Background: TTFields are electric fields that disrupt processes critical for cancer cell viability. TTFields are delivered by a noninvasive portable device that is FDA approved for glioblastoma and mesothelioma. Preclinical NSCLC studies demonstrated that TTFields enhance the antitumor immune response, through disruption of mitosis and subsequent induction of immunogenic cell death. In addition, TTFields were shown to synergize with taxanes and immune checkpoint inhibitors (ICIs). The global, randomized, phase 3 LUNAR study (NCT02973789) assessed TTFields therapy with SOC (investigator’s choice ICI or docetaxel [DTX]) for previously treated mNSCLC. Methods: Adults with mNSCLC progressing on or after platinum therapy (prior ICI permitted) and ECOG PS ≤2 were randomized 1:1 to TTFields + SOC or SOC. TTFields therapy (150 kHz) was delivered continuously until progression or intolerable toxicity. Primary endpoint was overall survival (OS). Key secondary endpoints were OS in ICI and DTX subgroups. Other secondary endpoints included progression-free survival (PFS) and adverse events (AEs). Results: 276 patients were randomized between Feb 2017 and Nov 2021 to receive TTFields + SOC (n=137) vs SOC (n=139). Baseline characteristics were balanced: median (m) age 64 years (range, 22–86); 65% male; 56% non-squamous; 96% ECOG PS 0–1; 89% one prior line of systemic therapy; 31% prior ICI. OS was significantly extended with TTFields + SOC vs SOC. After a minimum follow-up of 12 months (mo), mOS (95% CI) was 13.2 (10.3–15.5) mo with TTFields + SOC vs 10.0 (8.2–12.2) mo with SOC (HR 0.74; 95% CI 0.56–0.98; P=0.037). 1-year survival rates (95% CI) were 53% (44–61) and 42% (34–50), respectively (P=0.040). mPFS was 4.8 (4.1–5.7) mo and 4.1 (3.0–4.7) mo (HR 0.87; 95% CI 0.67–1.14), respectively. In patients receiving an ICI (n=134), TTFields significantly improved OS vs ICI alone: mOS (95% CI) 18.5 (10.6–30.3) vs 10.6 (8.2–17.6) mo (HR 0.63; 95% CI 0.41–0.96; P=0.032). In the DTX subgroup (n=142), patients who received TTFields had a numerically higher mOS vs DTX alone: 11.1 (95% CI 8.2–14.1) mo vs 8.9 (95% CI 6.5–12.2) mo (HR 0.87; 95% CI 0.60–1.26). The rate of AEs was similar between groups (97% TTFields + SOC vs 91% SOC). The incidence of TTFields-related AEs was 71%; majority were grade 1 and 2 local skin irritation; 8 patients (6%) reported a grade 3 AE. There were no grade 4 toxicities and no deaths attributable to TTFields. Conclusions: TTFields therapy significantly extended OS in patients with mNSCLC following platinum failure without exacerbating systemic toxicities, and with few high-grade device-related AEs. The efficacy and safety demonstrated in this phase 3 study warrant inclusion of TTFields therapy as part of second line SOC in mNSCLC. Clinical trial information: NCT02973789.