The safety and effectiveness of immune checkpoint blockade in lung cancer with COPD: a systematic review and meta-analysis

Introduction

Chronic obstructive pulmonary disease (COPD) is a group of diseases characterized by an irreversible obstructive ventilatory dysfunction that is pathologically characterized by emphysema and chronic bronchitis (1-4). de Torres et al. (4) found that approximately 215 of 2,507 patients with COPD progressed to lung cancer in 5 years (annual incidence =1.71%). In addition, approximately 44% of the 215 patients with lung cancer had squamous carcinoma, the predominant histological type. However, the worldwide incidence of lung cancer in 2020 was 0.0018–0.05%. Young et al. (5) demonstrated that COPD is an independent risk factor for lung cancer, independent of patient age and smoking history.

Lung cancer with COPD is typically characterized by a low epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutation rate, high proportion of squamous cell carcinoma, more aggressive invasion, and advanced stage at diagnosis (5-8). It has a poorer prognosis with either radiotherapy or chemotherapy, and has a worse progression-free survival (PFS)/overall survival (OS) with target therapy compared to lung cancer without COPD (NAÏVE lung cancer) (9-16). Immune checkpoint blockade (ICB) therapy has transformed the treatment of patients with advanced lung cancer over the past 10 years (17,18). However, the favorable efficacy of ICB therapy is accompanied by immune-related adverse events (irAEs) for patients of lung cancer with COPD. This common side effect of ICB treatment may be related to the over-activation of normal immune responses caused by ICB (19).

Among these irAEs, immune checkpoint inhibitor-related pneumonitis (CIP) is a common and fatal reaction (20). A series of retrospective studies suggested that the overall incidence of CIP is higher in lung cancer than in other tumors, ranging from 10% to 15% (21-24). Patients of lung cancer with COPD may have a higher incidence of CIP than those of NAÏVE lung cancer, ranging from 14% to 24% (22,25). Certain studies suggested that such patients may experience more favorable outcomes both in the short and long term, characterized by elevated disease control rate (DCR)/objective response rate (ORR) rates and extended durations of PFS/OS (8,23,25-27). Conversely, other research proposed that patients of lung cancer with COPD tend to exhibit reduced ORR/DCR (28). Additionally, while a number of studies indicated prolonged PFS and OS in patients of lung cancer with COPD compared to those without, these findings lacked statistical significance (26,28).

It can be hypothesized that ICB treatment against lung cancer with COPD is effective, albeit accompanied by an increased incidence of irAEs such as CIP. However, most of the current studies have small sample sizes. Therefore, we conducted this meta-analysis to clarify the safety and effectiveness of ICB treatment in patients of lung cancer with COPD. We present this article in accordance with the PRISMA reporting checklist (29) (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-356/rc).

Methods

Literature search and selection

We conducted a systematic and comprehensive search of online databases, including PubMed, Web of Science, and Cochrane Library (Table S1). To obtain more literature, we sourced three additional studies from the references of included studies. This combined literature was subsequently evaluated independently by two researchers.

The inclusion criteria were determined based on the Population, Intervention, Comparison, Outcomes and Study (PICOS) principles as follows (30): study population: patients with lung cancer treated with ICB; cohorts: patients of lung cancer with and without COPD or emphysema; outcomes measure: at least one of the primary outcomes was reported, such as CIP, DCR/ORR or PFS/OS; time interval of the search: from January 2011 to July 2023.

The exclusion criteria were as follows: meeting abstracts, case reports or cases with a sample size <10, non-comparative studies, review articles, and non-English language literature (Figure 1).

Figure 1 A flow diagram showing the inclusion criteria of studies eligible for this meta-analysis. CIP, checkpoint inhibitor-related pneumonitis; COPD, chronic obstructive pulmonary disease; ICB, immune checkpoint blockade; OS, overall survival; PFS, progression-free survival; WOS, Web of Science.

Data extraction and quality assessment

Data extraction and literature quality assessment were performed independently by two researchers. Variables were extracted, including the types of studies, sample size, targets of ICB treatment received by patients with lung cancer, and primary endpoint events (CIP, ORR/DCR, and PFS/OS).

The Newcastle Ottawa Scale (NOS) was applied to evaluate case-control and cohort studies (31). All disagreements were decided by another author.

Statistical analysis

The pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence interval (95% CI) were estimated for dichotomous outcomes and survival data, respectively. Heterogeneity between studies was assessed using the Cochran Chi-square test. I²>50% suggested a significant heterogeneity between the included studies. The combined effect sizes were calculated using a random-effects model, wherein I²<50% suggested a lack of heterogeneity between the included studies. Finally, the combined effect sizes were calculated using a fixed-effects model.

Publication bias was detected using the funnel plot test, as well as Begg’s and Egger’s tests. The effect of publication bias on the model was analyzed using the Trim and Fill method in instances of publication bias (32); one-study-removed sensitivity analysis were performed. P<0.05 was considered statistically significant (2-sided). All statistical analyses were conducted using STATA version 12.0 (Stata Corporation, College Station, TX, USA) and RevMan version 5.3 (Oxford, UK).

Results

Literature inclusion and quality assessment

Our search strategy yielded 133, 156, 19, and 3 articles from PubMed, Web of Science, the Cochrane Library, and references from included studies, respectively. This resulted in a total of 236 articles after excluding duplicates.

Finally, 18 studies were included based on the inclusion criteria (Figure 1, Table 1). Eleven of the included studies reported the incidence of CIP in patients of lung cancer with COPD treated with ICB. In addition, eight, six, four, and three studies reported the HR (95% CI) of PFS, HR (95% CI) of OS, ORR, and DCR, respectively. The literature quality of all 18 included studies, comprising nine case-control studies and nine cohort studies (Tables S2,S3), was evaluated.

Immunotherapy-related adverse effects: CIP

Eleven studies with a total of 2,432 participants were included to evaluate the incidence of CIP in patients of lung cancer with COPD (Table S4). The overall incidence of CIP in patients of lung cancer with COPD and those of NAÏVE lung cancer were 20.40% and 11.48%, respectively. The pooled OR was 2.23 (95% CI: 1.48–3.37). However, a high heterogeneity was found (I²=65.1%).

Five of the included studies investigated emphysema, a subtype of COPD. These studies were divided into two subgroups: COPD-CIP (n=7) and emphysema-CIP (n=5). As the case-control study by Deng et al. (25) examined both COPD and emphysema, it was included in both subgroups. The pooled OR for COPD-CIP subgroup and emphysema-CIP subgroup were 2.28 (95% CI: 1.64–3.18) and 2.16 (95% CI: 0.90–5.19), respectively (Figure 2A).

Figure 2 Pooled analysis of the effect of ICB on CIP in patients of lung cancer with COPD. (A) Subgroup analysis based on the subtype of COPD; (B) subgroup analysis based on immune checkpoint inhibitor targets; (C) subgroup analysis based on severity of CIP (severe CIP); (D) subgroup analysis based on severity of CIP (mild CIP). CI, confidence interval; CIP, checkpoint inhibitor-related pneumonitis; COPD, chronic obstructive pulmonary disease; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; ICB, immune checkpoint blockade; OR, odds ratio; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1.

Based on the 3 targets programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) of immune checkpoint inhibitors received by patients within each subgroup, all studies were divided into two subgroups: the PD-1/PD-L1/CTLA-4 subgroup (patients received drugs targeting multiple checkpoints including PD-1/PD-L1/CTLA-4), the PD-1/PD-L1 subgroup (patients received drugs targeting both PD-1 and PD-L1).

The pooled OR for the PD-1/PD-L1/CTLA-4 subgroup and the PD-1/PD-L1 subgroup were 3.64 (95% CI: 1.64–8.11) and 1.76 (95% CI: 1.35–2.29), respectively. It can be observed that the use of CTLA-4 inhibitors significantly increases the risk of CIP (Figure 2B).

According to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE V5.0) (43), irAEs can be classified into five grades. Based on the extractable data from the included literature, we defined CIP ≥ grade 3 as severe CIP and the rest as mild CIP, and conducted a subgroup analysis (Figure 2C,2D; Table S5). The pooled OR for the severe CIP subgroup and the mild CIP subgroup were 2.00 (95% CI: 1.33–3.00) and 1.59 (95% CI: 1.12–2.24), respectively.

We also divided patients into three groups based on the history of thoracic radiotherapy: (I) studies excluding patients with a history of thoracic radiotherapy; (II) studies including patients with a history of thoracic radiotherapy; and (III) studies including patients with a history of only single-agent ICB treatment [only Isono 2021 (21)]. The results showed that in lung cancer patients without a history of chest radiotherapy, COPD/emphysema was associated with an increased risk of CIP, with a pooled OR of 1.89 (95% CI: 1.00–3.63), and in patients with a history of chest radiotherapy, the pooled OR was 1.92 (95% CI: 1.47–2.52) (Figure S1). Sensitivity analysis and publication bias detection suggested stable results without publication bias (Figure S2, Table S6).

Short-term outcome: ORR/DCR

In the meta-analysis examining the effect of ICB on ORR/DCR in lung cancer with COPD, four studies with 637 participants (ORR) and three studies with 509 participants (DCR) were included (Table S7).

Short-term outcome in patients of lung cancer with COPD treated with ICB was better than NAÏVE-lung cancer (ORR: 32.95% vs. 20.21%; DCR: 66.51% vs. 50.83%). The heterogeneity test of these two endpoint events suggested good consistency. The meta-analysis suggested that patients of lung cancer with COPD receiving ICB treatment had higher radiological response (ORR: pooled OR: 2.04, 95% CI: 1.38–3.01; DCR: pooled OR: 1.58, 95% CI: 1.05–2.38; Figure 3A,3B).

Figure 3 Pooled analysis of the effects of ICB on the (A) ORR and (B) DCR in patients of lung cancer with COPD. CI, confidence interval; COPD, chronic obstructive pulmonary disease; DCR, disease control rate; ICB, immune checkpoint blockade; OR, odds ratio; ORR, objective response rate.

Sensitivity analysis and publication bias detection suggested stable results without publication bias (Table S6, Figures S3,S4).

Long-term survival: PFS/OS

Eight studies with a total of 1018 participants were included in the meta-analysis examining the effect of ICB on PFS/OS in patients of lung cancer with COPD (Table 2).

Patients of lung cancer with COPD treated with ICB showed longer median PFS (213.0±71.08 vs. 97.5±60.02 days) and OS (501.5±164.8 vs. 394.0±101.2 days) compared to NAÏVE-lung cancer.

Heterogeneity tests demonstrated a good consistency of all the literature included. Furthermore, the meta-analysis suggested that patients of lung cancer with COPD had significantly better survival compared with NAÏVE-lung cancer (OS: pooled HR: 0.57; 95% CI: 0.47–0.68; PFS: pooled HR: 0.57; 95% CI: 0.49–0.67).

ICB improved the PFS/OS in lung cancer with COPD even after further differentiation of COPD subtypes. The pooled HRs for COPD-PFS subgroup and COPD-OS subgroup were 0.55 (95% CI: 0.43–0.70) and 0.64 (95% CI: 0.45–0.89), whereas the pooled HRs for emphysema-PFS subgroup and emphysema-OS subgroup were 0.59 (95% CI: 0.49–0.71) and 0.54 (95% CI: 0.43–0.67) (Figure 4).

Figure 4 Pooled analysis of the effects of ICB on the PFS/OS in patients of lung cancer with COPD. (A) Subgroup analysis of PFS; (B) subgroup analysis of OS. COPD, chronic obstructive pulmonary disease; HR, hazard ratio; ICB, immune checkpoint blockade; IO, immunotherapy + chemotherapy/radiotherapy; IT, immunotherapy; LCI, lower confidence interval; OS, overall survival; PFS, progression-free survival; UCI, upper confidence interval.

We then divided the included studies into the single-agent immunotherapy (IT) and immunotherapy + chemotherapy/radiotherapy (IT+ others, IO) subgroups based on the treatment administered. The pooled HRs for IT-PFS subgroup and IT-OS subgroup were 0.63 (95% CI: 0.51–0.79) and 0.62 (95% CI: 0.47–0.81); whereas those for IO-PFS subgroup and IO-OS subgroup were 0.52 (95% CI: 0.42–0.64) and 0.53 (95% CI: 0.41–0.69), respectively (Figure 4).

Sensitivity analysis of PFS suggested that the results were stable (Figure S5). The funnel plot reflected that all studies were not symmetrically distributed, and Egger’s test (P=0.03) demonstrated a potential publication bias in eight studies (Table S6). Our results after two iterations of calculations using the linear method suggested that there was no missing literature, and the result was unchanged. Therefore, the potential publication bias did not affect the robustness of the results. In contrast, sensitivity analysis and publication bias detection suggested stable OS results without publication bias (Figure S6, Table S6).

Discussion

This meta-analysis evaluated the safety and effectiveness of ICB therapy in patients of lung cancer with COPD. Lung cancer with COPD treated with ICB achieved better survival and higher radiologic response compared to NAÏVE-lung cancer. However, it was associated with a higher incidence of CIP.

Meta-analysis of the ORR, DCR, PFS, and OS revealed that treatment of lung cancer with COPD with ICB prolonged PFS and OS by 1.75 times (1/HR) and elevated ORR and DCR by 2.04 and 1.58 times, respectively, compared to NAÏVE-lung cancer. The meta-analysis of PFS/OS suggested that patients of lung cancer with COPD can benefit from immunotherapy, with better survival regardless of the treatment and COPD subtype.

The higher ORR/DCR and longer PFS/OS of lung cancer with COPD may be related to the unique molecular characteristics and tumor related immune microenvironment (TIME) of the disease.

In patients of lung cancer with COPD, TIME exhibits high levels of T-cell exhaustion, which correlates with the severity of COPD. This exhaustion is predominantly observed in regions with a high infiltration of CD8⁺ T cells within the TIME, and is more pronounced in patients with COPD (26). Moreover, evidence has shown that there is substantial infiltration of CD3⁺, CD4⁺, and CD8⁺ T cells in the lung tissues of patients of lung cancer with COPD (8,44-46). The pronounced infiltration of CD8⁺ T cells is typically associated with “hot tumors”, which are known to respond more effectively to immunotherapy (47,48). This may help elucidate the mechanism behind the improved efficacy of immunotherapeutic treatments in these patients.

Based on their surface molecules and biological functions, macrophages can be categorized into two subtypes: M1, which exert anti-tumor effects, and M2, which aid in tumor growth (49-54). In patients with COPD, a significant presence of CD68⁺ macrophages is observed within both bronchoalveolar lavage fluid (BALF) and airway tissues. Nonetheless, the phenotypes of these macrophages demonstrate heterogeneity across different pulmonary locations, with a dominance of M2 phenotypes in BALF and M1 phenotypes within airway tissues (55). Mateu-Jimenez et al. investigated the distribution of M1 and M2 macrophages within tumor tissues of lung cancer patients, indicated a higher M1/M2 ratio among tumor-infiltrating macrophages in patients of lung cancer with COPD (56). Therefore, the predominant distribution of M1 macrophages may contribute to the mechanism underlying the improved prognoses following immunotherapy in these patients.

Highly infiltrated PD-L1⁺ macrophages can also serve as biomarker for predicting the prognosis of lung cancer patients undergoing immunotherapy (57). Narayanapillai et al. (46) induced mouse models of both pure lung cancer and lung cancer with COPD using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and NNK + lipopolysaccharide, respectively. They found that the mouse model combining lung cancer with COPD exhibited a highly immunosuppressive phenotype, with a significant increase in the density of PD-L1⁺ macrophages in tumor tissues. Consequently, CD8⁺ T cells may become deactivated. By intervening in the PD-L1/PD-1 pathway, immunotherapy may help reverse this immunosuppressive state, thereby activating and enhancing cellular immune responses, potentially leading to improved immune-related prognosis in patients of lung cancer with COPD. PD-L1 tumor proportion score (TPS) is a widely accepted biomarker for assessing the effectiveness of immunotherapy. Some studies suggested that in patients of lung cancer with COPD, upregulation of the DNA repair signaling pathway and increased genomic instability lead to higher tumor mutation burden (TMB) and upregulation of PD-1/PD-L1 expression (2,58). This mechanism may also contribute to the improvement in the effectiveness of immunotherapy in such patients. However, there is still controversy regarding whether PD-L1 TPS is elevated in patients of lung cancer with COPD.

Our meta-analysis indicated that, compared with NAÏVE lung cancer, ICB treatment for lung cancer with COPD increased the risk of CIP by approximately 2.23 times. We performed several subgroup analyses and found that the combined use of CTLA-4 inhibitors and thoracic radiotherapy significantly increased the risk of CIP occurrence. Moreover, we clarified that COPD’s promoting effect on CIP risk was independent of thoracic radiotherapy. After further classifying CIP into mild and moderate categories based on CTCAE (43), we confirmed that COPD contributed to the occurrence of CIP of different severities. Our analysis found that COPD increases the risk of severe CIP by about 2.00 times and mild CIP by about 1.59 times. The two subgroups have low heterogeneity (≤40%), but their 95% CIs overlap. Thus, we cannot yet conclude that COPD is more likely to increase the incidence of severe CIP. Further studies with higher evidence levels or larger sample sizes are needed to confirm the relationship between COPD and CIP severity.

The elevated risk of CIP in patients of lung cancer with COPD does not conflict with our conventional perception. As an example, Sha et al. (14) demonstrated that both COPD and emphysema are independent risk factors for the development of radiotherapy-related lung injury in patients with lung cancer treated with radiotherapy (OR =3.949, 95% CI: 1.06–5.733), which may be related to increased lung tissue fragility in patients with COPD. Thus, fragile lung tissue may be involved in the elevated risk of CIP in patients of lung cancer with COPD. Furthermore, the recruitment and activation of immune cells, including macrophages, CD4⁺ and CD8⁺ T cells, dendritic cells, B cells, and neutrophils in the lung tissues of patients with COPD caused chronic inflammation (59). In addition, highly activated T cells may be involved in the development of CIP (60,61). Therefore, we hypothesized that the elevated CIP in lung cancer with COPD was related to its specific inflammatory phenotype. In fact, numerous studies have demonstrated that patients undergoing ICB treatment who experience adverse events (AEs) may exhibit a more favorable long-term prognosis. This phenomenon has been observed across various types of malignancies and different categories of AE events (62-64). Mild CIP has been identified as a protective predictor for several survival outcomes, including PFS, OS, and ORR (65). However, severe CIP, despite potentially being associated with a higher ORR, appears to have an adverse effect on long-term OS (66). This may be related to the short-term lethality of severe CIP and the resulting ICB treatment discontinuation.

As far as we know, this is the first meta-analysis in this field, which incorporates all relevant studies from a specific time period, making the findings representative. We’ve performed relatively comprehensive subgroup and sensitivity analyses, and the results are fairly robust. However, there are some limitations in this meta-analysis: (I) although we clarified the effect of ICB on the prognosis of lung cancer with COPD, there were insufficient published data to further elucidate the relationship between prognosis/irAEs and Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade/Goddard scores; (II) to the best of our knowledge, there are no randomized controlled studies published in this area, with only case-control and cohort studies included in this meta-analysis. Therefore, our findings need to be updated as relevant randomized controlled trials (RCTs) are published in the future. (III) We only evaluated CIP, not other types of irAEs, mainly limited by the lack of included studies on other irAEs types. Isono et al. and Zhang et al. (21,28) concluded that lung cancer with COPD leads to an elevated risk of total morbidity in irAEs (32.5% vs. 21.1%, P<0.003). However, more extensive literature is required to evaluate the risk of varying irAEs types in patients of lung cancer with COPD.

The higher effectiveness of ICB treatment in patients of lung cancer with COPD supports its application in clinical settings, despite its adverse effects. Therefore, this meta-analysis could facilitate the early identification of CIP when utilizing ICB to treat of lung cancer with COPD. Moreover, this meta-analysis could help identify more lung cancer subtypes potentially suitable for ICB treatment.

Conclusions

This meta-analysis demonstrated that ICB shows superior effectiveness in lung cancer patients with COPD, supporting its clinical application despite associated adverse effects. These results provide evidence-based guidance for risk-benefit assessment in clinical decision-making.

Acknowledgments

We would like to thank Editage (https://www.editage.cn/) for the English language editing.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-356/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-356/prf

Funding: This study was supported by the National Natural Science Foundation of China (No. 82172848); and Shanghai Municipal Health Commission Special Clinical Research Project for the Hygiene Industry, Shanghai Pulmonary Hospital Fund (No. fkcx2305).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-356/coif). The 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.

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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