growth or the hydrogel reduces array adhesion to the skin.

TTFields therapy is delivered through a portable medical device.

The complete delivery system, called Optune or Optune Lua, includes a portable electric field generator, arrays, rechargeable batteries and accessories.

Sterile, single-use arrays are placed directly on the skin in the region surrounding the tumor and connected to the electric field generator to deliver therapy.

Arrays are changed when hair growth or the hydrogel reduces array adhesion to the skin.

The therapy is designed to be delivered continuously throughout the day and night, and efficacy is strongly correlated to time on therapy.

If the device is not on, the patient is not being treated.

When the device is turned on, TTFields are continuously generated within the specific region of the body covered by the arrays.

Healthy tissues located outside of this region remain unaffected by the therapy.

The electric field generator can be run from a standard power outlet or carried with a battery in a specially designed bag that we provide to patients.

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We plan to specifically target individual solid tumor types by optimizing field generator parameters such as frequency and power output.

Our transducer arrays have been developed and are in use, either commercially or clinically, for application on the head, chest and abdomen.

Through engineering efforts, we plan to continue to enhance our Products to improve efficacy and usability for patients.

Our engineering efforts are primarily focused on innovations to the portable electric field generator, transducer arrays and treatment planning software.

We are developing a second generation torso system, a flexible torso transducer array, a high intensity transducer array, a remote download capability for the monthly usage report and next generation transducer array layout planning software.

Our arrays have been developed and are in use, either commercially or clinically, for application on the head, chest and abdomen.

Through engineering efforts, we plan to continue to advance our Products to optimize TTFields therapy for patients.

We have several product development programs underway intended to extend survival and maintain quality of life.

Our development programs will prioritize impact on both TTFields dose and patient ease of use and are primarily focused on enhancements to the field generator, arrays and software applications.

We are developing a third generation device to optimize the use of electric fields to treat tumors, next generation arrays to be more flexible and deliver higher intensities, next generation array layout planning software, and patient-centered software to support larger patient populations in multiple indications.

Over time, we may have the opportunity to optimize the energy delivered to individual patients, potentially improving efficacy.

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Optune is currently marketed in our active markets for the treatment of GBM, the most common form of primary brain cancer and an aggressive disease for which there are few effective treatment options.

NovoTTF-100L is currently marketed in the U.S.

for the treatment of MPM, a rare cancer that has been strongly linked to asbestos

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Optune Lua is currently marketed in the U.S.

for the treatment of MPM, a rare cancer that has been strongly linked to asbestos exposure.

Our first commercial priority in each active market is to generate awareness of our Products and our clinical trial data.

EF-14 phase 3 pivotal clinical trial data for the treatment of newly diagnosed GBM

Treatment of newly diagnosed GBM

In 2015, we received FDA approval to market Optune for the treatment of adult patients with newly diagnosed supratentorial GBM in combination with temozolomide.

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A post-hoc analysis of EF-14 showed that more time on Optune predicted increased survival in GBM patients.

An Optune monthly usage threshold as low as 50 percent correlated with significantly improved outcomes in patients treated with Optune together with temozolomide compared to patients treated with temozolomide alone.

An Optune monthly usage threshold as low as 50 percent correlated with significantly improved outcomes in patients

treated with Optune together with temozolomide compared to patients treated with temozolomide alone.

The greater the patients’ monthly usage of Optune, the better their outcomes.

Patients who used Optune more than 90 percent

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of the time (n=43) had the greatest chance of survival:

Patients who used Optune more than 90 percent of the time (n=43) had the greatest chance of survival:

a median survival of 24.9 months from randomization and a five-year probability of survival of 29.3 percent.

In 2018, a separate post-hoc analysis of EF-14 showed that higher levels of energy at the tumor bed predicted increased survival in GBM patients.

Patients treated with Optune at higher energy levels (power loss densities greater than or equal to 1.1 mW/cm 3;

n=122) had a median overall survival of 25.2 months compared to a median overall survival of 21.0 months for patients treated with Optune at lower energy levels (power loss densities less than 1.1 mW/cm 3 ;

In these analyses, both time on therapy and higher levels of energy (or higher power loss density) were associated with improved overall survival, independent of each other.

Patients who used Optune more than 20 hours per day at higher energy levels (n=36) had a median overall survival of 37 months (95% CI 21-48 months).

For Optune, dose density can be defined as time on therapy times the energy delivered, or cumulative energy

EF-11 phase 3 pivotal clinical trial data for the treatment of recurrent GBM

In 2019, a separate post-hoc analysis of EF-14 showed that higher intensities at the tumor bed were associated with increased survival in GBM patients.

Patients treated with Optune at higher intensities (greater than or equal to 1.06 V/cm;

n=119) had a median overall survival of 24.3 months compared to a median overall survival of 21.6 months for patients treated with Optune at lower intensities (less than 1.06 V/cm;

In these analyses, both time on therapy and higher levels of energy (power loss density) were associated with improved overall survival, independent of each other.

In addition, patients who used Optune at least 18 hours per day at higher energy levels (n=78) had a median overall survival of 25.1 months (95% CI 20.8-39.4).

Treatment of recurrent GBM

We initially received FDA approval for Optune in 2011 for use as a monotherapy treatment for adult patients with GBM, following confirmed recurrence after chemotherapy.

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Participants received either Optune as a monotherapy (n=120) or the physician’s choice of chemotherapy (n=117).

Chemotherapies chosen for the active control arm included mainly bevacizumab, nitrosureas and temozolomide.

Chemotherapies chosen for the active control arm included mainly bevacizumab, nitrosoureas and temozolomide.

The primary endpoint was superiority in overall survival.

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The trial demonstrated that Optune provided clinically comparable survival with an overall better quality of life.

Twice as many EF-11 patients responded to Optune than to active chemotherapy (12 patients versus 6 patients).

More objective radiological responses were observed in the Optune group than in the active control chemotherapy group (14 patients versus 7 patients).

Three patients in the Optune alone arm had a complete response versus no patients in the active chemotherapy arm.

STELLAR phase 2 registration trial data for the treatment of MPM

In 2019, we received FDA approval via the HDE pathway to market NovoTTF-100L for the treatment of adult patients with unresectable, locally advanced or metastatic MPM concurrent with pemetrexed and platinum-based chemotherapy.

The FDA approved NovoTTF-100L for MPM based on the STELLAR trial ("STELLAR").

In 2020, the FDA-mandated EF-19 post-approval registry trial confirmed the effectiveness and safety of Optune as monotherapy and further strengthened Optune's clinical profile in recurrent GBM.

The EF-19 trial studied Optune as a monotherapy for the treatment of recurrent GBM in 192 patients compared to the 117 recurrent GBM patients who received best standard of care chemotherapy in Novocure’s EF-11 registration trial.

Optune as monotherapy reduced the risk of death with fewer adverse events compared to best standard of care chemotherapy.

For patients who received at least one course of therapy, Optune prolonged survival by a median 1.7 months.

No new safety signals were noted.

Treatment of MPM

In 2019, we received FDA approval via the HDE pathway to market Optune Lua (then known as NovoTTF-100L) for the treatment of adult patients with unresectable, locally advanced or metastatic MPM concurrent with pemetrexed and platinum-based chemotherapy.

The FDA approved Optune Lua for MPM based on the STELLAR trial ("STELLAR").

STELLAR was a single-arm, open-label, multi-center trial designed to test the safety and efficacy of Optune in combination with pemetrexed combined with cisplatin or carboplatin in patients with unresectable, previously untreated MPM.

The trial was powered to prospectively determine the overall survival in patients treated with NovoTTF-100L plus chemotherapy.

The trial was powered to prospectively determine the overall survival in patients treated with Optune Lua plus chemotherapy.

Secondary endpoints included overall response rate (per mRECIST criteria), progression-free survival and safety.

STELLAR investigated safety and efficacy among 80 patients treated with NovoTTF-100L plus standard of care chemotherapy.

In STELLAR, the median overall survival was 18.2 months (95% CI, 12.1-25.8 months) across all patients treated with NovoTTF-100L plus chemotherapy.

STELLAR investigated safety and efficacy among 80 patients treated with Optune Lua plus standard of care chemotherapy.

In STELLAR, the median overall survival was 18.2 months (95% CI, 12.1-25.8 months) across all patients treated with Optune Lua plus chemotherapy.

The median overall survival was 21.2 months for patients with epithelioid MPM (n=53) and 12.1 months for patients with non-epithelioid MPM (n=27).

62% of patients enrolled in STELLAR who used NovoTTF-100L plus chemotherapy were still alive at one year, with 42% of patients alive at two years.

62% of patients enrolled in STELLAR who used Optune Lua plus chemotherapy were still alive at one year, with 42% of patients alive at two years.

The disease control rate in patients with at least one follow-up CT scan performed (n=72) was 97%.

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The median progression-free survival was 7.6 months (95% CI, 6.7-8.6 months).

There was no increase in serious systemic adverse events when NovoTTF-100L was added to chemotherapy.

Mild-to-moderate skin irritation was the only device-related side effect with NovoTTF-100L.

There was no increase in serious systemic adverse events when Optune Lua was added to chemotherapy.

Mild-to-moderate skin irritation was the only device-related side effect with Optune Lua.

The STELLAR data were published in The Lancet Oncology in 2019.

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We have built a commercial organization and market Optune for the treatment of GBM in the U.S., Austria, Germany, Israel, Japan, Sweden and Switzerland, which we refer to as our active markets.

We have also built a commercial organization to market NovoTTF-100L for the treatment of MPM in the U.S.

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We have also built a commercial organization to market Optune Lua for the treatment of MPM in the U.S.

In 2021, we estimate that approximately:

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We estimate that approximately 900 of eligible patients will actively seek treatment.

In 2020, we estimate that approximately 3,000 people are diagnosed with MPM in the U.S.

Of this population, we estimate that approximately 2,400 patients are candidates for treatment with NovoTTF-100L based upon the rate of disease progression and medical eligibility.

We believe there are many more patients who could benefit from treatment with Tumor Treating Fields than are currently on therapy.

In 2021, we estimate that approximately 3,000 people are diagnosed with malignant mesothelioma in the U.S.

Of this population, we estimate that approximately 1,600 patients are candidates for treatment with Optune Lua based upon the rate of disease progression and medical eligibility.

We believe there are many more patients who could benefit from treatment with TTFields than are currently on therapy.

We continue to focus on increasing penetration for GBM in our active markets and on successfully expanding our MPM business in the U.S.

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Commercial execution

As of December 31, 2020, we had 84 sales force colleagues globally.

Healthcare providers must undergo a certification training in order to prescribe our Products.

As of December 31, 2020, we trained more than 3,700 GBM prescribers in our active markets.

We believe these prescribers treat the majority of GBM patients in our active markets.

We have initiated a phased launch for MPM shaped by our learnings from our GBM rollout.

As of December 31, 2019, we trained 36 MPM prescribers in the U.S.

As of December 31, 2019, we had more than 80 sales force colleagues globally.

With respect to the treatment of GBM, our sales and marketing efforts are principally focused on driving adoption with both neuro-oncologists and radiation oncologists.

In certain countries, neurosurgeons and medical oncologists also drive adoption.

With respect to the treatment of MPM, our sales and marketing efforts are principally focused on certification training and supporting the required Institutional Review Board ("IRB") approval process.

Radiation oncologists are the exclusive prescribers in the U.S.

for the treatment of MPM.

We believe that radiation oncologists will continue to play an increasingly important role in driving adoption of our Products in both current and future indications.

We continue to focus on driving key academic center engagement in our active markets.

As of December 31, 2020, we trained more than 130 MPM prescribers in the U.S.

With respect to the treatment of MPM, our sales and marketing efforts are principally focused on certification training, supporting the required Institutional Review Board approval process, and driving awareness among radiation oncologists and thoracic oncologists.

We believe the benefit of our education efforts will extend beyond MPM to future indications treated by the same prescribers and that radiation oncologists will continue to play an increasingly important role in driving adoption of our Products in both current and future indications.

We currently operate as a direct-to-patient distributor of our Products in all active markets except for Japan.

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Once treatment is initiated, we provide 24/7 technical support for patients and caregivers as well as assistance with insurance reimbursement.

We also provide the healthcare provider and the patient with a monthly usage report for monitoring patient time on therapy.

We also provide the healthcare provider and the patient with a usage report for monitoring patient

time on therapy.

We believe we have the experience, expertise and infrastructure to scale our sales and marketing efforts in our active markets.

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We provide our Products directly to patients following receipt of a prescription order and a signed patient service agreement (except in Japan as described above).

The number of active patients on therapy is our principal revenue

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The number of active patients on therapy and the amount of net revenue recognized per active patient are our principal revenue drivers.

An active patient is a patient who is receiving treatment under a commercial prescription order as of the measurement date, including patients who may be on a temporary break from treatment and who plan to resume treatment in less than 60 days.

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We continue to work with payers to expand access to Optune for patients with GBM.

As of December 31, 2019, a substantial majority of Americans with private health insurance had coverage of Optune for newly diagnosed GBM and/or recurrent GBM.

As of December 31, 2020, we have received national reimbursement for Optune in Austria, Germany, Israel, Japan, Sweden and Switzerland, where coverage becomes effective on April 1, 2021.

In the U.S., a substantial majority of Americans with private health insurance had coverage of Optune for newly diagnosed GBM and/or recurrent GBM as of December 31, 2020.

As of September 2019, Americans who are beneficiaries of the Medicare fee-for-service program also have coverage of Optune for newly diagnosed GBM.

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We are actively appealing Medicare fee-for-service coverage denials up to and including the Administrative Law Judge ("ALJ") process with Centers for Medicare and Medicaid Services ("CMS").

In Germany, we bill healthcare payers for individual cases, and each case is evaluated individually on its merits and under the payer’s specific rules for such cases.

In 2019, the German Institute for Quality and Efficiency in Healthcare ("IQWiG") published its rapid report concluding that, based on a review of EF-14 data, patients with newly diagnosed GBM lived longer when treated with Optune in addition to standard chemotherapy without affecting quality of life.

According to the published timeline, we now expect a national reimbursement decision in Germany no later than October 2020.

We will continue to bill payers for individual cases as we advance through the review process in Germany.

We have received national reimbursement for Optune in Austria, Israel, Japan and Sweden.

We are pursuing national reimbursement for Optune in Switzerland.

As of December 31, 2019, the total number of contracted GBM lives was approximately 263 million in the U.S., approximately 19 million in our active EMEA markets and approximately 127 million in Japan.

We are engaged in an initial dialogue with certain payers regarding access to NovoTTF-100L for patients with MPM.

We are engaged in an initial dialogue with certain payers regarding access to Optune Lua for patients with MPM.

We anticipate that MPM claims during initial commercialization will go through an appeal process with payers, similar to our early experience with GBM.

We anticipate that our ability to gain meaningful coverage for NovoTTF-100L will be dependent on inclusion in the relevant clinical guidelines for MPM.

Our clinical pipeline

Based on the results of our preclinical research, we have developed a pipeline strategy to advance Tumor Treating Fields through phase 2 pilot, phase 3 pivotal trials and phase 4 post-marketing studies across multiple solid tumor types.

We anticipate that our ability to gain meaningful coverage for Optune Lua will be dependent on inclusion in the relevant clinical guidelines for MPM.

Our development pipeline

Based on the results of our preclinical research, we have developed a pipeline strategy to advance TTFields through phase 2 pilot, phase 3 pivotal trials and phase 4 post-marketing studies across multiple solid tumor types.

We anticipate expanding our clinical pipeline over time to include additional solid tumor cancer indications.

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Current Clinical Pipeline

The solid tumor cancers subject to our phase 2 pilot and phase 3 pivotal trials, as well as the trials themselves, are described in greater detail below.

Current Development Pipeline

The solid tumor cancers subject to our phase 2 pilot, phase 3 pivotal, and phase 4 post-marketing trials, as well as the trials themselves, are described in greater detail below.

We continue to conduct research in our approved indications to further advance the scientific evidence supporting the use of TTFields in GBM and to gather additional information about our therapy's optimal use.

EF-33 phase 2 pilot trial

In 2020, we enrolled the first patient in our EF-33 trial, an open-label, single-arm phase 2 pilot clinical trial to study if Optune delivered at 200 kHz to the brain using high-intensity arrays in the treatment of recurrent GBM significantly improves the clinical outcomes of patients compared to using standard transducer arrays.

The primary endpoint is progression-free survival.

Secondary endpoints include overall survival, progression-free survival rate at six months, overall survival rate at one year and two years, overall radiological response, and severity and frequency of adverse events.

All comparisons will be made against historical control data from the EF-11 study.

EF-33 is expected to enroll 25 patients and we anticipate data will be available in 2022.

TRIDENT phase 4 post-marketing trial

In 2020, we enrolled the first patient in our TRIDENT trial ("TRIDENT"), a phase 4 post-marketing trial testing the potential survival benefit of initiating Optune concurrent with radiation therapy in patients with newly diagnosed GBM.

The primary endpoint is overall survival.

Secondary endpoints include progression-free survival, survival rates at one and two years, overall radiological response, severity and frequency of adverse effects, pathological changes in resected GBM tumors post treatment, quality of life, and correlation of overall survival to TTFields dose.

TRIDENT is designed to accrue 950 patients with 24 months minimum follow-up after the last patient enrolled.

Brain metastases

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The exact incidence of brain metastases is unknown because no national cancer registry documents brain metastases, and estimates from scientific literature vary greatly based on the study methodology applied.

However, it has been estimated that up to 200,000 new cases are diagnosed in the U.S.

Brain metastases occur in roughly 20% of all cancer patients, and we believe that between 25 to 40% of patients with NSCLC develop brain metastases.

It is estimated that between 100,000 and

240,000 new cases are diagnosed in the U.S.

each year with brain metastases estimated to occur in between 10% to 40% of all cancer patients.

Brain metastases are commonly treated with a combination of surgery and radiation.

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This practice results in a window of unmet need after localized surgery and SRS are used and before whole brain radiation therapy is administered to delay or prevent the additional spread of brain metastases.

Phase 3 pivotal trial

In 2016, we enrolled the first patient in our METIS trial ("METIS"), a phase 3 pivotal trial testing the effectiveness of SRS plus Tumor Treating Fields compared to SRS alone in patients with brain metastases resulting from NSCLC.

METIS phase 3 pivotal trial

In 2016, we enrolled the first patient in our METIS trial ("METIS"), a phase 3 pivotal trial testing the effectiveness of SRS plus TTFields compared to SRS alone in patients with brain metastases resulting from NSCLC.

It is estimated that between 20 to 40% of patients with NSCLC develop brain metastases, with an estimated 38,000 to 77,000 patients diagnosed each year in the U.S.

with brain metastases resulting from NSCLC.

The primary endpoint of METIS is time to first intracranial progression.

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The study is designed to accrue 270 patients with data analyzed 12 months after the last patient in.

The majority of clinical sites were on board leading into 2019, but per site enrollment has been slower than anticipated.

We are now focused on accelerating enrollment at each clinical site and are working closely with investigators to ensure they have the tools and resources needed to effectively communicate the trial protocol to as many eligible patients as possible.

We anticipate data will be available in 2022.

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Lung cancer is the most common cause of cancer-related death worldwide, and NSCLC accounts for approximately 85% of all lung cancers.

The incidence of NSCLC is approximately 193,000 new cases annually in the U.S., approximately 400,000 new cases annually in Europe, and approximately 101,000 new cases annually in Japan.

It is estimated that approximately 193,000 patients are diagnosed with NSCLC each year in the U.S.

Physicians use different combinations of surgery, radiation and pharmacological therapies to treat NSCLC, depending on the stage of the disease.

Surgery, which may be curative in a subset of patients, is usually used in

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early stages of the disease.

Surgery, which may be curative in a subset of patients, is usually used in early stages of the disease.

Since 1991, radiation with a combination of platinum-based chemotherapy drugs has been the first line standard of care for locally advanced or metastatic NSCLC.

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The standard of care for second line treatment is also evolving and may include platinum-based chemotherapy for patients who received immune checkpoint inhibitors as their first line regimen, pemetrexed, docetaxel or immune checkpoint inhibitors.

Phase 2 pilot trial

In 2013, we published the results of our phase 2 pilot trial, the EF-15 trial ("EF-15"), evaluating the safety and efficacy of Tumor Treating Fields in the treatment of advanced NSCLC.

EF-15 focused on the effects of treatment with Tumor Treating Fields in combination with standard of care pemetrexed chemotherapy.

EF-15 phase 2 pilot trial

In 2013, we published the results of our phase 2 pilot trial, the EF-15 trial ("EF-15"), evaluating the safety and efficacy of TTFields in the treatment of advanced NSCLC.

EF-15 focused on the effects of treatment with TTFields in combination with standard of care pemetrexed chemotherapy.

Results of the pemetrexed Phase 3 FDA registration trial were used as a historical control in this trial.

A total of 42 patients were recruited to the study with a minimum follow-up of six months.

Efficacy results based on 41 evaluable patients showed both progression-free survival and overall survival for patients receiving Tumor Treating Fields in combination with pemetrexed increased compared to historical control data for pemetrexed alone.

Median time to in-field progression in the Tumor Treating Fields-treated group was 6.5 months (compared to 2.9 months in the historical control) and median overall survival was 13.8 months (compared to 8.3 months in the historical control).

Adverse events reported in this combination study were comparable to those reported with pemetrexed alone, suggesting minimal added toxicities due to Tumor Treating Fields.

Phase 3 pivotal trial

In 2017, we enrolled the first patient in our LUNAR trial ("LUNAR"), a phase 3 pivotal trial testing the effectiveness of Tumor Treating Fields in combination with immune checkpoint inhibitors or docetaxel versus immune checkpoint inhibitors or docetaxel alone for patients who progressed during or after platinum-based therapy.

The primary endpoint is superior overall survival of patients treated with Tumor Treating Fields plus immune checkpoint inhibitors or docetaxel versus immune checkpoint inhibitors or docetaxel alone.

Efficacy results based on 41 evaluable patients showed both progression-free survival and overall survival for patients receiving TTFields in combination with pemetrexed increased compared to historical control data for pemetrexed alone.

Median time to in-field progression in the TTFields-treated group was 6.5 months (compared to 2.9 months in the historical control) and median overall survival was 13.8 months (compared to 8.3 months in the historical control).

Adverse events reported in this combination study were comparable to those reported with pemetrexed alone, suggesting minimal added toxicities due to TTFields.

KEYNOTE B36 phase 2 pilot trial

In July 2020, we entered into a clinical trial collaboration with MSD, a trade name of Merck & Co., Inc.

through a subsidiary, to develop TTFields together with MSD’s anti-PD-1 therapy pembrolizumab for treatment of first-line NSCLC, expanding our research in the lung cancer space.

We plan to conduct a phase 2 pilot study.

KEYNOTE B36, evaluating TTFields concomitant with pembrolizumab for first-line treatment of intrathoracic advanced or

metastatic, PD-L1 positive NSCLC.

KEYNOTE B36 is expected to enroll its first patient in the second quarter of 2021.

LUNAR phase 3 pivotal trial

In 2017, we enrolled the first patient in our LUNAR trial ("LUNAR"), a phase 3 pivotal trial testing the effectiveness of TTFields in combination with immune checkpoint inhibitors or docetaxel versus immune checkpoint inhibitors or docetaxel alone for patients with stage 4 NSCLC who progressed during or after platinum-based therapy.

It is estimated that approximately 46,000 patients receive second-line treatment for stage 4 NSCLC each year in the U.S.

The primary endpoint is superior overall survival of patients treated with TTFields plus immune checkpoint inhibitors or docetaxel versus immune checkpoint inhibitors or docetaxel alone.

We believe our protocol incorporates the evolving standard of care for second-line treatment of NSCLC.

TTFields is intended principally for use in combination with other standard-of-care treatments, and LUNAR was designed to generate data that contemplates multiple outcomes, all of which we believe will be clinically meaningful.

LUNAR is designed to enroll 534 patients with data analyzed 18 months after the last patient in.

The lung cancer clinical space is currently very active with substantial competition for sites and patients.

We have more than 80 trial sites in North America and Europe and we intend to increase the footprint of the study by more than 50 percent to include additional clinical sites and additional countries across Eastern Europe and Asia to accelerate enrollment.

We anticipate final data will be available in 2023.

The protocol specifies an enrollment-driven interim analysis at 432 patients, which we anticipate will occur in the second half of 2020.

The protocol specifies an enrollment-driven interim analysis at 432 patients, which we anticipate will occur in the fourth quarter of 2021.

Liver cancer is a leading cause of cancer deaths worldwide and is the sixth leading cause of cancer deaths annually in the U.S.

The incidence of liver cancer is approximately 42,000 new cases annually in the U.S.

The five-year survival rate with existing standards of care is less than 20%.

Hepatocellular carcinoma is the most widespread type of cancer that originates from the liver.

Advanced liver cancer has spread either to the lymph nodes or to other organs and, because these cancers are widespread, they cannot be treated with surgery.

The current common standard treatment for patients with advanced disease and those who progressed on loco-regional therapy is systemic therapy with sorafenib, lenvatinib, or atezolizumab plus bevacizumab.

HEPANOVA phase 2 pilot trial

In 2018, we opened our HEPANOVA trial, a single-arm, phase 2 pilot clinical trial in liver cancer testing the safety and efficacy of TTFields in combination with sorafenib for the treatment of advanced hepatocellular cancer that are not eligible for standard local therapies or surgery.

The primary endpoint is overall response rate, and secondary endpoints include progression-free and overall survival at one year.

We have completed enrollment of 25 patients at multiple centers across Europe and anticipate data will be available in the second quarter of 2021.

Gastric cancer

Gastric cancer is the third leading cause of cancer deaths worldwide and the third leading cause of cancer deaths in China.

The incidence of gastric cancer is approximately 478,500 new cases annually in China, and approximately 26,000 new cases annually in the U.S.

The five-year overall survival rate of gastric cancer is approximately 36%.

Current therapies include surgery, chemotherapy, radiotherapy and targeted therapy.

A commonly used chemotherapy regimen in treating gastric cancer is XELOX, a combination of oxaliplatin and capecitabine.

In patients diagnosed with advanced gastric cancer that is no longer operable, combination chemotherapy extends progression-free survival and overall survival to 3-6 months and 8-14 months, respectively.

EF-31 phase 2 pilot trial

In 2020, we opened our EF-31 trial, a single-arm, phase 2 pilot clinical trial in gastric cancer in partnership with Zai testing the safety and efficacy of TTFields and XELOX chemotherapy as first-line treatment for patients with unresectable gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

The primary endpoint is investigator-assessed objective response rate, and secondary endpoints include progression-free and overall survival.

The trial is expected to enroll a total of 28 patients in multiple centers across Greater China, and we anticipate data will be available in 2022.

Ovarian cancer

In the U.S., ovarian cancer ranks fifth in cancer deaths among women, with approximately 24,000 women diagnosed each year.

Ovarian cancer incidence increases with age, and the median age at time of diagnosis is 63 years old.

Physicians use different combinations of surgery and pharmacological therapies to treat ovarian cancer, depending on the stage of the disease.

Surgery is usually used in early stages of the disease and is usually combined with chemotherapy, including paclitaxel and platinum-based chemotherapy.

Unfortunately, the majority of patients are diagnosed at an advanced stage when the cancer has spread outside of the ovaries to include regional tissue involvement and/or metastases.

Platinum-based chemotherapy remains part of the standard of care in advanced ovarian cancer, but most patients with advanced ovarian cancer will have tumor progression or, more commonly, recurrence.

Almost all patients with recurrent disease ultimately develop platinum resistance, and the prognosis for this population remains poor.

INNOVATE phase 2 pilot trial

In 2018, we published the results of our phase 2 pilot trial in recurrent ovarian cancer, the INNOVATE trial ("INNOVATE"), examining TTFields in combination with standard of care chemotherapy.

INNOVATE was a multi-center, non-randomized, open-label trial designed to test the feasibility, safety and preliminary efficacy of TTFields in combination with weekly paclitaxel.

The paclitaxel control arm from the bevacizumab phase 3 FDA registration trial was used as a historical control in this trial.

A total of 31 patients were recruited to the study with a minimum follow-up of six months.

Safety results suggested that TTFields in combination with weekly paclitaxel may be tolerable and safe as second-line treatment for patients with recurrent ovarian cancer.

Median progression-free survival in the TTFields-treated group was 8.9 months (compared to 3.9 months in the paclitaxel-alone historical control), and median overall survival was not yet reached.

The one-year survival rate was 61%.

Efficacy results based on the 31 evaluable patients suggested more than doubling of the progression-free survival and an improvement in overall survival among patients who received TTFields therapy with paclitaxel compared to paclitaxel alone.

INNOVATE-3 phase 3 pivotal trial

In 2019, we enrolled the first patient in our INNOVATE-3 trial ("INNOVATE-3"), a phase 3 pivotal trial testing the effectiveness of TTFields with paclitaxel in patients with platinum-resistant ovarian cancer.

It is estimated that approximately 16,000 patients are diagnosed with platinum-resistant ovarian cancer each year in the U.S.

The primary endpoint of INNOVATE-3 is overall survival.

Secondary endpoints include progression-free survival, objective response rate, severity and frequency of adverse events, time to undisputable deterioration in health-related quality of life or death, and quality of life.

The study is designed to accrue 540 patients with data analyzed 18 months after the last patient in.

We anticipate final data in 2023.

The protocol specifies an enrollment-driven interim analysis at last patient in, which we anticipate will occur in the third quarter of 2021.

The European Network for Gynaecological Oncological Trial groups ("ENGOT") and The GOG Foundation, Inc.

("GOG"), third-party clinical trial networks, are collaborating with us on the trial.

ENGOT and GOG were involved in the development of the trial, and the collaborations are intended to facilitate enrollment of INNOVATE-3 at leading cancer centers in Europe and the United States.

Pancreatic cancer

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While overall cancer incidence and death rates are remaining stable or declining, the incidence and death rates for pancreatic cancer are increasing.

The incidence of pancreatic cancer is approximately 51,000 new cases annually in the U.S., approximately 132,500 new cases annually in Europe, and approximately 43,000 new cases annually in Japan.

It is estimated that approximately 53,000 patients are diagnosed with pancreatic cancer each year in the U.S.

Pancreatic cancer has a five-year relative survival rate in the single digits, at just 10 percent.

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Unfortunately, the majority of locally advanced cases are diagnosed once the cancer is no longer operable, generally leaving chemotherapy with or without radiation as the only treatment option.

Phase 2 pilot trial

In 2018, we published the results of our phase 2 pilot trial in advanced pancreatic adenocarcinoma, the PANOVA trial ("PANOVA"), examining Tumor Treating Fields in combination with standard of care chemotherapy.

PANOVA phase 2 pilot trial

In 2018, we published the results of our phase 2 pilot trial in advanced pancreatic adenocarcinoma, the PANOVA trial ("PANOVA"), examining TTFields in combination with standard of care chemotherapy.

PANOVA was a multicenter, non-randomized, open-label trial.

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Patients were enrolled between 2014 and 2016 in two cohorts:

The first cohort of 20 patients received Tumor Treating Fields with standard doses of gemcitabine alone.

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The second cohort of 20 patients received Tumor Treating Fields with standard doses of nab-paclitaxel plus gemcitabine.

In the first cohort, efficacy results showed that progression-free survival and overall survival of patients treated with Tumor Treating Fields combined with gemcitabine were more than double those of gemcitabine-treated historical controls.

Median progression-free survival in the Tumor Treating Fields-treated group was 8.3 months (compared to 3.7 months in the gemcitabine historical control), with locally advanced patients reaching a median progression-free survival of 10.3 months and patients with metastatic disease reaching a median progression-free survival of 5.7 months.

The first cohort of 20 patients received TTFields with standard doses of gemcitabine alone.

The second cohort of 20 patients received TTFields with standard doses of nab-paclitaxel plus gemcitabine.

In the first cohort, efficacy results showed that progression-free survival and overall survival of patients treated with TTFields combined with gemcitabine were more than double those of gemcitabine-treated historical controls.

Median progression-free survival in the TTFields-treated group was 8.3 months (compared to 3.7 months in the gemcitabine historical control), with locally advanced patients reaching a median progression-free survival of 10.3 months and patients with metastatic disease reaching a median progression-free survival of 5.7 months.

The median overall survival for all patients was 14.9 months (compared to 6.7 months in the gemcitabine historical control).

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Of 11 patients with available CT scans, 5 (45%) had a partial response (compared to 7% with gemcitabine alone), 5 (45%) had stable disease, which means that the cancer is neither decreasing nor increasing in extent or severity, and 1 (10%) had progressive disease.

In the second cohort, efficacy results showed that progression-free survival and overall survival of patients treated with Tumor Treating Fields combined with nab-paclitaxel plus gemcitabine were more than double those of nab-paclitaxel plus gemcitabine-treated historical controls.

Median progression-free survival in the Tumor Treating Fields-treated group was 12.7 months (compared to 5.5 months in the nab-paclitaxel plus gemcitabine historical control) and median overall survival was not yet reached.

In the second cohort, efficacy results showed that progression-free survival and overall survival of patients treated with TTFields combined with nab-paclitaxel plus gemcitabine were more than double those of nab-paclitaxel plus gemcitabine-treated historical controls.

Median progression-free survival in the TTFields-treated group was 12.7 months (compared to 5.5 months in the nab-paclitaxel plus gemcitabine historical control) and median overall survival was not yet reached.

The one-year survival rate was 72% (compared to 35% in nab-paclitaxel plus gemcitabine historical control).

Of the 15 patients with available CT scans, 6 (40%) had a partial response (compared to 23% with the nab-paclitaxel plus gemcitabine alone), 7 (47%) had stable disease and 2 (13%) had progressive disease.

Safety results from both cohorts suggested that Tumor Treating Fields plus first-line chemotherapies nab-paclitaxel and/or gemcitabine may be tolerable and safe in patients with advanced pancreatic cancer.

Patients reported no serious adverse events related to Tumor Treating Fields.

Phase 3 pivotal trial

In 2018, we enrolled the first patient in our PANOVA-3 trial ("PANOVA-3"), a phase 3 pivotal trial testing the effectiveness of Tumor Treating Fields with nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine alone as a front-line treatment for unresectable locally advanced pancreatic cancer.

Safety results from both cohorts suggested that TTFields plus first-line chemotherapies nab-paclitaxel and/or gemcitabine may be tolerable and safe in patients with advanced pancreatic cancer.

Patients reported no serious adverse events related to TTFields.

PANOVA-3 phase 3 pivotal trial

In 2018, we enrolled the first patient in our PANOVA-3 trial ("PANOVA-3"), a phase 3 pivotal trial testing the effectiveness of TTFields with nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine alone as a front-line treatment for unresectable locally advanced pancreatic cancer.

It is estimated that approximately 43,000 patients are diagnosed with unresectable pancreatic cancer each year in the U.S.

The primary endpoint of PANOVA-3 is overall survival.

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The study is designed to accrue 556 patients with data analyzed 18 months after the last patient in.

With 85 sites on board at the end of 2019, we have seen an increase in our enrollment rates in recent quarters.

Recruitment is expected to continue to accelerate in 2020 given the anticipated international expansion of the study, which will increase the total number of sites to approximately 135 by year end.

We anticipate final data will be available in 2023.

The protocol specifies an enrollment-driven interim analysis at last patient in, which we anticipate will occur in 2021.

Ovarian cancer

In the U.S., ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system.

Ovarian cancer incidence increases with age, and the median age at time of diagnosis is 63 years old.

The incidence of ovarian cancer is approximately 24,500 new cases annually in the U.S., approximately 68,000 new cases annually in Europe, and approximately 11,000 new cases annually in Japan.

Physicians use different combinations of surgery and pharmacological therapies to treat ovarian cancer, depending on the stage of the disease.

Surgery is usually used in early stages of the disease and is usually combined with chemotherapy, including paclitaxel and platinum-based chemotherapy.

Unfortunately, the majority of patients are diagnosed at an advanced stage when the cancer has spread outside of the ovaries to include regional tissue involvement and/or metastases.

Platinum-based chemotherapy remains part of the standard of care in advanced ovarian cancer, but most patients with advanced ovarian cancer will have tumor progression or, more commonly,

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Almost all patients with recurrent disease ultimately develop platinum resistance, and the prognosis for this population remains poor.

Phase 2 pilot trial

In 2018, we published the results of our phase 2 pilot trial in recurrent ovarian cancer, the INNOVATE trial ("INNOVATE"), examining Tumor Treating Fields in combination with standard of care chemotherapy.

INNOVATE was a multi-center, non-randomized, open-label trial designed to test the feasibility, safety and preliminary efficacy of Tumor Treating Fields in combination with weekly paclitaxel.

The paclitaxel control arm from the bevacizumab phase 3 FDA registration trial was used as a historical control in this trial.

A total of 31 patients were recruited to the study with a minimum follow-up of six months.

Safety results suggested that Tumor Treating Fields in combination with weekly paclitaxel may be tolerable and safe as second-line treatment for patients with recurrent ovarian cancer.

Median progression-free survival in the Tumor Treating Fields-treated group was 8.9 months (compared to 3.9 months in the paclitaxel-alone historical control), and median overall survival was not yet reached.

The one-year survival rate was 61%.

Efficacy results based on the 31 evaluable patients suggested more than doubling of the progression-free survival and an improvement in overall survival among patients who received Tumor Treating Fields therapy with paclitaxel compared to paclitaxel alone.

Phase 3 pivotal trial

In 2019, we enrolled the first patient in our INNOVATE-3 trial ("INNOVATE-3"), a phase 3 pivotal trial testing the effectiveness of Tumor Treating Fields with paclitaxel in patients with platinum-resistant ovarian cancer.

The primary endpoint of INNOVATE-3 is overall survival.

The European Network for Gynaecological Oncological Trial groups ("ENGOT") and The GOG Foundation, Inc.

("GOG"), third-party clinical trial networks, are collaborating with us on the trial.

ENGOT and GOG were involved in the development of the trial, and the collaborations are intended to facilitate enrollment of INNOVATE-3 at leading cancer centers in Europe and the United States.

The study is designed to accrue 540 patients with data analyzed 18 months after the last patient in.

We are encouraged by the initial speed of enrollment, which we view as a sign of enthusiasm from the investigator community and anticipate final data in 2024.

The protocol specifies an enrollment-driven interim analysis at last patient in, which we anticipate will occur in 2022.

Liver cancer is a leading cause of cancer deaths worldwide and is the fifth leading cause of cancer deaths annually in the U.S.

The incidence of liver cancer is approximately 38,000 new cases annually in the U.S., approximately 82,500 new cases annually in Europe, and approximately 35,500 new cases annually in Japan.

The five-year survival rate with existing standards of care is less than 18%.

Hepatocellular carcinoma is the most widespread type of cancer that originates from the liver.

Advanced liver cancer has spread either to the lymph nodes or to other organs and, because these cancers are widespread, they cannot be treated with surgery.

The current common standard treatment for patients with advanced disease and those who progressed on loco-regional therapy is systemic therapy with sorafenib.

Phase 2 pilot trial

In 2018, we opened our HEPANOVA trial, a single-arm, phase 2 pilot clinical trial in liver cancer testing the safety and efficacy of Tumor Treating Fields in combination with sorafenib for the treatment of advanced hepatocellular cancer that are not eligible for standard local therapies or surgery.

The primary endpoint is overall response rate, and secondary endpoints include progression-free and overall survival at one year.

The trial is expected to enroll a total of 25 patients in multiple centers across Europe and we anticipate data will be available in 2021.

Gastric cancer

Gastric cancer is the third leading cause of cancer deaths worldwide and the second leading cause of cancer deaths in China.

The incidence of gastric cancer is approximately 456,000 new cases annually in China, approximately 26,000 new cases annually in the U.S., approximately 133,000 new cases annually in Europe and 116,000 new cases annually in Japan.

The five-year overall survival rate of gastric cancer is approximately 36%.

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Current therapies include surgery, chemotherapy, radiotherapy and targeted therapy.

A commonly used chemotherapy regimen in treating gastric cancer is XELOX, a combination of oxaliplatin and capecitabine.

Phase 2 pilot trial

In 2020, we opened our EF-31 trial, a single-arm, phase 2 pilot clinical trial in gastric cancer in partnership with Zai testing the safety and efficacy of Tumor Treating Fields and XELOX chemotherapy as first-line treatment for patients with unresectable gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

The primary endpoint is investigator-assessed objective response rate, and secondary endpoints include progression-free and overall survival.

The trial is expected to enroll a total of 28 patients in multiple centers across Greater China.

The protocol specifies an enrollment-driven interim analysis at last patient in, which we now anticipate will occur in 2022.

Zai License and Collaboration Agreement

In September 2018, we announced a strategic collaboration with Zai.

The collaboration agreement grants Zai a license to commercialize our Products in Greater China and establishes a development partnership intended to accelerate the development of Tumor Treating Fields in multiple solid tumor cancer indications.

Zai has launched Optune for the treatment of newly diagnosed GBM in Hong Kong.

The Chinese regulatory authorities designated Optune as an Innovative Medical Device and have accepted the Marketing Authorization Application for the GBM application in China.

Zai is pursuing a clinical trial waiver and, should a clinical trial waiver be granted, Zai intends to launch Optune in China in 2020.

In 2018, we announced a strategic collaboration with Zai.

The collaboration agreement grants Zai a license to commercialize our Products in Greater China and establishes a development partnership intended to accelerate the development of TTFields in multiple solid tumor cancer indications.

Zai has launched Optune for the treatment of newly diagnosed GBM in Hong Kong and for the treatment of newly diagnosed and recurrent GBM in mainland China.

Zai has also launched Optune Lua for the treatment of MPM in Hong Kong and intends to file a Marketing Authorization Application in mainland China in 2021.

For additional information, see Note 12 to the Consolidated Financial Statements.

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We outsource production of all of our system components to qualified partners.

Disposable transducer array manufacturing, the dominant activity in our manufacturing supply chain, includes several specialized processes.

Disposable array manufacturing, the dominant activity in our manufacturing supply chain, includes several specialized processes.

Production of the durable system components follows standard electronic medical device methodologies.

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We believe we own global commercialization rights to our Products in oncology and are well-positioned to extend those rights into the future as we continue to find innovative ways to improve our Products.

Our robust global patent and intellectual property portfolio consists of over 180 issued patents covering various aspects of Tumor Treating Fields and our Products.

Our robust global patent and intellectual property portfolio consists of over 185 issued patents covering various aspects of TTFields and our Products.

In the U.S., our patents have expected expiration dates between 2021 and 2037.

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patent applications in 2020, that, if issued, may protect aspects of our platform beyond the current last-to-expire patent in the relevant market.

These pending applications cover innovations relating to our transducer arrays, field generators and software platform, in addition to other topics related to Tumor Treating Fields.

These pending applications cover innovations relating to our arrays, field generators and software platform, in addition to other topics related to TTFields.

Our reliance on intellectual property involves certain risks, as described under the heading "Risk factors—Risks relating to intellectual property."

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These agreements also generally provide that we own, or the individual is required to assign to us, all inventions conceived by the individual in the course of rendering services to us.

Despite measures taken to protect our intellectual

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property, unauthorized parties may copy certain aspects of our products or obtain and use information that we believe is proprietary.

Pursuant to our strategic collaboration with Zai, we granted Zai a license to commercialize Tumor Treating Fields in Greater China.

Despite measures taken to protect our intellectual property, unauthorized parties may copy certain aspects of our products or obtain and use information that we believe is proprietary.

Pursuant to our strategic collaboration with Zai, we granted Zai a license to commercialize TTFields in Greater China.

For additional information, see Note 12 to the Consolidated Financial Statements.

In 2015, we entered into a settlement agreement with the Technion Research and Development Foundation to resolve certain potential disputes regarding intellectual property developed by our founder and previously assigned to us.

For additional information, see Note 12 to the Consolidated Financial Statements.

In 2005, we granted an exclusive license to a third party, NovoBiotic LLC, to certain of our key intellectual property for use outside the field of oncology.

We are not entitled to any future revenues from this license.

In December 2020, we entered into an agreement with Novobiotic LLC that terminated all pre-existing agreements between the parties, including any restrictions on our use of intellectual property outside the field of oncology.

The market for cancer treatments is intensely competitive, subject to rapid change and significantly affected by new product and treatment introductions and other activities of industry participants.

The general bases of competition are overall effectiveness, side effect profile, cost, availability of reimbursement and general market acceptance of a product as a suitable cancer treatment.

We believe our intellectual property rights would provide an obstacle to the introduction of Tumor Treating Fields delivery systems by a competitor, and we intend to protect and enforce our intellectual property.

In addition, even after the expiration of our U.S.

Our intellectual property portfolio is continuously expanding as we find new and unique ways to improve TTFields therapy.

We believe these intellectual property rights would provide an obstacle to the introduction of state of the art

TTFields delivery systems by a competitor.

However, competitors may be able to offer less sophisticated TTFields delivery systems that utilize technology described in expired patents and/or choose to market their system(s) in countries where we have limited or no enforceable intellectual property rights.

Competitors could also pursue alternative technologies for the application of TTFields into a patient that we did not foresee or protect.

We are aware of a few third parties in the United States and China developing devices and filing for intellectual property protection related to TTFields.

Even after the expiration of our U.S.

patents, we believe that potential U.S.

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Government regulation

In the United States, our Products and our operations are subject to extensive regulation by the FDA under the Federal Food, Drug, and Cosmetic Act ("FDCA").

In the U.S., our Products and our operations are subject to extensive regulation by the FDA under the Federal Food, Drug, and Cosmetic Act ("FDCA").

In the EU member states where we market our Products and operate, we are currently subject to, inter alia, the Medical Device Directive ("MDD") as implemented into national legislation by the EU member states.

From May 26, 2021, the MDD will be replaced and repealed by the Medical Device Regulation ("MDR"), which will apply directly in all EU member states.

In Switzerland, our Products and operations are subject to, inter alia, the Medical Devices Ordinance, which implements the MDD into Swiss law.

In Switzerland, our Products and operations are subject to, inter alia, the Medical Devices Ordinance, which implements the MDD into Swiss law (See "Foreign approvals and CE mark" below).

In Japan, our Products and operations are subject to regulation by the Pharmaceuticals and Medical Device Agency ("PMDA") under the Pharmaceuticals and Medical Devices Act ("PMD Act").

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Our research, development and clinical programs, as well as our manufacturing and marketing operations, are also subject to extensive regulation.

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Failure by us or by our suppliers to comply with applicable regulatory requirements can result in enforcement action by the FDA or other regulatory authorities, which may result in any number of regulatory enforcement actions, or civil or criminal liability.

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Premarket approval (PMA) pathway

Optune and NovoTTF-100L are classified as Class III devices as they are deemed to be life-sustaining devices.

Optune and Optune Lua are classified as Class III devices as they are deemed to be life-sustaining devices.

Accordingly, we were required to receive PMA for Optune, which the FDA granted in April 2011 and October 2015 for the treatment of recurrent and newly diagnosed supratentorial GBM, respectively, in adult patients.

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New PMAs or PMA supplements are required for modifications that affect the safety or effectiveness of our delivery systems, including, for example, certain types of modifications to a delivery system’s indication for use, manufacturing process, labeling and design.

PMA supplements often require submission of the same type of information as a PMA, except that the supplement is limited to information needed to support any changes from the

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device covered by the original PMA and may not require any or as extensive clinical data as the original PMA required, or the convening of an advisory panel.

PMA supplements often require submission of the same type of information as a PMA, except that the supplement is limited to information needed to support any changes from the device covered by the original PMA and may not require any or as extensive clinical data as the original PMA required, or the convening of an advisory panel.

The FDA requires a company to make the determination as to whether a new PMA or PMA supplement application is to be filed.

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The FDA may review a company’s decisions when reviewing the PMA Annual Report and require the filing of an application.

As is typical with medical device companies, we have received approval for a number of post-approval PMA supplements for GBM, including for modifications to Optune’s electric field generator, transducer arrays, software, manufacturing processes and labeling.

As is typical with medical device companies, we have received approval for a number of post-approval PMA supplements for GBM, including for modifications to Optune’s electric field generator, arrays, software, manufacturing processes and labeling.

Future modifications may be considered by us as the need arises, some of which we may deem to require a PMA supplement application and others to require reporting in our PMA Annual Report.

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Approval basis for an HDE is a "reasonable assurance of safety" and that the probable benefit to health outweighs risk of injury from its use, which means a traditional phase 3 pivotal trial usually is not required to support approval.

In 2019, the FDA approved NovoTTF-100L for the treatment of MPM under the HDE pathway.

Devices approved through an HDE application are subject to certain requirements, including specific labeling restrictions and the requirement that a facility’s IRB or Local Committee approve the use of the device before it can be distributed in that facility.

In 2019, the FDA approved Optune Lua (then known as "NovoTTF-100L") for the treatment of MPM under the HDE pathway.

Devices approved through an HDE application are subject to certain requirements, including specific labeling restrictions and the requirement that a facility’s institutional review board ("IRB") or Local Committee approve the use of the device before it can be distributed in that facility.

In addition, there is a general prohibition on profiting from sales of devices approved under the HDE standard.

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Foreign approvals and CE mark

Sales and marketing of medical devices outside of the U.S.

Market access, sales and marketing of medical devices outside of the U.S.

are subject to foreign regulatory requirements that vary widely from country to country.

These include the requirement to obtain CE Certification and to affix a CE mark to our medical devices in the EU.

Whether or not we have obtained FDA approval, our delivery systems must be subject to conformity assessment procedure involving a notified body, a private organization designated by an EU member state to conduct conformity assessment procedures under the MDD/MDR.

Apart from low risk medical devices (Class I with no measuring function and which are not sterile), where the manufacturer can issue a declaration of conformity based on a self-assessment of the conformity of its products with the Essential Requirements laid down in the MDD, a conformity assessment procedure requires the intervention of a notified body.

The notified body typically audits and examines the products’ technical file, including the clinical data, and the quality system for the manufacture, design and final inspection of our devices before issuing a CE Certificate

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demonstrating compliance with the relevant Essential Requirements or the quality system requirements laid down in the relevant Annexes to the MDD.

Following the issuance of this CE Certificate, we can draw up a declaration of conformity and affix the CE mark to the delivery systems covered by this CE Certificate and the declaration of conformity.

In the European Economic Area (“EEA”), for Novocure’s devices these include the requirement to obtain a CE Certificate and to affix a CE mark to our Products.

In the EEA, whether or not we have obtained FDA approval, our delivery systems must be subject to conformity assessment procedure involving an EEA notified body, a private organization accredited by an EEA member state to conduct conformity assessment procedures under the MDD/MDR.

Apart from low risk medical devices (Class I with no measuring function and which are not sterile), where the manufacturer can issue a declaration of conformity based on a self-assessment of the conformity of its products with the MDD’s Essential Requirements or the MDR’s General Safety and Performance Requirements, a conformity assessment procedure requires the intervention of a notified body.

The notified body typically audits and examines the device’s technical documentation, including the clinical evaluation, and the quality system for the manufacture, design and final inspection of our devices before issuing a CE Certificate demonstrating compliance with the relevant requirements or the quality system requirements laid down in the relevant Annexes to the MDD/MDR.

Following the issuance of this CE Certificate, we can draw up a declaration of conformity and affix the CE mark to the delivery systems covered by this CE Certificate.

The time required to CE mark our delivery systems or to obtain approval from other non-U.S.

authorities may be longer or shorter than that required for FDA approval.

Currently, pursuant to the Mutual Recognition Agreement ("MRA") in place between the EU and Switzerland, our Products bearing a CE mark may be exported from the EU to Switzerland.

Moreover, the MDR, which becomes applicable on May 26, 2021, imposes new stricter requirements that we must comply with in order to renew the CE Certificates for our Products when these expire or May 25, 2025, whichever comes first.

In Switzerland, pursuant to the Mutual Recognition Agreement ("MRA") in place between the EEA and Switzerland, our Products bearing a CE mark may currently be exported from the EEA to Switzerland.

However, this MRA is only valid until May 25, 2021 and if no new MRA has been agreed to by then, Switzerland will be considered a third country with respect to medical devises.

In the EU, before carrying out a clinical study, the sponsor must receive a positive opinion from a local ethics committee and approval from the national competent authority in the relevant EU member states in which the clinical study will be conducted.

When a clinical study relates to a CE marked medical device that will be used as part of the study according to its intended use, the approval of the national competent authorities is not required for the use of such medical device in the study.

In Japan, we must obtain approvals from the MHLW to market our delivery systems.

In the EEA, before carrying out a clinical investigation with a device to assess its safety or performance when in accordance with its intend use, the sponsor must receive a positive opinion from the local ethics committee and approval from the national competent authority in the relevant EEA member states in which the clinical investigation will be conducted.

When a CE marked medical device is used in a clinical study in accordance with its intended use,

the approval of the national competent authorities is not required for the use of such medical device in the study.

In Japan, we must obtain approvals from the Ministry of Health, Labour, and Welfare ("MHLW") to market our delivery systems.

Each regulatory approval process outside of the U.S.

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• QSR, which requires manufacturers, including third-party manufacturers, to follow stringent design, testing, control, documentation and other quality assurance procedures during all aspects of the manufacturing process for products marketed in the U.S.;

• labeling regulations and FDA and equivalent competent authority in other jurisdictions requiring promotion is truthful and non-misleading and prohibiting the promotion of products for uncleared, unapproved or off-label uses;

• labeling regulations and FDA and equivalent competent authority in other jurisdictions requiring promotion be truthful and non-misleading and prohibiting the promotion of products for uncleared, unapproved or off-label uses;

• approval of product modifications that affect the safety or effectiveness of one of our delivery systems that has been approved or is the subject of a CE Certificate;

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Moreover, the FDA and other applicable regulatory authorities can order a mandatory recall if there is a reasonable probability that our delivery system would cause serious adverse health consequences or death.

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The FDA has broad post-market and regulatory enforcement powers.

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In some cases, our practices may not meet all of the technical elements for protection under a federal Anti-Kickback Statute exception or safe harbor.

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as a supplier, we are also subject to the federal beneficiary anti-inducement statute, which prohibits us from offering any remuneration to a beneficiary of Medicare or Medicaid that is likely to influence that beneficiary’s choice of therapy, unless an exception applies.

Similarly, as a supplier, we are also subject to the federal beneficiary anti-inducement statute, which prohibits us from offering any remuneration to a beneficiary of Medicare or Medicaid that is likely to influence that beneficiary’s choice of therapy, unless an exception applies.

This can include, but is not limited to, the provision of inappropriate financial assistance to purchase our Products.

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The False Claims Act prohibits any person from knowingly presenting, or causing to be presented, a false claim for payment to the federal government, or knowingly making, or causing to be made, a false statement to get a false claim paid.

The government has pursued numerous cases under the False Claims Act in connection with the off-label promotion of medical products and various other health care law violations.Notably, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act.

The government has pursued numerous cases under the False Claims Act in connection with the off-label promotion of medical products and various other health care law violations.

Notably, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act.

The majority of states also have statutes or regulations similar to the federal Anti-Kickback Statute, Stark Law and False Claims Act laws, which apply to items and services reimbursed under Medicaid and other state programs, or, in several states, that apply regardless of the payer (e.g., including private/commercial payors or cash-pay scenarios).

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federal health care programs to track and then report certain payments and transfers of value given to "Covered Recipients." The term "Covered Recipients" currently includes U.S.-licensed physicians and teaching hospitals, and, for reports submitted on or after January 1, 2022, physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, and certified nurse-midwives.

The Sunshine Act requires that manufacturers collect this information on a yearly basis and then

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report it to Centers for Medicare & Medicaid Services by the 90th day of each subsequent year.

The Sunshine Act requires that manufacturers collect this information on a yearly basis and then report it to Centers for Medicare & Medicaid Services by the 90th day of each subsequent year.

We have adopted policies and codes of conduct regarding our interactions with Covered Recipients and believe we are in material compliance with the Sunshine Act.

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Legislation similar to the FCPA has been adopted in foreign countries, including a number of EU member states.

As of December 31, 2019, we had 782 employees.

Human Capital Resources

As of December 31, 2020, we had 1,023 employees, compared to 782 employees as of December 31, 2019.

We believe relations with our employees are good.

To achieve commercial success for our Products, we believe we must continue to develop and grow our sales and marketing, patient support and research and development teams, along with the necessary staff to support it.

This need accounts for the significant increase in the number of employees in 2020.

Developing and managing a growing organization is a difficult, expensive and time consuming process.

To be successful we must:

• recruit and retain adequate numbers of effective and experienced sales and marketing, patient support and research and development personnel;

• effectively train our personnel on the benefits and risks of our Products and healthcare compliance;

• establish and maintain successful and compliant education programs that educate health care providers so they can appropriately inform their patients about our Products;

• manage geographically disbursed business operations.

We compete with other medical device, pharmaceutical and life sciences companies to recruit, hire, train and retain the personnel that we anticipate we will need.

Because our current Products require, and we anticipate our future Products will require, physician training and education, we expect that our sales and marketing and patient support teams will continue to grow substantially as we expand our approved indications and markets.

Available information

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business