{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:55:01Z","timestamp":1789761301009,"version":"4.0.1"},"reference-count":32,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"unspecified","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,7,31]]},"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>With nearly one-third of patients with advanced non-small cell lung cancer (NSCLC) and PD-L1 Tumor Proportion Score\u226550% surviving beyond 5 years following first-line pembrolizumab, long-term outcomes challenge traditional paradigms of cancer prognostication. The emergence of non-cancer-related factors and time-dependent trends underscores the need for advanced analytical frameworks to unravel their complex interplay.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analyzed the Pembro-real 5Y registry, a global real-world dataset of 1050 patients treated across 61 institutions in 14 countries with a long-term follow-up and a large panel of baseline variables. Two complementary approaches were employed: ridge regression, chosen for its ability to address multicollinearity while retaining interpretability, and not another imputation method (NAIM), a transformer-based artificial intelligence model designed to handle missing data without imputation. Endpoints included risk of death at 6, 12, 24, 60 months and 5-year survival.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The ridge regression model achieved a c-statistic of 0.66 (95% CI: 0.59 to 0.72) for the risk of death and an area under the curve (AUC) of 0.72 (95% CI: 0.65 to 0.78) for 5-year survival, identifying Eastern Cooperative Oncology Group Performance Status (ECOG-PS)\u22652, increasing age, and metastatic burden as primary risk factors. However, wide CIs for some predictors highlighted statistical instability. NAIM demonstrated robust handling of missing data, with a c-index of 62.98\u00b12.11 for risk of death and an AUC of 60.52\u00b13.71 for 5-year survival. The comprehensive SHapley Additive exPlanations analysis revealed dynamic, time-dependent patterns, with early mortality dominated by acute factors (eg, ECOG-PS, steroids) and long-term outcomes increasingly influenced by systemic health markers (eg, absence of hypertension, increasing body mass index). Unexpected insights included the protective role of dyslipidemia (but not statins) and the nuanced impact of smoking status, reflecting evolving disease dynamics and host-tumor interplay.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our integrative framework illuminates the complexity of long-term outcomes in patients with NSCLC treated with pembrolizumab, uncovering dynamic, non-linear prognostication trends. This analysis provides insights into patient trajectories, emphasizing the need for holistic, long-term management strategies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2025-012423","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T11:25:16Z","timestamp":1759145116000},"page":"e012423","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Transformer-based AI approach to unravel long-term, time-dependent prognostic complexity in patients with advanced NSCLC and PD-L1 \u226550%: insights from the pembrolizumab 5-year global registry"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1209-5735","authenticated-orcid":false,"given":"Alessio","family":"Cortellini","sequence":"first","affiliation":[{"name":"Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy"},{"name":"Department of Medicine and Surgery, Universit\u00e0 Campus Bio-Medico di Roma, Rome, Italy"},{"name":"Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Santo","sequence":"additional","affiliation":[{"name":"Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy"},{"name":"Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy"},{"name":"Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Garbo","sequence":"additional","affiliation":[{"name":"Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3529-0103","authenticated-orcid":false,"given":"David J","family":"Pinato","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College London, London, UK"},{"name":"Translational Medicine Department, University of Eastern Piedmont, Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"La Cava","sequence":"additional","affiliation":[{"name":"Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarushka","family":"Naidoo","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beaumont Hospital, Beaumont RCSI Cancer Centre, Dublin, Ireland"},{"name":"RCSI University of Health Sciences, Dublin, Ireland"},{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Katz","sequence":"additional","affiliation":[{"name":"Oncology Center, Hospital S\u00edrio-Liban\u00eas, S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Loza","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Oncology, Stanford University, Stanford Cancer Institute, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel W","family":"Neal","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Oncology, Stanford University, Stanford Cancer Institute, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Genova","sequence":"additional","affiliation":[{"name":"Academic Oncology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Gettinger","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4102-5880","authenticated-orcid":false,"given":"So Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Internal Medicine, Yale Cancer Center, Yale School of 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