Real-world outcomes and association between immune-related adverse events and therapeutic efficacy of nivolumab plus ipilimumab in elderly patients (≥75 years) with advanced non-small cell lung cancer

Introduction

Background

Lung cancer remains the leading cause of cancer-related death in Japan, with over 75,762 deaths reported in 2023, and nearly half of lung cancer patients are aged 75 years or older, with most being diagnosed with non-small cell lung cancer (NSCLC) (1). Since the approval of nivolumab in 2015, immune checkpoint inhibitors (ICIs) have become a cornerstone in the standard treatment of advanced NSCLC (2,3). However, elderly patients represent a distinct population, often underrepresented in clinical trials due to comorbidities, reduced organ function, and concerns about tolerability. In addition to these factors, immunosenescence, the age-related decline in immune function, may impair antitumor responses and reduce ICI efficacy (4). This includes decreased naive T cells, increased regulatory T cells, and chronic inflammation, potentially compromising treatment effectiveness and durability (5).

Rationale and knowledge gap

Accumulating evidence has demonstrated the feasibility and efficacy of ICI-based therapies in older patients. ICI monotherapy has been shown to be effective and well-tolerated in older adults (3,6-8). In contrast, the addition of cytotoxic chemotherapy to ICIs may increase treatment efficacy but is associated with a higher incidence of adverse events in patients aged ≥75 years, as reported in the NEJ057 study (9). It should be noted, however, that the NEJ057 trial did not include nivolumab plus ipilimumab (NIVO + IPI), and its findings are limited to ICI monotherapy and chemo-ICI combinations. Regarding NIVO + IPI, this combination has demonstrated promising and durable efficacy in advanced NSCLC (10). A pooled analysis of NIVO + IPI trials showed consistent benefits across multiple patient subgroups, including older adults (11). Furthermore, the ENERGY trial, a phase 3 randomized study comparing NIVO + IPI with chemotherapy in patients aged ≥70 years or with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, suggested a survival advantage in patients aged ≥75 years (12). However, its applicability in elderly patients remains uncertain due to limited direct evidence.

Immune-related adverse events (irAEs) are a hallmark of ICI therapy and have been associated with favorable clinical outcomes in several cancer types, including NSCLC (13-18). However, older adults typically exhibit reduced physiological reserve and increased vulnerability to treatment-related complications, which may alter both the incidence and clinical consequences of irAEs, so the relevance of irAEs as surrogate markers of ICI’s efficacy in elderly patients remains unclear. In particular, dual ICI therapy with NIVO + IPI is known to carry a higher risk of irAEs compared to monotherapy (10). Given the growing interest in expanding this regimen to older patients, further investigation is warranted to determine whether irAEs can reliably serve as prognostic markers in the elderly treated with NIVO + IPI.

Objective

This study aimed to evaluate the real-world efficacy and safety of NIVO + IPI in elderly patients with advanced NSCLC and to determine whether the occurrence of irAEs is associated with improved survival outcomes in this population. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-640/rc).

Methods

Study design and data collection

This single-center, retrospective observational study included patients aged ≥75 years with histologically or cytologically confirmed NSCLC, classified as stage III (unresectable and not eligible to definitive radiotherapy) or stage IV, who initiated treatment with NIVO + IPI at Sendai Kousei Hospital, Japan, between February 1, 2021, and October 31, 2023. The data cut-off for follow-up was February 11, 2025. All patients received NIVO + IPI according to the CheckMate 227 regimen (nivolumab 240 mg every 2 weeks or 360 mg every 3 weeks, plus ipilimumab 1 mg/kg every 6 weeks), without the addition of chemotherapy. All patients were confirmed negative for driver oncogenes, including EGFR mutations and ALK rearrangements, using validated molecular diagnostic techniques. Tumor staging was determined according to the 8th edition of the tumor-node-metastasis (TNM) Classification of Malignant Tumors. Tumor response was assessed by treating oncologists using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. irAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Baseline demographic and clinical characteristics were obtained from electronic medical records, including age, sex, smoking history, comorbidities, laboratory parameters [e.g., neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase], histological subtype, ECOG PS, TNM stage, and programmed cell death 1 ligand 1 (PD-L1) tumor proportion score (TPS). Descriptive statistics were used to summarize these variables. Quantitative variables were analyzed as continuous variables where appropriate. For exploratory and survival analyses, some variables were categorized based on clinically meaningful cutoffs or prior literature. Missing data were handled by case-wise deletion in the multivariable analysis. No imputation was performed. No sensitivity analyses were performed in this study.

Statistical analysis

Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, with median values and corresponding 95% confidence intervals (CIs) reported. To identify independent prognostic factors, Cox proportional hazards regression analysis was performed for both PFS and OS. To assess the prognostic impact of early irAEs, we performed a 6-week landmark analysis. Only patients who had achieved disease control or were alive at 42 days after the first administration were included. Only irAEs that developed within the first 6 weeks were considered in the landmark analysis; events occurring after this time point were excluded to avoid time-dependent bias. All statistical analyses were conducted using EZR version 1.61, a graphical user interface for R (19). Subgroup analyses were conducted based on sex, ECOG PS, histological type, PD-L1 TPS, presence of bone or brain metastasis, occurrence of irAEs (any grade and ≥ grade 3), immune-related interstitial lung disease (ILD), skin rash, NLR, derived neutrophil-to-lymphocyte ratio (dNLR), and Lung Immune Prognostic Index (LIPI) score. Subgroup analyses were conducted based on clinically relevant cutoffs, such as NLR (<4 vs. ≥4) and LIPI (0 vs. 1–2). Potential interaction effects between variables were not evaluated because of the limited sample size and exploratory nature of the study.

Ethical statement

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the institutional review board at Sendai Kousei Hospital (No. 6-40), which also granted a waiver for informed consent due to the retrospective design and use of anonymized data.

Results

Patient characteristics

A total of 27 patients aged ≥75 years were included in the final analysis. The median age was 80 years (range, 75–90 years). Eighteen patients (66.7%) were male, 9 (33.3%) had a PS of 0, and 18 (66.7%) had a PS of 1. The PD-L1 TPS was ≥1% in 8 patients (29.6%), <1% in 18 (66.7%), and unknown in 1 patient (3.7%). At baseline, 6 patients (22.2%) presented with brain metastases. The overall cohort was divided into two subgroups based on the occurrence of irAEs: 15 patients (55.6%) experienced irAEs, while 12 patients (44.4%) did not. Detailed demographic, clinical, and laboratory data stratified by irAE status are summarized in Table 1.

Efficacy outcomes

The median follow-up duration, calculated using censored data from OS, was 23.7 months. The median PFS was 6.5 months (95% CI: 2.6–13.6), and the median OS was 13.0 months (95% CI: 4.4–32.7) (Figure 1). The objective response rate (ORR) was 22.2%, and the disease control rate (DCR) was 62.9%. This included 6 patients who achieved a partial response (PR), 11 with stable disease (SD), and 10 with progressive disease (PD) as their best overall response (Table 2).

Figure 1 Kaplan-Meier curves of PFS (A) and OS (B) in all patients (n=27). Kaplan-Meier curves illustrate PFS and OS in patients aged ≥75 years with advanced NSCLC who received NIVO + IPI. The median PFS was 6.5 months, and the median OS was 13.0 months. Survival estimates were calculated using the Kaplan-Meier method. NIVO + IPI, nivolumab plus ipilimumab; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival.

Safety outcomes

Fifteen patients (55.6%) developed irAEs, with a median onset of 21 days following NIVO + IPI initiation. Among them, 11 patients (40.7%) experienced grade ≥3 irAEs. The most common irAEs were skin rash (n=8), ILD (n=4), and colitis (n=4). Notably, all ILD cases were grade ≥3, including one grade 5 event resulting in treatment-related death (Table 3).

Exploratory analysis

In exploratory univariate analysis for PFS, the presence of bone metastasis [hazard ratio (HR) 17.21; 95% CI: 3.27–90.45; P<0.01], brain metastasis (HR 5.82; 95% CI: 1.86–18.24; P<0.01), and NLR ≥4 (HR 3.45; 95% CI: 1.14–10.42; P=0.03) were identified as independent predictors of shorter PFS. For OS, brain metastasis (HR 3.92; 95% CI: 1.37–11.20; P=0.01) and the occurrence of any grade irAEs (HR 0.29; 95% CI: 0.11–0.80; P=0.02) were statistically significant independent prognostic factors (Table 4). In multivariate analysis, the occurrence of any-grade irAEs was independently associated with improved OS (HR 0.33, 95% CI: 0.11–0.98, P=0.046), while showing a non-significant trend toward longer PFS (HR 0.43, 95% CI: 0.16–1.13, P=0.09). Neither ECOG PS nor PD-L1 expression significantly impacted survival outcomes (Table 5). In the analysis, continuous variables were categorized according to predefined thresholds based on clinical relevance or previous reports. Specifically, the NLR was dichotomized at 3.0 or 4.0, and dNLR at 3.0.

Landmark analysis

To minimize time-dependent bias, a 6-week landmark analysis was performed. Three patients were excluded from the PFS analysis due to disease progression or death before day 43, and 1 patient was excluded from the OS analysis due to death prior to this time point. Among the remaining patients, those without early irAEs had a median PFS of 5.3 months (95% CI: 1.87–10.05), whereas those with early irAEs had a median PFS of 15.1 months (95% CI: 2.30–not reached) (P=0.046). Similarly, median OS was 12.4 months (95% CI: 1.94–32.72) in patients without early irAEs and 26.4 months (95% CI: 6.57–not reached) in those with early irAEs (P=0.048) (Figure 2).

Figure 2 Landmark analysis of PFS (A) and OS (B) stratified by occurrence of irAEs within 6 weeks. Patients who developed irAEs within 6 weeks showed significantly longer PFS (median: 15.1 vs. 5.3 months; P=0.046) and OS (median: 26.4 vs. 12.4 months; P=0.047) compared to those without early irAEs. Survival estimates were calculated using the Kaplan-Meier method and compared using the log-rank test. irAE, immune-related adverse event; OS, overall survival; PFS, progression-free survival.

Discussion

Key findings

In this retrospective analysis, we evaluated the efficacy and safety of NIVO + IPI in elderly patients (aged ≥75 years) with advanced NSCLC. The observed ORR and DCR were 22.2% and 62.9%, respectively, with a median PFS of 6.5 months and a median OS of 13.0 months. Importantly, patients who experienced early irAEs had significantly prolonged PFS (15.1 vs. 5.3 months; P=0.046) and OS (26.4 vs. 12.4 months; P=0.048), supporting the hypothesis that irAEs may serve as surrogate markers of therapeutic efficacy. Conversely, immune-related ILD appeared to correlate with inferior outcomes (median PFS: 2.8 months and median OS: 5.5 months) in this population.

Strengths and limitations

The strengths of this study include its focus on a clinically underrepresented population of elderly patients receiving dual ICI and the use of a 6-week landmark analysis to minimize time-dependent bias when evaluating the prognostic impact of irAEs. However, several limitations must be acknowledged. First, the relatively small sample size (n=27) limits the statistical power and generalizability of the findings. However, this reflects the rarity of elderly patients receiving dual ICI therapy in real-world settings, a population often underrepresented in clinical trials. Given this context, our study provides valuable real-world insights and should be regarded as a hypothesis-generating pilot investigation that suggests clinical trends to be validated in future multicenter studies. Second, the retrospective, single-center design introduces potential selection and information bias. Third, an imbalance in PD-L1 expression existed, as patients with PD-L1-negative tumors were more likely to receive NIVO + IPI at our institution. Lastly, the timing of imaging assessments was determined at the discretion of the treating physician, which may have introduced variability in PFS measurement and resulted in potential evaluation bias.

Comparison with similar research

Regarding survival outcomes in unselected populations, the updated 5-year analysis of the CheckMate 227 trial reported a median PFS of approximately 5.0 months and a median OS of 17.1 months across all age groups (20). In the Asian subpopulation analysis of the same trial, patients treated with NIVO + IPI achieved a median PFS of 8.5 months and OS of 36.2 months, while Japanese patients in this subgroup exhibited a median OS of 48.8 months, suggesting particularly favorable long-term outcomes (21,22).

In contrast, data specific to older adults remains limited. In the ENERGY trial, a prespecified subgroup analysis showed that fit elderly patients (PS 0–1) achieved a notably prolonged OS of 22.6 months (95% CI: 18.1–36.0), and in a pooled analysis combining data from four clinical trials, CheckMate 227 Part 1, CheckMate 817 Cohort A, CheckMate 568 Part 1, and CheckMate 012, evaluated 1,255 patients receiving first-line NIVO + IPI, 186 patients (14.8%) were aged ≥75 years, and their median OS was 20.1 months (95% CI: 14.7–26.9) (11,12).

In comparison, the median OS in our real-world elderly cohort was 13.0 months, which, although modest relative to clinical trial results, likely reflects the greater clinical complexity and frailty of our patient population. Notably, our outcomes are highly consistent with those of previous real-world studies in similar elderly populations treated with NIVO + IPI. Ebi et al. reported a median PFS and OS of 4.0 and 13.9 months, respectively, in a cohort of 28 elderly patients who received NIVO + IPI, with or without chemotherapy (23). Similarly, Endo et al. evaluated 57 elderly patients treated with NIVO + IPI and observed a median PFS of 7.1 months and OS of 14.1 months (24). This convergence across real-world studies suggests that the clinical effectiveness of NIVO + IPI in broader, less selected elderly populations may be inherently lower than that reported in controlled trial settings, which often exclude patients with poor PS or significant comorbidities. Nevertheless, our findings reinforce the feasibility and real-world applicability of NIVO + IPI for elderly patients.

The association between irAEs and favorable clinical outcomes in NSCLC has been well established. Haratani et al. retrospectively analyzed 134 patients treated with nivolumab and found that irAEs occurred in 51% of cases and were significantly associated with prolonged survival (13). To mitigate time-dependent bias where patients must survive long enough to experience irAEs, they applied a 6-week landmark analysis, which strengthened the reliability of their findings. Similarly, Cook et al. conducted a larger study involving 803 patients with advanced NSCLC receiving ICI monotherapy, reporting that irAEs were observed in 37.0% of patients and were associated with improved survival using a 12-week landmark analysis (25). These results collectively support the notion that the development of irAEs may serve as a surrogate marker of immune activation and therapeutic efficacy. In the context of NIVO + IPI, Ebi et al. reported that irAE occurrence independently predicted improved PFS and OS in a cohort of 28 patients treated with NIVO + IPI (23). Similarly, Endo et al. demonstrated that patients who experienced treatment-related adverse events had significantly longer OS than those who did not (20.4 vs. 9.0 months; log-rank P=0.01), even though their study did not utilize landmark analysis and may be subject to immortal time bias (24). These findings suggest that the positive prognostic association between irAEs and survival may also extend to elderly patients receiving NIVO + IPI in real-world settings. Consistent with these observations, our study demonstrated a strong association between irAE development and favorable clinical outcomes. Using a 6-week landmark analysis, we found that patients who developed irAEs within the first 6 weeks of NIVO + IPI treatment exhibited significantly longer median PFS and OS than those who did not. These results reinforce prior evidence that irAEs may reflect enhanced immunologic activity and can be a predictive marker of treatment benefit in elderly NSCLC patients. However, not all irAEs confer a favorable prognosis. Immune-related ILD appears to be a notable exception. In Endo et al.’s cohort, ILD was reported in 24.5% of patients, including 12.3% with grade 3–4 severity (24). In our cohort, ILD occurred in 14.8% of patients (4 of 27), with three grade 3–4 cases and one treatment-related death. In comparison, the CheckMate 227 trial reported an ILD incidence of 8.3% among patients receiving NIVO + IPI, with grade 3–4 events in 3.3% and four treatment-related deaths (0.7%) (10). These findings suggest that ILD may occur more frequently and with greater severity in elderly patients compared to those enrolled in broader clinical trials, possibly due to age-related physiological vulnerabilities. Previous meta-analyses have demonstrated that the prognostic significance of irAEs differs by organ system. In a meta-analysis focusing on lung cancer, Wang et al. reported that dermatologic, endocrine, and gastrointestinal irAEs were significantly associated with improved survival, whereas ILDs were not (HR for OS: 1.28, 95% CI: 0.58–2.85, P=0.54) (26). Consistently, Zhao et al. found no survival benefit associated with pulmonary irAEs in NSCLC patients treated with anti-PD-1 therapy (HR 0.98, 95% CI: 0.53–1.83, P=0.96) (27). In our cohort, ILD was associated with numerically shorter PFS and OS, suggesting a potential negative prognostic impact. These findings align with previous reports and indicate that, unlike other irAEs, ILD may not serve as a favorable prognostic marker, particularly in older patients. Although the small sample size limits definitive conclusions, our results highlight the importance of vigilant monitoring and support the need for further research in larger, age-stratified cohorts.

Explanations of findings

In this study, the efficacy of NIVO + IPI in elderly patients was found to be comparable to outcomes reported in landmark trials such as CheckMate 227 (10). Moreover, the observed association between irAE development and improved clinical outcomes suggests that this age group may share similar immunological and therapeutic characteristics with the broader, all-age patient population.

On the other hand, the relatively high incidence and severity of immune-related ILD observed in our cohort, along with its association with poor survival, may reflect age-related physiological vulnerabilities, such as diminished organ reserve in the elderly.

Implications and actions needed

This study highlights the feasibility of NIVO + IPI in elderly patients with advanced NSCLC and suggests that early irAE development may serve as a useful prognostic indicator. Given the potential adverse impact of immune-related ILD, particularly in patients with reduced physiological reserve, careful monitoring of pulmonary toxicity is essential. The development of risk-stratification tools and predictive biomarkers will be crucial to personalize treatment strategies. Further prospective, multicenter studies are needed to confirm these findings and inform clinical decision-making in this population.

Conclusions

In this retrospective observational cohort study, our findings demonstrated that NIVO + IPI provided feasible efficacy and acceptable safety in NSCLC patients aged ≥75 years. The occurrence of irAEs within 6 weeks since the first administration was associated with improved survival, whereas irAE-ILD was linked to poorer outcomes, emphasizing the importance of vigilant monitoring in this population.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-640/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-640/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-640/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-640/coif). Y.T. reports honoraria from AstraZeneca, Chugai Pharma, Pfizer, Taiho Pharmaceutical, Kyowa Kirin, Bristol-Myers Squibb, Ono Pharmaceutical, and MSD K.K., outside the submitted work. J.S. reports honoraria from AstraZeneca, MSD, Chugai Pharmaceutical, and Kyowa Kirin, outside the submitted work. S.Y. reports honoraria from AstraZeneca, Novartis, Sanofi, GSK, and Nippon Boehringer Ingelheim, outside the submitted work. S.S. reports institutional research funding from AnHeart, AstraZeneca, Chugai Pharma, MSD, Daiichi Sankyo, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, AbbVie, Amgen, Taiho Pharmaceutical, Parexel International, PPD, IQVIA, Novocure, Pharma Mar, GSK, and Delta-Fly Pharma, outside the submitted work; and reports personal honoraria from AstraZeneca, Chugai Pharma, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Lilly, Novartis, Kyowa Kirin, Takeda, Nippon Kayaku, Merck, Amgen, Daiichi Sankyo, Thermo Fisher Scientific, Sysmex, and Eisai, outside the submitted work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional review board at Sendai Kousei Hospital (No. 6-40), which also granted a waiver for informed consent due to the retrospective design and use of anonymized data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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