Pivotal, Open-label, Randomized Study of Radiosurgery With or Without Tumor Treating Fields (TTFields) for 1-10 Brain Metastases From Non-small Cell Lung Cancer (NSCLC).

Summary

Objectives

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 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 randomized 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-200M 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-200M 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-200M arm of the study and receive TTFields with or without
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.