SYSTEMATIC REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1635056
This article is part of the Research TopicPersonalized Immuno-Oncology: The Impact of Age and Sex on Anti-Tumor Immune ResponsesView all articles
Do age and performance status matter? A systematic review and network meta-analysis of immunotherapy studies in untreated advanced/metastatic non-oncogene addicted NSCLC
Provisionally accepted- 1Dipartimento di Oncologia, AO Pugliese Ciaccio, Catanzaro, Italy
- 2Oncology Unit, Tiberio Evoli Hospital, Melito di Porto Salvo, Reggio Calabria, Italy., Melito di Porto Salvo, Italy
- 3Universita degli Studi Magna Graecia di Catanzaro Dipartimento di Medicina Sperimentale e Clinica, Catanzaro, Italy
- 4Tuscany Tumor Association, Florence, Italy, Florence, Italy
- 5Oncology Unit, Azienda Ospedaliera-Universitaria Sant’Andrea, Rome, Italy, Rome, Italy
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Background. Immune checkpoint inhibitors (ICIs) redefined the treatment of non-small cell lung cancer (NSCLC) but their efficacy in elderly and frail patients remains unclear due to immune-senescence and the underrepresentation of these populations in clinical trials. This systematic review and meta-analysis aimed to evaluate and rank first-line ICI-based therapies in NSCLC, stratified by age and performance status (PS). Methods. A comprehensive search for randomized controlled trials (RCTs) of ICI regimens, pairwise and network meta-analyses (NMA) based on age (<65, ≥65, ≥75 years) and PS (0 vs. 1) were conducted. Endpoints were overall survival (OS) and progression-free survival (PFS). Results. ICIs significantly improved OS and PFS versus chemotherapy (CT) in most subgroups. No OS benefit was observed in patients over 75 years. In younger patients, ICI+CT combinations (e.g. pembrolizumab+CT, cemiplimab+CT, camrelizumab+CT) ranked highest for OS and PFS. Among ≥65y patients, cemiplimab ranked first reaching statistical significance in most comparisons, while pembrolizumab was the most effective option for PFS. Stratified by PS, cemiplimab+CT ranked highest for OS in PS 0 patients, whereas cemiplimab was preferred in PS 1 patients. Overall, combination regimens were more effective in younger/fit patients, while monotherapy was more effective in older/PS 1 patients, suggesting a different benefit-risk balance. Anti-PD-1 therapies (alone or in combination) outperformed anti-PD-L1 and anti-CTLA-4 therapies in OS. Conclusions. This meta-analysis highlights how the efficacy of ICIs in advanced NSCLC varies by age and PS. These findings support a tailored approach to immunotherapy and emphasize the need for trials specifically targeting frail and elderly populations.
Keywords: Non-small cell lung cancer, Checkpoint inhibitors, Network metanalysis, Systematic review, Frail, older
Received: 25 May 2025; Accepted: 05 Sep 2025.
Copyright: © 2025 Siciliano, d'Apolito, Del Giudice, Caridà, Grillone, PORZIO, Giusti, Tassone, Barbieri and Tagliaferri. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Pierosandro Tagliaferri, Universita degli Studi Magna Graecia di Catanzaro Dipartimento di Medicina Sperimentale e Clinica, Catanzaro, Italy
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