BACKGROUND: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell survival, leading to immunogenic cell death and enhanced antitumour immune response. In preclinical models of non-small-cell lung cancer, TTFields amplified the effects of chemotherapy and immune checkpoint inhibitors. We report primary results from a pivotal study of TTFields therapy in metastatic non-small-cell lung cancer. METHODS: This randomised, open-label, pivotal phase 3 study recruited patients at 130 sites in 19 countries. Participants were aged 22 years or older with metastatic non-small-cell lung cancer progressing on or after platinum-based therapy, with squamous or non-squamous histology and ECOG performance status of 2 or less. Previous platinum-based therapy was required, but no restriction was placed on the number or type of previous lines of systemic therapy. Participants were randomly assigned (1:1) to TTFields therapy and standard systemic therapy (investigator's choice of immune checkpoint inhibitor [nivolumab, pembrolizumab, or atezolizumab] or docetaxel) or standard therapy alone. Randomisation was performed centrally using variable blocked randomisation and an interactive voice-web response system, and was stratified by tumour histology, treatment, and region. Systemic therapies were dosed according to local practice guidelines. TTFields therapy (150 kHz) was delivered continuously to the thoracic region with the recommendation to achieve an average of at least 18 h/day device usage. The primary endpoint was overall survival in the intention-to-treat population. The safety population included all patients who received any study therapy and were analysed according to the actual treatment received. The study is registered with ClinicalTrials.gov, NCT02973789. FINDINGS: Between Feb 13, 2017, and Nov 19, 2021, 276 patients were enrolled and randomly assigned to receive TTFields therapy with standard therapy (n=137) or standard therapy alone (n=139). The median age was 64 years (IQR 59-70), 178 (64%) were male and 98 (36%) were female, 156 (57%) had non-squamous non-small-cell lung cancer, and 87 (32%) had received a previous immune checkpoint inhibitor. Median follow-up was 10·6 months (IQR 6·1-33·7) for patients receiving TTFields therapy with standard therapy, and 9·5 months (0·1-32·1) for patients receiving standard therapy. Overall survival was significantly longer with TTFields therapy and standard therapy than with standard therapy alone (median 13·2 months [95% CI 10·3-15·5] vs 9·9 months [8·1-11·5]; hazard ratio [HR] 0·74 [95% CI 0·56-0·98]; p=0·035). In the safety population (n=267), serious adverse events of any cause were reported in 70 (53%) of 133 patients receiving TTFields therapy plus standard therapy and 51 (38%) of 134 patients receiving standard therapy alone. The most frequent grade 3-4 adverse events were leukopenia (37 [14%] of 267), pneumonia (28 [10%]), and anaemia (21 [8%]). TTFields therapy-related adverse events were reported in 95 (71%) of 133 patients; these were mostly (81 [85%]) grade 1-2 skin and subcutaneous tissue disorders. There were three deaths related to standard therapy (two due to infections and one due to pulmonary haemorrhage) and no deaths related to TTFields therapy. INTERPRETATION: TTFields therapy added to standard therapy significantly improved overall survival compared with standard therapy alone in metastatic non-small-cell lung cancer after progression on platinum-based therapy without exacerbating systemic toxicities. These data suggest that TTFields therapy is efficacious in metastatic non-small-cell lung cancer and should be considered as a treatment option to manage the disease in this setting. FUNDING: Novocure.

Abramson Cancer Center Perelman School of Medicine University of Pennsylvania Philadelphia PA USA

Cancer Cluster Salzburg Austria

Center for Thoracic Oncology Tisch Cancer Institute at Icahn School of Medicine Mount Sinai New York NY USA

College of Medicine University of Saskatchewan Saskatoon SK Canada

Department of Pulmonary Medicine The Erasmus MC Cancer Institute Erasmus University Medical Center Rotterdam Netherlands

Geisinger Cancer Institute Danville PA USA

General University Hospital Prague Prague Czech Republic

Harold C Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center Dallas TX USA

Huntsman Cancer Institute University of Utah Salt Lake City UT USA

IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori Meldola Italy

Ironwood Cancer and Research Centers Chandler AZ USA

Jules Bordet Institute Hôpital Universitaire de Bruxelles Université Libre de Bruxelles Brussels Belgium

Kantonsspital Winterthur Winterthur Switzerland

Medical Oncology Intercenter Unit Regional and Virgen de la Victoria University Hospitals IBIMA Málaga Spain

Medical University of Lublin Lublin Poland

Miami Cancer Institute Baptist Health South Florida Miami FL USA

Nemocnice AGEL Ostrava Vítkovice Ostrava Czech Republic

Paracelsus Medical University Salzburg Salzburg Austria

Poznan University of Medical Sciences Poznan Poland

Salzburg Cancer Research Institute Center for Clinical Cancer and Immunology Trials Salzburg Austria

St Francis Hospital Indianapolis IN USA

State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat sen University Cancer Center Guangzhou China

Thomayer Hospital Prague Czech Republic

University Clinical Hospital Centre Bezanijska Kosa Belgrade Serbia

University of Louisville Louisville KY USA

Washington University School of Medicine St Louis MO USA

Winship Cancer Institute at Emory University Atlanta GA USA

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