The study is a prospective, randomized controlled phase III trial aimed to test the efficacy and safety of TTFields, using the NovoTTF-200T device, concurrent with standard therapies for stage 4 NSCLC patients, following progression while on or after platinum based treatment. The device is an experimental, portable, battery operated device for chronic administration of alternating electric fields (termed TTFields or TTF) to the region of the malignant tumor, by means of surface, insulated electrode arrays.

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 (some regional variations to inclusion age exist)

2. Life expectancy of ≥ 3 months

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

4. Diagnosis of radiological progression while on or after first platinum-based systemic therapy administered for advanced or metastatic disease.

   1. Patients who received adjuvant or neoadjuvant platinum-based chemotherapy (after surgery and/or radiation therapy) and developed metastatic disease within 6 months of completing therapy are eligible.
   2. Patients with metastatic disease more than 6 months after adjuvant or neoadjuvant platinum-based chemotherapy, who also subsequently progressed during or after a platinum- based regimen given to treat the advanced or metastatic disease, are eligible.
   3. Patients should not receive any systemic therapy after platinum failure before enrollment into the study. Maintenance therapy after platinum based therapy and prior to progression is allowed.

5. ECOG Score of 0-2

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

7. Able to operate the NovoTTF-200T device independently or with the help of a caregiver

8. Signed informed consent for the study protocol

Exclusion Criteria:

1. Metastases to central nervous system (CNS) with clinical symptoms or evidence of new metastases to CNS during screening. Patients who previously received treatments for the metastases to CNS, are stable and meet the following requirements are allowed to be enrolled:

   1. The patients are neurologically returned to baseline (except for residual signs or symptoms related to CNS treatment).
   2. No treatment for the metastases to CNS during the screening period (e.g. surgery, radiotherapy, corticosteroid therapy- prednisone > 10 mg/day or equivalent).
   3. No progress in CNS lesions as indicated by MRI within 14 days prior to randomization.
   4. No meningeal metastasis or spinal cord compression.

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