LUNAR - A Phase 3 Trial of TTFields in Combination with PD-1 Inhibitors or Docetaxel for 2nd Line Treatment of Non-Small-Cell Lung Cancer (NSCLC)

Background: Tumor Treating Fields (TTFields) is a novel, non‐invasive, anti‐mitotic treatment modality, based on low intensity alternating electric fields. TTFields predominantly affect two phases of mitosis: metaphase ‐ by disrupting the mitotic spindle, and cytokinesis ‐ by dielectrophoretic dislocation of organelles. TTFields were shown to extend the survival of newly diagnosed glioblastoma patients when combined with temozolomide. Efficacy of TTFields in non‐small cell lung cancer (NSCLC) of all histologies has been demonstrated multiple preclinical models as well as in a phase I/II study in combination with pemetrexed, where overall survival was extended in more than five months compared to historical controls. Methods: The hypothesis of the study is that the addition of TTFields to standard of care second line therapies in advanced NSCLC will increase OS compared to treatment with standard second line alone. 512 patients with either squamous or non‐squamous NSCLC will be enrolled in this prospective, randomized study. Patients will be stratified based on: 1) second line therapy (either PD‐1 inhibitor or docetaxel), histology (squamous Vs. non‐squamous) and geographical region. The main eligibility criteria are first disease progression (per RECIST Criteria 1.1), ECOG score of 0‐1, no prior surgery or radiation therapy, no electronic medical devices in the upper torso and absence of brain metastasis. Docetaxel or PD‐1 inhibitors (nivolumab or pembrolizumab) will be administered at the standard dose. TTFields will be applied to the upper torso using a small, portable medical device for at least 18 hours/day at home, allowing patients to maintain daily activities. TTFields will be continued until progression in the thorax and/or liver according to the immune‐related response criteria (irRC). Follow up will be performed once q6 weeks, including a CT scan. Following progression in the upper torso, patients will be followed monthly for survival. The primary endpoint will be superiority in overall survival (OS) between patients treated with TTFields in combination with either docetaxel or PD‐1 inhibitors, compared to docetaxel or PD‐1 inhibitors alone. A coprimary endpoint will compare the OS in patients treated with TTFields and docetaxel to those treated with PD‐1 inhibitors alone in a non‐inferiority analysis. Secondary endpoints include progression‐free survival, radiological response rate based on the irRC, quality of life based on the EORTC QLQ C30 questionnaire and severity & frequency of adverse events. The sample size is powered to detect a Hazard Ratio of 0.75 of TTFieldstreated patients compare to the control group.