Effect of Tumor Treating Fields (TTFields) (150 kHz) Concurrent With Standard of Care Therapies for Treatment of Stage 4 Non-small Cell Lung Cancer (NSCLC) Following Platinum Failure (LUNAR)

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 and PD-1 inhibitors. TTFields have been demonstrated to act
synergistically with taxanes and have been shown to be additive when combined with PD-1
inhibitors. In addition, TTFields have 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). The combination was well tolerated and the only device-related adverse event
was mild to moderate contact dermatitis. 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).

DESCRIPTION OF THE TRIAL:

All patients included in this trial are patients with squamous or non-squamous, stage 4 NSCLC
who had disease progression on or after receiving platinum based chemotherapy. In addition,
all patients must meet all eligibility criteria.

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

Patients receive docetaxel or immune checkpoint inhibitor in combination with TTFields using
the NovoTTF-100L System.

Patients receive docetaxel or immune checkpoint inhibitor without TTFields. 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-100L group, the patients will be treated continuously with
the device until disease progression in the thorax and/or liver according to RECIST or
irRECIST (Immune-Related Response Evaluation Criteria In Solid Tumors) (depending if the
patient is receiving docetaxel or immune checkpoint inhibitor, respectively).

On both arms, patients who have disease progression according to RECIST or irRECIST
(depending if the patient is receiving docetaxel or immune checkpoint inhibitor,
respectively) will switch to a third line treatment according to local practice.

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 NSCLC with
very few side effects.

Inclusion Criteria:

1. 22 years of age and older

2. Life expectancy of ≥ 3 months

3. Histological diagnosis of squamous or non-squamous, inoperable, stage 4 NSCLC

4. Diagnosis of radiological progression while on or after first platinum-based systemic
therapy

5. Randomization within 28 days of diagnosis of last progression

6. ECOG Score of 0-2

7. Assigned by the physician to receive either docetaxel or immune checkpoint inhibitor
per standard of care regimens

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

9. Signed informed consent for the study protocol

Exclusion Criteria:

1. Presence of brain metastasis or leptomeningeal spread of the disease

2. Patients planned to receive immune checkpoint inhibitor with contra-indications to
receive immunotherapy

3. Patients planned to receive docetaxel with contra-indications to receive docetaxel

4. Severe comorbidities:

1. Clinically significant (as determined by the investigator) hematological, hepatic
and renal dysfunction, defined as: Neutrophil count < 1.5 x 10^9/L and platelet
count < 100 x 10^9/L; bilirubin > 1.5 x ULN; AST and/or 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 pericarditis

5. History of interstitial lung disease

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

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

8. 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

9. Any other malignancy requiring anti-tumor treatment in the past three years,
excluding treated stage I prostate cancer, in situ cervical cancer, in situ
breast cancer and non-melanomatous skin cancer

5. Concurrent treatment with other experimental treatments for NSCLC while on the study

6. Implantable electronic medical devices (e.g. pacemaker, defibrillator) in the upper
torso

7. Known allergies to medical adhesives or hydrogel

8. Pregnancy or breast-feeding (patients with reproductive potential must use effective
contraception methods throughout the entire study period, as determined by their
investigator/gynecologist)

9. Admitted to an institution by administrative or court order