{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T07:25:39Z","timestamp":1770708339114,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T00:00:00Z","timestamp":1770508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FEDER\u2014Fundo Europeu de Desenvolimento Regional"},{"name":"Portuguese funds","award":["UIDB\/4255\/2020"],"award-info":[{"award-number":["UIDB\/4255\/2020"]}]},{"name":"Portuguese funds","award":["RISE\u2014LA\/P\/0053\/2020"],"award-info":[{"award-number":["RISE\u2014LA\/P\/0053\/2020"]}]},{"name":"FCT and FEDER","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]},{"name":"FCT and FEDER","award":["PRR-09\/C06-834I07\/2024.P11721"],"award-info":[{"award-number":["PRR-09\/C06-834I07\/2024.P11721"]}]},{"name":"FCT and FEDER","award":["2024.18026.PEX"],"award-info":[{"award-number":["2024.18026.PEX"]}]},{"name":"Chair of Onco-Innovation at the FMUP"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Lung cancer in never-smokers is increasingly recognized as a distinct clinical and biological entity, often enriched for actionable oncogenic alterations and characterized by molecular profiles that differ from tobacco-associated disease. However, therapeutic evidence for this growing patient population has frequently been extrapolated from trials in which smokers predominate, potentially limiting treatment optimization and biomarker-driven decision-making. In this review, we map and critically appraise clinical trials registered in ClinicalTrials.gov that explicitly target never-smokers with lung cancer, focusing on therapeutic strategies, molecular stratification approaches, trial design features, and temporal trends. We discuss how eligibility definitions, histological and genomic enrichment, and endpoints have been handled across studies, and we highlight persistent gaps in dedicated trial activity, particularly in prospective biomarker-guided designs and contemporary platform strategies. Finally, we propose priorities for future trials to better reflect never-smoker lung cancer biology, improve external validity, and accelerate evidence generation for personalized therapeutic approaches in this population.<\/jats:p>","DOI":"10.3390\/cancers18040551","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T12:42:42Z","timestamp":1770640962000},"page":"551","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Landscape of Clinical Trials in Never-Smoker Non-Small-Cell Lung Cancer: Registered Evidence and Persistent Gaps"],"prefix":"10.3390","volume":"18","author":[{"given":"Raquel","family":"Ramos","sequence":"first","affiliation":[{"name":"PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty 12 of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0708-6874","authenticated-orcid":false,"given":"Carlos","family":"Sousa","sequence":"additional","affiliation":[{"name":"PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"Molecular Biology Department, SYNLAB Portugal, Rua Manuel Pinto de Azevedo, 401, 4100-321 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty 12 of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Laboratory of Personalized Medicine, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,8]]},"reference":[{"key":"ref_1","unstructured":"Ferlay, J.E.M., Lam, F., Laversanne, M., Colombet, M., Mery, L., Pi\u00f1eros, M., Znaor, A., Soerjomataram, I., and Bray, F. (2026, January 08). Global Cancer Observatory: Cancer Today, Available online: https:\/\/gco.iarc.who.int\/today."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e001021","DOI":"10.1136\/esmoopen-2020-001021","article-title":"Lung cancer symptoms at diagnosis: Results of a nationwide registry study","volume":"5","author":"Provencio","year":"2020","journal-title":"ESMO Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1158\/1055-9965.EPI-19-0221","article-title":"Cancer Progress and Priorities: Lung Cancer","volume":"28","author":"Schabath","year":"2019","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"981","DOI":"10.7150\/ijms.34739","article-title":"Molecular heterogeneity in lung cancer: From mechanisms of origin to clinical implications","volume":"16","author":"Bianco","year":"2019","journal-title":"Int. J. Med. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nooreldeen, R., and Bach, H. (2021). Current and Future Development in Lung Cancer Diagnosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168661"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S0140-6736(21)00312-3","article-title":"Lung cancer","volume":"398","author":"Thai","year":"2021","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ramos, R., Moura, C.S., Costa, M., Lamas, N.J., Correia, R., Garcez, D., Pereira, J.M., Lindahl, T., Sousa, C., and Vale, N. (2025). Lung Cancer Therapy: The Role of Personalized Medicine. Cancers, 17.","DOI":"10.3390\/cancers17050725"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ramos, R., Moura, C.S., Costa, M., Lamas, N.J., Correia, R., Garcez, D., Pereira, J.M., Sousa, C., and Vale, N. (2024). Enhancing Lung Cancer Care in Portugal: Bridging Gaps for Improved Patient Outcomes. J. Pers. Med., 14.","DOI":"10.3390\/jpm14050446"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s12935-023-02990-y","article-title":"Recent advances in non-small cell lung cancer targeted therapy; an update review","volume":"23","author":"Araghi","year":"2023","journal-title":"Cancer Cell Int."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ku\u015bnierczyk, P. (2023). Genetic differences between smokers and never-smokers with lung cancer. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1063716"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e174643","DOI":"10.1172\/jci.insight.174643","article-title":"The genomic landscape of lung cancer in never-smokers from the Women\u2019s Health Initiative","volume":"9","author":"Moorthi","year":"2024","journal-title":"JCI Insight"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Colombino, M., Paliogiannis, P., Cossu, A., Santeufemia, D.A., Pazzola, A., Fadda, G.M., Pirina, P., Fois, A., Putzu, C., and Ginesu, G. (2019). EGFR, KRAS, BRAF, ALK, and cMET genetic alterations in 1440 Sardinian patients with lung adenocarcinoma. BMC Pulm. Med., 19.","DOI":"10.1186\/s12890-019-0964-x"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Garrido, J., Bernal, Y., Gonz\u00e1lez, E., Blanco, A., Sep\u00falveda-Hermosilla, G., Freire, M., Or\u00f3stica, K., Rivas, S., Marcelain, K., and Owen, G. (2024). Beyond tobacco: Genomic disparities in lung cancer between smokers and never-smokers. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-12737-1"},{"key":"ref_14","unstructured":"Russo, A., Lopes, A.R., Scilla, K.A., Mehra, R., Adamo, V., Oliveira, J., Liu, S.V., and Rolfo, C. (2026, January 15). NTRK and NRG1 Gene Fusions in Advanced Non-Small Cell Lung Cancer (NSCLC). Available online: https:\/\/pcm.amegroups.org\/article\/view\/5551."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1200\/JCO.21.01691","article-title":"Genomic Profiling of Lung Adenocarcinoma in Never-Smokers","volume":"39","author":"Devarakonda","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.gpb.2023.03.006","article-title":"Non-small Cell Lung Cancer Epigenomes Exhibit Altered DNA Methylation in Smokers and Never-smokers","volume":"21","author":"Karlow","year":"2023","journal-title":"Genom. Proteom. Bioinform."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s00408-023-00661-3","article-title":"Lung Cancer in Never Smokers: Delving into Epidemiology, Genomic and Immune Landscape, Prognosis, Treatment, and Screening","volume":"201","author":"Daylan","year":"2023","journal-title":"Lung"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/s41571-023-00844-0","article-title":"Lung cancer in patients who have never smoked\u2014An emerging disease","volume":"21","author":"LoPiccolo","year":"2024","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1038\/s41588-021-00920-0","article-title":"Genomic and evolutionary classification of lung cancer in never smokers","volume":"53","author":"Zhang","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1016\/j.ejca.2013.06.035","article-title":"Three-arm randomised controlled phase 2 study comparing pemetrexed and erlotinib to either pemetrexed or erlotinib alone as second-line treatment for never-smokers with non-squamous non-small cell lung cancer","volume":"49","author":"Lee","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.lungcan.2012.03.011","article-title":"Randomized phase II trial of first-line treatment with pemetrexed-cisplatin, followed sequentially by gefitinib or pemetrexed, in East Asian, never-smoker patients with advanced non-small cell lung cancer","volume":"77","author":"Ahn","year":"2012","journal-title":"Lung Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1016\/j.ejca.2014.05.011","article-title":"First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: A randomised, phase 3 trial","volume":"50","author":"Yang","year":"2014","journal-title":"Eur. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"de Alencar, V.T.L., Figueiredo, A.B., Corassa, M., Gollob, K.J., and Cordeiro de Lima, V.C. (2022). Lung cancer in never smokers: Tumor immunology and challenges for immunotherapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.984349"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4072","DOI":"10.1158\/1078-0432.CCR-20-0397","article-title":"Identification of a RAS-activating TMEM87A-RASGRF1 Fusion in an Exceptional Responder to Sunitinib with Non-Small Cell Lung Cancer","volume":"26","author":"Cooper","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.cllc.2017.06.016","article-title":"Paired Phase II Studies of Erlotinib\/Bevacizumab for Advanced Bronchioloalveolar Carcinoma or Never Smokers With Advanced Non-Small-cell Lung Cancer: SWOG S0635 and S0636 Trials","volume":"19","author":"West","year":"2018","journal-title":"Clin. Lung Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.cllc.2015.12.006","article-title":"Results of a Phase II Trial of Carboplatin, Pemetrexed, and Bevacizumab for the Treatment of Never or Former\/Light Smoking Patients With Stage IV Non-Small Cell Lung Cancer","volume":"17","author":"Weiss","year":"2016","journal-title":"Clin. Lung Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e242","DOI":"10.1016\/j.cllc.2023.05.003","article-title":"Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked","volume":"24","author":"Bodor","year":"2023","journal-title":"Clin. Lung Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6234","DOI":"10.1002\/cncr.27630","article-title":"Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): An open-label, phase 3 trial","volume":"118","author":"Sun","year":"2012","journal-title":"Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1200\/JCO.2011.36.8456","article-title":"First-SIGNAL: First-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung","volume":"30","author":"Han","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8483","DOI":"10.1038\/s41598-017-08399-8","article-title":"Intercalating and maintenance gefitinib plus chemotherapy versus chemotherapy alone in selected advanced non-small cell lung cancer with unknown EGFR status","volume":"7","author":"Jian","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1200\/JCO.2011.40.1315","article-title":"Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial","volume":"30","author":"Wang","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.biopha.2018.04.117","article-title":"Molecular Landscape in Alveolar Soft Part Sarcoma: Implications for Molecular Targeted Therapy","volume":"103","author":"Soheilifar","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e37348","DOI":"10.1016\/j.heliyon.2024.e37348","article-title":"Sorafenib safety evaluation: Real-world analysis of adverse events from the FAERS database","volume":"10","author":"Ning","year":"2024","journal-title":"Heliyon"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Adamopoulos, C., Papavassiliou, K.A., Poulikakos, P.I., and Papavassiliou, A.G. (2024). RAF and MEK Inhibitors in Non-Small Cell Lung Cancer. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25094633"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3845","DOI":"10.7150\/ijbs.70958","article-title":"VEGF\/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment","volume":"18","author":"Zhao","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s40880-017-0187-6","article-title":"Proportion and clinical features of never-smokers with non-small cell lung cancer","volume":"36","author":"Cho","year":"2017","journal-title":"Chin. J. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s41512-024-00166-4","article-title":"Risk prediction models for lung cancer in people who have never smoked: A protocol of a systematic review","volume":"8","author":"Issanov","year":"2024","journal-title":"Diagn. Progn. Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Giansanti, D., and Morelli, S. (2025). Exploring the Potential of Digital Twins in Cancer Treatment: A Narrative Review of Reviews. J. Clin. Med., 14.","DOI":"10.3390\/jcm14103574"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1186\/s12967-025-06371-z","article-title":"From virtual to reality: Innovative practices of digital twins in tumor therapy","volume":"23","author":"Shen","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1001\/jama.287.9.1132","article-title":"Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution","volume":"287","author":"Pope","year":"2002","journal-title":"JAMA"},{"key":"ref_41","first-page":"460","article-title":"Outdoor air pollution and cancer: An overview of the current evidence and public health recommendations","volume":"70","author":"Turner","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1164\/rccm.201106-1011OC","article-title":"Long-term ambient fine particulate matter air pollution and lung cancer in a large cohort of never-smokers","volume":"184","author":"Turner","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/4\/551\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T13:04:22Z","timestamp":1770642262000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/4\/551"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,8]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cancers18040551"],"URL":"https:\/\/doi.org\/10.3390\/cancers18040551","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,8]]}}}