Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study

Ticiana Leal*, Rupesh Kotecha, LUNAR Study Investigators, Rodryg Ramlau, Li Zhang, Janusz Milanowski, Manuel Cobo, Jaromir Roubec, Lubos Petruzelka, Libor Havel, Sujith Kalmadi, Jeffrey Ward, Zoran Andric, Thierry Berghmans, David E. Gerber, Goetz Kloecker, Rajiv Panikkar, Joachim Aerts, Angelo Delmonte, Miklos PlessRichard Greil, Christian Rolfo, Wallace Akerley, Michael Eaton, Mussawar Iqbal, Corey Langer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1002-1017
Number of pages16
JournalThe Lancet Oncology
Volume24
Issue number9
DOIs
Publication statusPublished - Sept 2023

Bibliographical note

Funding Information:
The study was funded by Novocure. The authors thank the patients, their families, and all investigators involved in this study. Statistical analysis was performed by sponsor-funded personnel, including Gitit Lavy-Shahaf (Novocure, Haifa, Israel). Medical writing support under the direction of the authors was provided by Chelsea Higgins and Huda Ismail Abdullah (Global Publications, Novocure, New York, NY, USA), Rose Goodchild, and Melissa Purves (Prime, Knutsford, UK). Writing and editorial support provided by Prime was funded by Novocure and conducted according to Good Publication Practice guidelines. Simulations work was by Oshrit Zeevi (Novocure, Haifa, Israel). Authors DEG and JW receive funding from the National Institutes of Health. TL was previously affiliated with the University of Wisconsin Carbone Cancer Center (Madison, WI, USA). The sponsor was involved in the study design, collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.

Funding Information:
The study was funded by Novocure. The authors thank the patients, their families, and all investigators involved in this study. Statistical analysis was performed by sponsor-funded personnel, including Gitit Lavy-Shahaf (Novocure, Haifa, Israel). Medical writing support under the direction of the authors was provided by Chelsea Higgins and Huda Ismail Abdullah (Global Publications, Novocure, New York, NY, USA), Rose Goodchild, and Melissa Purves (Prime, Knutsford, UK). Writing and editorial support provided by Prime was funded by Novocure and conducted according to Good Publication Practice guidelines. Simulations work was by Oshrit Zeevi (Novocure, Haifa, Israel). Authors DEG and JW receive funding from the National Institutes of Health. TL was previously affiliated with the University of Wisconsin Carbone Cancer Center (Madison, WI, USA). The sponsor was involved in the study design, collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.

Publisher Copyright:
© 2023 Elsevier Ltd

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