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.

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.

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests TL reports support towards this manuscript from Novocure; institutional grants or contracts from Advaxis and Pfizer; consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint, Daiichi-Sankyo, Eisai, Eli Lilly, EMD Serono, Genentech, Janssen, Jazz Pharmaceuticals, Merck, Mirati, Novocure, Regeneron, Roche, and Takeda; honoraria from Aptitude Health, ASTRO, Bioascend, Cardinal Health, Curio, GRACE, I3 Health, IDEO, Larvol, Medscape, Peerview Institute for Medical Education, OncLive, Opinions in Lung Cancer, Society for Immunotherapy of Cancer, Targeted Oncology, UpToDate, and Vindico; and board participation or a leadership position for the National Cancer Institute and Georgia Society of Clinical Oncology. RK reports institutional grants or contracts from AstraZeneca, Blue Earth Diagnostics, Brainlab, Cantex Pharmaceuticals, Exelixis, GT Medical Technologies, Medtronic, Novocure, and ViewRay; consulting fees from Castle Biosciences, Elekta, Kazia Therapeutics, and ViewRay; honoraria from Accuray, Brainlab, Elekta, Elsevier, Novocure, Peerview Institute for Medical Education, and ViewRay; support for travel or meeting attendance from Accuray, Elekta, Novocure, and the Peerview Institute for Medical Education; and participation on an advisory board for ViewRay. RR reports consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Merck, MSD, Parexel, Pfizer, Roche, and Takeda; advising or speaking fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, MSD, Novartis, Parexel, Pfizer, and Roche; support for meetings or travel from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, MSD, Novartis, Parexel, Pfizer, Roche, and Takeda; and participation on an advisory board for Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Parexel, Pfizer, Roche, and Takeda. LZ reports participation on a data safety monitoring board or advisory board for AstraZeneca and BeiGene. SK reports honoraria as a speaker for AstraZeneca, Bayer, G1 Therapeutics, Genentech, and Pfizer. JW reports institutional grants from the American Cancer Society, American Lung Association, AstraZeneca, Central Society for Clinical and Translational Research, Gateway for Cancer Research, National Institutes of Health, and Siteman Cancer Center; consulting fees from Novoure and Takeda; honoraria from Washington University Continuing Medical Education and OncLive; support for travel or meeting attendance from Neon Therapuetics; and participation on a data safety monitoring or advisory board for Washington University. TB reports consultancy fees from InhaTarget; participation on a safety monitoring board or advisory board for Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Merck, and Roche; support for travel or meeting attendance from Takeda. DEG reports institutional grants from AstraZeneca, BerGenBio, Karyoparhm, and Novocure; consulting fees from Catalyst Pharmaceuticals; participation on a data safety monitoring or advisory board for BeiGene, Daiichi-Sankyo, Elevation Oncology, Janssen, Mirati, Regeneron, and Sanofi; stock or stock options with Gilead, Medtronic, and Walgreens; and a financial interest in OncoSeer Diagnostics. GK reports honoraria as a speaker or advisory board member from Amgen, AstraZeneca, Bristol-Myers Squibb, EMD Serono, Genentech, Merck, Novartis, and Regeneron; royalties from McGraw Hill; and consulting fees from Primum. RP reports institutional funding from the National Cancer Institute, and a leadership position and travel support from the National Community Oncology Dispensing Association. JA reports honoraria from AstraZeneca, Eli Lilly, and MSD; participation on a data safety monitoring or advisory board for Amphera, AstraZeneca, Bristol-Myers Squibb, MSD, and Takeda; stock or stock options with Amphera; and a leadership role with The International Association for the Study of Lung Cancer (IASLC). AD reports honoraria from Bristol-Myers Squibb; support for meeting attendance or travel from MSD and Roche; and participation on a data safety or advisory board for Novartis, Sanofi, and Takeda. MP reports consulting fees from Abbvie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eisei, Merck, MSD, Novartis, Pfizer, Roche, and Takeda; honoraria from Amgen, Bayer, Janssen, Nestle, and Sanofi; and support for meeting attendance or travel from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Takeda, and Vifor. RG reports consulting fees, honoraria, participation on a safety monitoring board or advisory board, or support for attending meetings or travel from Abbvie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Janssen, Merck, MSD, Novartis, Roche, Takeda, Sandoz, and Sanofi; and stock or stock options for Eli Lilly and Novo Nordisk. CR reports institutional funding from Pfizer and U54; consulting fees from Archer, Bayer, Boston Pharm, CEA, Daiichi Sankyo, EMD Serono, Eisai, General Dynamics, Genzyme, Inivata, Janssen, Medstar, Mirati, Novartis, Regeneron, and Sanofi; honoraria from AstraZeneca, COR2ED, Intellisphere, MSD, Physicians’ Education Resource, and Roche; and leadership roles with the European Society for Medical Oncology, Elsevier, the European School of Oncology, the International Society of Liquid Biopsy, and the IASLC. WA reports institutional grants from AstraZeneca and Bristol-Myers Squibb. CL reports research funding from AstraZeneca, Eli Lilly, Fujifilm, Janssen Pharmaceuticals, Inovio, Merck, Oncocyte, Takeda, and Trizell, consulting fees from AstraZeneca, Boehringer lngelheim, Genentech/Roche, Gilead, GSK, Merck, Mirati, Novocure, Pfizer, Regeneron, Sanofi-Aventis, and Takeda; participation on a safety monitoring board or advisory board for Amgen, OncocyteDX, the Radiation Therapy Oncology Group Foundation, and the Veterans Administration; and received medical writing support from Novartis. All other authors declare no competing interests.