A text-mining approach to study the real-world effectiveness and potentially fatal immune-related adverse events of PD-1 and PD-L1 inhibitors in older patients with stage III/IV non-small cell lung cancer

(2023) 23:247 Abedian Kalkhoran et al. BMC Cancer https://doi.org/10.1186/s12885-023-10701-z BMC Cancer Open Access RESEARCH A text‑mining approach to study the real‑world effectiveness and potentially fatal immune‑related adverse events of PD‑1 and PD‑L1 inhibitors in older patients with stage III/IV non‑small cell lung cancer Hanieh Abedian Kalkhoran1,2*, Juliëtte Zwaveling1, Bert N. Storm2, Sylvia A. van Laar1, Johanneke EA Portielje3, Henk Codrington4, Dieuwke Luijten4, Pepijn Brocken4, Egbert F. Smit5 and Loes E. Visser2,6,7 Abstract Background This study was designed to investigate the impact of age on the effectiveness and immune-related adverse events (irAEs) of programmed death-(ligand)1 [PD-(L)1] inhibitors in patients with non-small cell lung cancer (NSCLC) using a novel text-mining technique. Methods This retrospective study included patients with stage III/IV NSCLC treated with a PD-(L)1 inhibitor (nivolumab, pembrolizumab, atezolizumab and durvalumab) at Leiden University Medical Centre and Haga Teaching hospital, (both in The Netherlands) from September 2016 to May 2021. All the relevant data was extracted from the structured and unstructured fields of the Electronic Health Records using a novel text-mining tool. Effectiveness [progression-free survival (PFS) and overall survival (OS)] and safety (the incidence of nine potentially fatal irAEs and systemic corticosteroid requirement) outcomes were compared across age subgroups (young: < 65 years, Middleaged: 65–74 years, and old: ≥ 75 years) after adjustment for confounding. Results Of 689 patients, 310 patients (45.0%) were < 65 years, 275 patients (39.9%) were aged between 65 and 74 years, and 104 patients (15.1%) were ≥ 75 years. There was no significant difference between younger and older patients regarding PFS (median PFS 12, 8, 13 months respectively; Hazard ratio (HR)middle-aged = 1.14, 95% CI 0.92–1.41; HRold = 1.10, 95% CI 0.78–1.42). This was also the case for OS (median OS 19, 14, 18 months respectively; HRmiddle-aged = 1.22, 95% CI 0.96–1.53; HRold = 1.10, 95% CI 0.79–1.52). Safety analysis demonstrated a higher incidence of pneumonitis among patients aged 65–74. When all the investigated irAEs were pooled, there was no statistically significant difference found between age and the incidence of potentially fatal irAEs. Conclusions The use of PD-(L)1 inhibitors is not associated with age related decrease of PFS and OS, nor with increased incidence of serious irAEs compared to younger patients receiving these treatments. Chronological age must therefore not be used as a predictor for the effectiveness or safety of ICIs. *Correspondence: Hanieh Abedian Kalkhoran Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Abedian Kalkhoran et al. BMC Cancer (2023) 23:247 Page 2 of 12 Keywords Non-small cell lung cancer (NSCLC), Immune checkpoint inhibitor (ICI), Anti-PD-(L)1 therapy, Real-world, Elderly Background Lung cancer is the leading cause of cancer-related mortality worldwide, with 2.21 million new cases and approximately 1.8 million deaths reported globally in 2020 [1]. The poor prognosis of this disease is largely due to its often late diagnosis at advanced or metastatic stage. Incidence increases significantly with age, with a median age of 70 years old at diagnosis [2]. Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases [3]. The introduction of immune checkpoint inhibitors (ICIs), in particular anti-programmed cell death-protein 1 (anti-PD-1, nivolumab and pembrolizumab) and antiprogrammed death ligand-1 (anti-PD-L1, atezolizumab and durvalumab) antibodies, has revolutionised the management of NSCLC in the last decade. PD-(L)1 inhibitors, as monotherapy or in combination with chemotherapy, are currently indicated for the first-line treatment or as consolidation therapy of stage III and IV NSCLC. Several randomised clinical trials (RCTs) and observational studies have shown improved patient outcomes in terms of progression-free survival (PFS) and overall survival (OS) compared to conventional cancer treatment options [4–8]. Additionally, the safety profile of PD-(L)1 inhibitors appears to be more favourable compared to cytotoxic chemotherapy agents [9]. However, due to the activation of autoreactive T cells in a variety of host tissues, ICIs are associated with a considerable risk of immune-related adverse events (irAEs). These irAEs can affect any organ, but are mainly detected in colon, liver, lungs, pituitary, thyroid and skin [10]. Additionally, several reports have been made about uncommon, potentially fatal irAEs during the past years [11–14]. In fact, ICIs have been associated with potentially fatal toxicities in 0.4% to 1.2% of the patients [15]. Due to the scarcity of these fatal irAEs, the exact estimation of their incidence is challenging. According to an analysis from the World Health Organization (WHO) pharmacovigilance database, colitis, pneumonitis, hepatitis, myocarditis, myositis, nephritis, myasthenia gravis, encephalitis and meningitis are among the most common fatal toxic effects associated with PD-(L)1 inhibitors [16]. All the aforementioned adverse events are listed as potential irADRs in the summary of product characteristics (SmPC) of PD-(L)1 inhibitors. While older adults constitute the majority of NSCLC patients in clinical practice, our knowledge on effectiveness and safety of many novel treatment options in elderly patients has remained limited due to their underrepresentation in clinical trials. Despite the fact that over 60% of patients with NSCLC receiving ICIs in clinical practice are older than 65 years, this group only made up 8% of the clinical trial participants in the CheckMate 017 and 057 trials [4, 5] and 10–15% in the Keynote 042 and 024 trials [16, 17]. It is worth mentioning that the results of a small subgroup anal (...truncated)