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.