Lung cancer is the leading cause of cancer-related deaths worldwide (1). Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases, with the majority of NSCLC cases being diagnosed at an advanced, unresectable, and metastatic disease stage (2). Immune checkpoint inhibitors (ICIs), such as programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) antibodies, have improved the prognosis of advanced NSCLC. The PD-L1 tumor proportion score (TPS) is used as a predictor associated with treatment response (3, 4). In several phase 3 clinical trials, ICI monotherapy (MONO) has shown outstanding efficacy compared to chemotherapy in patients with NSCLC and PD-L1 TPS ≥ 50% and has been established as a standard first-line treatment option for such patients (5, 6). Concurrently, numerous phase 3 clinical trials for advanced NSCLC, regardless of PD-L1 TPS, have reported significantly improved clinical outcomes in patients treated with combination therapy of ICI and chemotherapy (COMBO) compared to those treated with chemotherapy alone. COMBO is thus considered as a standard first-line treatment for NSCLC (7–10). Similar to MONO, an association between PD-L1 TPS and therapeutic response has been reported in patients who received COMBO. Long-term follow-up analyses have shown favorable treatment responses particularly in the PD-L1 TPS ≥50% population (11, 12). Therefore, both MONO and COMBO are effective first-line treatment options for NSCLC patients with PD-L1 TPS ≥ 50%.

The proportion of older patients diagnosed with advanced-stage lung cancer has been increasing owing to the aging of the population (13), with almost half of all lung cancer cases occurring in patients aged 70 years or more (14). Consequently, formulating a treatment strategy for older patients with NSCLC is essential. However, evidence based on the clinical trials specifically for older patients is limited.

Pooled analyses of clinical trials involving pembrolizumab monotherapy in patients with PD-L1-positive advanced NSCLC reported a longer overall survival (OS) and superior safety profiles compared to standard chemotherapy in older patients with PD-L1 TPS ≥ 50%. However, approximately 40% of the older patients with NSCLC still experience mortality within 1 year, thus limiting the benefits of pembrolizumab monotherapy in this subgroup (15). Nonetheless, data on the efficacy and safety of COMBO for older patients are lacking, as COMBO may lead to more severe adverse events in older patients and is currently recommended only for a select group of patients (16). As such, the question of whether MONO or COMBO should be the preferred treatment choice for older patients with NSCLC and PD-L1 TPS ≥ 50% remains unanswered.

To this end, in this retrospective study, we conducted a real-world assessment to compare the efficacy and safety of MONO and COMBO in older patients with NSCLC and PD-L1 TPS ≥ 50%. In this study, we aimed to provide clarity on which clinical populations benefit from the addition of chemotherapy to ICI treatment.

Aging is a complex process characterized by the accrual of genetic and environmental factors, leading to a diverse array of alterations, such as diminished telomeres, genomic instability, impaired mitochondrial function, disruption of protein homeostasis, epigenetic modifications, declining immune system functionality, and the onset of cellular senescence. Furthermore, increasing age heightens the susceptibility to developing lung cancer, a phenomenon that is exacerbated by the growing aging population worldwide (21). Aging has also been reported to reduce the generation of new T cells from the thymus and impair T cell diversity, indicating that the adverse consequences of aging on T cells could potentially influence therapeutic efficacy (22).

In this study, we retrospectively analyzed the treatment outcomes in older patients with NSCLC and with PD-L1 TPS ≥ 50% who received MONO or COMBO as first-line treatment, both of which are recognized as standard first-line treatment options for patients with NSCLC and high PD-L1 TPS. Our findings indicated that there were no significant differences in PFS and OS between MONO and COMBO in patients with NSCLC aged ≥ 70 years with PD-L1 TPS ≥ 50%. However, notably, in patients with an ECOG PS 0 or those with non-squamous cell carcinoma, both PFS and OS were significantly longer in the COMBO group compared to the MONO group. To the best of our knowledge, this study is the first to identify clinical factors in an older NSCLC population that may benefit from COMBO rather than from MONO, which may be applied as predictors for clinical decision-making in this population.

Despite the valuable insights provided by our study, several limitations should be acknowledged. First, this study was a retrospective, nonrandomized study. Thus, the possibility of selection bias cannot be ruled out. However, we conducted PSM to reduce selection bias. Second, adverse events and complications are always a concern in chemotherapy for older patients, but this study did not mention either in detail. Third, in the MONO group, subsequent therapy after progression of first line pembrolizumab monotherapy may have affected the prognosis. However, our study had a lack of data about the detail of second line treatment, and we could not investigate these association. Finally, the study included only Japanese patients, and patient sample size was limited, essentializing the need for a global larger cohort to validate our novel findings.

In this study, the treatment efficacy did not differ between MONO and COMBO in the older population. A pooled analysis of phase 3 clinical trials previously reported that most patient subgroups with NSCLC and PD-L1 TPS ≥ 50% may achieve comparable or superior OS and PFS outcomes compared to MONO, whereas the outcomes of the subgroup analysis based on age in this study indicate that elderly patients receiving COMBO may not have improved outcomes over MONO (23). Additionally, recent analysis and real-world data reported MONO is generally preferred in older patients with NSCLC and PD-L1 TPS ≥ 50% (24, 25). In our subgroup analysis of patients ≥70 years, COMBO also did not show an improvement over MONO in OS or PFS outcomes, suggesting that the benefits of adding chemotherapy to MONO might be more limited in older patients with NSCLC compared to that in their younger counterparts. Based on these results, when considering the addition of chemotherapy to MONO for older NSCLC patients with high PD-L1 TPS, it becomes critical to appropriately select patients with predictive factors for better efficacy, particularly in this older demographic. Further studies are needed to identify clinical biomarkers that correlate with the treatment outcome for the efficacy and tolerability of COMBO in older patients.

Our study showed that COMBO yielded better clinical outcomes than MONO in patients with ECOG PS 0, while no significant difference was observed in patients with ECOG PS 1, suggesting that a more detailed assessment of general conditions at pretreatment may be useful for treatment selection in older patients. Similarly, the JCOG1210/WJOG7813L trial, in which carboplatin/pemetrexed treatment was compared with docetaxel treatment in older patients with NSCLC, indicated that the OS benefit for carboplatin/pemetrexed was notable in patients with ECOG PS 0 at baseline but not in those with ECOG PS 1 (26).

Given the results of this study, it may be necessary to subdivide PS and patient background when considering treatment strategies for older patients. ECOG PS is a simple and useful scoring system in a clinical setting. However, it is subject to high interobserver variability, and clinicians are more likely to evaluate better ECOG PS than patients themselves. ECOG PS can only assess patients from a functional perspective and may miss important impairments identified by the Geriatric Assessment (GA) (27). In recent years, several guidelines have recommended GA over ECOG PS for older patients, as it provides a comprehensive evaluation including physical, social, and spiritual aspects (28–30). Screening tools such as the G8, the Flemish version of the Triage Risk Screening Tool, and the Clinical Frailty Scale allow for a more detailed assessment of daily living and frailties of older patients (31, 32). In the field of geriatric oncology, several studies have reported the usefulness of these screening tools in prognosis prediction (33–35). Therefore, utilizing these tools may strongly assist in selecting better treatment choices for older patients with cancer.

The present study indicates that COMBO may be more effective than MONO in patients with non-squamous cell carcinoma. The tumor immune microenvironment, including the composition of CD8+ lymphocytes infiltrating the tumor, differs between squamous cell lung cancer and non-squamous cell carcinoma (36). In addition, the poor treatment efficacy of concomitant chemotherapy to MONO in older patients with squamous cell carcinoma is presumably based on a heavier smoking history and higher prevalence of comorbidities in these patients (37). Squamous cell carcinoma is strongly associated with aging and smoking; thus, patients with this carcinoma type are often prone to comorbidities, the most frequent of which are cardiovascular diseases and chronic obstructive pulmonary diseases (38). These comorbidities not only affect treatment choice and adherence to treatment but are also associated with poor survival outcome as comorbidity-related symptoms affect OS (39). Patients with severe comorbidities are more likely to experience hematologic toxicity after chemotherapy (40). For these reasons, the potential prognostic impact of comorbidities in squamous cell carcinoma of the lung is multifactorial, limiting the benefit of concomitant chemotherapy.

In conclusion, our study revealed that both PFS and OS were similar between MONO and COMBO treatments for patients with NSCLC aged ≥ 70 years with high PD-L1 TPS ≥ 50% but were significantly longer for COMBO than MONO in patients with ECOG PS 0 or non-squamous cell carcinoma. Therefore, ECOG PS and histological type may be important factors to consider when choosing between MONO or COMBO treatment in this population.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Ethics Review Board of the Kyoto Prefectural University of Medicine and the Ethics Review Board of each hospital (approval no. ERB-C-2113). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin because owing to the retrospective nature of the study.

ST: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. HK: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. TY: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft. Writing – review & editing. MT: Data curation, Writing – review & editing. YN: Data curation, Writing – review & editing. YG: Data curation, Writing – review & editing. AN: Data curation, Writing – review & editing. SS: Data curation, Writing – review & editing. KT: Data curation, Writing – review & editing. TT: Data curation, Writing – review & editing. AO: Data curation, Writing – review & editing. TH: Data curation, Writing – review & editing. KD: Data curation, Writing – review & editing. YC: Data curation, Writing – review & editing. IH: Data curation, Writing – review & editing. NT: Data curation, Writing – review & editing. YK: Writing – review & editing. NN: Writing – review & editing. KM: Writing – review & editing. MI: Writing – review & editing. ST: Writing – review & editing. TK: Writing – review & editing. KT: Supervision, Writing – review & editing.