TPS8665 Background: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability. TTFields are delivered by a noninvasive portable device that has the European CE Mark and FDA approval for glioblastoma and mesothelioma. Preclinical non-small cell lung cancer (NSCLC) studies demonstrated that TTFields enhance the antitumor immune response, through disruption of mitosis and subsequent induction of immunogenic cell death. The pivotal, phase III LUNAR study (NCT02973789) in metastatic NSCLC progressing on/after platinum-based therapy demonstrated that TTFields with an immune checkpoint inhibitor (ICI) or docetaxel provided a statistically significant and clinically meaningful 3.3-month improvement in median overall survival (OS) vs an ICI or docetaxel alone, with no added systemic toxicities and no clinically significant difference on quality of life between groups. Despite advances in the treatment of NSCLC, survival rates for stage IV disease remain poor and there is a need for effective and tolerable treatments. Methods: LUNAR-2 (NCT06216301) is a pivotal, global, randomized, trial investigating the efficacy and safety of TTFields concomitant with pembrolizumab (P) and platinum-based chemotherapy (C) in patients (pts) with metastatic NSCLC, with a planned enrollment of 734 pts at 134 sites. Pts with NSCLC, radiologically evaluable disease in the thorax, ECOG PS of 0–1, and no prior treatment for metastatic disease are eligible. Pts will be stratified by histology, PD-L1 Tumor Proportion Score (TPS) and prior treatment with immunotherapy. Randomization is 1:1 to TTFields/P+C or P+C alone. Standard doses of P+C will be administered to both arms on day 1 of a 21-day cycle for 4 cycles of induction followed by up to 31 cycles of maintenance with TTFields/P or P alone. TTFields generated by the NovoTTF-200T System, will be delivered to the thorax ≥ 18 h/day until local disease progression per iRECIST. The primary endpoints are OS and progression-free survival (PFS) per RECIST v1.1 as assessed by a blinded independent central review (BICR). Secondary endpoints include OS and PFS according to histology or PD-L1 TPS, objective response rate, duration of response, and disease control rate, all per RECIST v1.1 as assessed by BICR and by investigator, comparing TTFields/P+C vs. P+C alone. Other secondary endpoints include PFS rates at 6, 12, 24 and 36 months per RECIST v1.1 as assessed by BICR, 1-, 2-, and 3-year survival rates and safety. Device Support Specialists will provide technical and lifestyle integration training for pts and caregivers throughout TTFields therapy. Pts usage is tracked by the device and is provided to pts and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. The trial is currently recruiting. Clinical trial information: NCT06216301 .