Effect of TTFields (150 kHz) in Non-small Cell Lung Cancer (NSCLC) Patients With 1-10 Brain Metastases Following Radiosurgery (METIS)

PAST PRE-CLINICAL AND CLINICAL EXPERIENCE:

The effect of the electric fields (TTFields, TTF) has demonstrated significant activity in in
vitro and in vivo NSCLC pre-clinical models both as a single modality treatment and in
combination with chemotherapies. TTFields have also shown to inhibit metastatic spread of
malignant melanoma in in vivo experiment.

In a pilot study, 42 patients with advanced NSCLC who had had tumor progression after at
least one line of prior chemotherapy, received pemetrexed together with TTFields (150 kHz)
applied to the chest and upper abdomen until disease progression (Pless M., et al., Lung
Cancer 2011). Efficacy endpoints were remarkably high compared to historical data for
pemetrexed alone.

In addition, a phase III trial of Optune® (200 kHz) as monotherapy compared to active
chemotherapy in recurrent glioblastoma patients showed TTFields to be equivalent to active
chemotherapy in extending survival, associated with minimal toxicity, good quality of life,
and activity within the brain (14% response rate) (Stupp R., et al., EJC 2012). Finally, a
phase III trial of Optune® combined with maintenance temozolomide compared to maintenance
temozolomide alone has shown that combined therapy led to a significant improvement in both
progression free survival and overall survival in patients with newly diagnosed glioblastoma
without the addition of high grade toxicity and without decline in quality of life (Stupp R.,
et al., JAMA 2015).

Applying TTFields at 150 kHz to the brain for the treatment of 1-5 brain metastasis from
NSCLC using the NovoTTF-100M device has been demonstrated to be safe in a pilot study, where
patients were randomize after local therapy of their brain metastasis by neurosurgery and/or
stereotactic radiosurgery to receive either NovoTTF-100M treatment or supportive care alone.
Eighteen (18) patients have been enrolled in the study. There have been no device-related
serious adverse events (SAE) reported to date (Brozova H., et al., Neuro Oncol 2016).

DESCRIPTION OF THE TRIAL:

All patients included in this trial are patients with 1-10 brain metastases from NSCLC which
are amenable to stereotactic radiosurgery (SRS). In addition, all patients must meet all
eligibility criteria.

Eligible patients will be randomly assigned to one of two groups:

1. Patients undergo SRS followed by TTFields using the NovoTTF-100M System

2. Patients undergo SRS alone and receive supportive care.

Patients in both arms of the study may receive systemic therapy for their NSCLC at the
discretion of their treating physician.

Patients will be randomized at a 1:1 ratio. Baseline tests will be performed in patients
enrolled in both arms. If assigned to the NovoTTF-100M group, the patients will be treated
continuously with the device until second intracranial progression.

On both arms, patients who recur anywhere in the brain will be offered one of the following
salvage treatments (according to local practice) including, but not limited to:

- Surgery

- Repeat SRS

- Whole brain radiotherapy (WBRT)

Patients on the control arm will be offered to cross over to the NovoTTF-100M arm of the
study and receive TTFields after salvage therapy for second intracranial progression if the
investigator believes it is in the best interest of the patient and patient agrees.

SCIENTIFIC BACKGROUND:

Electric fields exert forces on electric charges similar to the way a magnet exerts forces on
metallic particles within a magnetic field. These forces cause movement and rotation of
electrically charged biological building blocks, much like the alignment of metallic
particles seen along the lines of force radiating outwards from a magnet.

Electric fields can also cause muscles to twitch and if strong enough may heat tissues.
TTFields are alternating electric fields of low intensity. This means that they change their
direction repetitively many times a second. Since they change direction very rapidly (150
thousand times a second), they do not cause muscles to twitch, nor do they have any effects
on other electrically activated tissues in the body (brain, nerves and heart). Since the
intensities of TTFields in the body are very low, they do not cause heating.

The breakthrough finding made by Novocure was that finely tuned alternating fields of very
low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in
the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are
multiplying, TTFields cause electrically-charged cellular components of these cells to change
their location within the dividing cell, disrupting their normal function and ultimately
leading to cell death.. In addition, cancer cells also contain miniature building blocks
which act as tiny motors in moving essential parts of the cells from place to place. TTFields
interfere with the normal orientation of these tiny motors related to other cellular
components since they are electrically-charged as well. As a result of these two effects,
tumor cell division is slowed, results in cellular death or reverses after continuous
exposure to TTFields.

Other cells in the body (normal healthy tissues) are affected much less than cancer cells
since they multiply at a much slower rate if at all. In addition TTFields can be directed to
a certain part of the body, leaving sensitive areas out of their reach. Finally, the
frequency of TTFields applied to each type of cancer is specific and may not damage normally
dividing cells in healthy tissues.

In conclusion, TTFields hold the promise of serving as a brand new treatment for brain
metastases from NSCLC with very few side effects.

Inclusion Criteria:

1. 18 years of age and older

2. Life expectancy of ≥ 3 months

3. New diagnosis of brain metastases from a histologically or cytologically confirmed
primary or metastatic NSCLC tumor within 5 years of registration on the study. If the
original histological proof of malignancy is greater than 5 years, then pathological
confirmation is required (i.e.: from extra-cranial or intracranial disease).

4. Karnofsky performance status (KPS) ≥ 70

5. 1 inoperable brain metastasis or 2- 10 brain lesions per screening MRI, confirmed by
contrast enhanced MRI amenable to SRS according to the following criteria:

1. largest tumor volume < 10 cc

2. longest tumor diameter < 3 cm

3. Cumulative volume of all tumors ≤ 15 cc

6. At least one measurable lesion per RANO-BM (Response Assessment in Neuro-Oncology
Brain Metastases) Criteria for brain metastasis

7. Patients must be receiving optimal therapy for their extracranial disease according to
local practice at each center. Patients may continue on systemic therapy while
receiving TTFields.

8. Able to operate the NovoTTF-100M device independently or with the help of a caregiver

9. Clinical trials prior to enrollment are allowed, as long as no brain directed therapy
was included (current treatment trials are exclusionary)

Exclusion Criteria:

1. Patients who are known to have somatic tumor mutations in the following genes, for
which targeted agents are available that directly affect the treatment of brain
metastasis: Anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR),
ROS-1 proto-oncogene, and proto-oncogene B-RAF

2. Patients who have a single, operable brain metastasis

3. Patients with significant edema leading to risk of brain herniation

4. Patients with midline shift > 10mm

5. Patients with intractable seizures

6. Leptomeningeal metastases

7. Recurrent brain metastases

8. Prior WBRT for newly diagnosed brain metastases

9. Severe comorbidities:

1. Clinically-significant inadequate hematological, hepatic and renal function,
defined as: Neutrophil count < 1.5 x 10 9/L and platelet count < 100 x 10^9/L;
bilirubin > 1.5 x upper limit of normal (ULN); aspartate transaminase (AST)
and/or alanine aminotransferase (ALT) > 2.5 x ULN or > 5 x ULN if patient has
documented liver metastases; and serum creatinine > 1.5 x ULN

2. History of significant cardiovascular disease unless the disease is well
controlled. Significant cardiac disease includes second/third degree heart block;
significant ischemic heart disease; poorly controlled hypertension; congestive
heart failure of the New York Heart Association (NYHA) Class II or worse (slight
limitation of physical activity; comfortable at rest, but ordinary activity
results in fatigue, palpitation or dyspnea).

3. History of arrhythmia that is symptomatic or requires treatment. Patients with
atrial fibrillation or flutter controlled by medication are not excluded from
participation in the trial.

4. History of cerebrovascular accident (CVA) within 6 months prior to randomization
or that is not stable

5. Active infection or serious underlying medical condition that would impair the
ability of the patient to received protocol therapy

6. History of any psychiatric condition that might impair patient's ability to
understand or comply with the requirements of the study or to provide consent

10. Implantable electronic medical devices in the brain

11. Known allergies to medical adhesives or hydrogel

12. Currently pregnant or breastfeeding

13. Concurrent brain directed therapy (beyond SRS and NovoTTF-100M as per protocol)