Evaluating the effect of immune checkpoint inhibitor treatment on chronic obstructive pulmonary disease in lung cancer patients.

Introduction
Immune checkpoint inhibitors (ICIs) have drastically changed the field of oncology and are frequently utilized as first line treatment in many different solid tumor malignancies, including lung cancer.1 ICIs are monoclonal antibodies that target proteins on T cells and cancer cells, blocking physiologic checkpoints of the immune system to restore and enhance its anti-tumor effect.2 Integration of ICIs into the multi-modality approach of lung cancer treatment has significantly improved survival3–5; however, ICI treatment is not without consequences. Upregulation of the immune system following ICI treatment can lead to autoimmune-mediated organ inflammation termed immune-related adverse events (iRAEs),6 and pulmonary complications related to ICIs can lead to significant treatment-related morbidity and mortality in lung cancer patients.7
Tobacco use is a shared risk factor for lung cancer and chronic obstructive pulmonary disease (COPD).8,9 The global prevalence of COPD is around 10.3%,10 but the prevalence in lung cancer patients is much higher, with estimates ranging from 40–70%.11,12 In patients with lung cancer, dyspnea and a low forced expiratory volume in 1 second (FEV1) on pulmonary function tests (PFTs), a physiologic marker for COPD severity, have been associated with worse overall survival.12
Despite increasing use of ICIs in patients with lung cancer and high rate of co-morbid COPD as well as the potential link between COPD severity and overall survival, little is known about the relationship between ICI treatment and COPD disease control. As checkpoint inhibitor pneumonitis (CIP) is a well-recognized cause of dyspnea following ICI treatment, misattribution of symptoms to CIP instead of to worsening COPD could lead to inappropriate and premature discontinuation of potentially effective lung cancer treatment and delay optimization of COPD management. To address this knowledge gap, we conducted a retrospective cohort study of lung cancer patients with COPD who received ICIs to determine the impact of ICI treatment on lung function, COPD exacerbations, and COPD-related hospitalizations.

Methods

Data collection
We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of an ICI at The Ohio State University (OSU) from 2011–2021. Study data were managed using REDCap (Research Electronic Data Capture).13,14 The study protocol was reviewed and approved by The Ohio State Institutional Review Board (2021C0177), and a waiver of informed consent was granted due to the retrospective nature of the study.

Included patients
All lung cancer patients who received at least one dose of an ICI from 2011–2021 at OSU were included. Patients were determined to have pre-treatment COPD if pre-ICI PFTs showed obstruction or air trapping (FEV1/forced vital capacity (FVC) or FEV1/slow vital capacity (SVC) < 0.7 or < lower limit of normal (LLN); residual volume (RV) > 120% predicted (pp)), if there was emphysema on chest imaging, or the diagnosis was documented by a treating provider before ICI initiation in the absence of radiographic emphysema or physiologic obstruction/air trapping on PFTs (clinical diagnosis). If patients received multiple ICIs, the first exposure was utilized to determine pre-ICI COPD. The following possible risk factors for exacerbating underlying COPD were collected: age, sex assigned at birth, race, body mass index (BMI), smoking status, eosinophil count before ICI initiation, ICI type, number of ICI doses, history of ICI pneumonitis, type of lung cancer (non-small cell lung cancer [NSCLC] or small cell lung cancer [SCLC]), stage of cancer, line of therapy, history of radiation, and previous chemotherapy. Pre-ICI treatment location (OSU vs non-OSU 12 months before ICI initiation) was also recorded. Lastly, overall survival (OS) was recorded for all patients.

Steroid use and respiratory-related hospitalizations in lung cancer patients with and without chronic obstructive pulmonary disease
The total number of systemic steroid courses and hospitalizations attributed to respiratory related symptoms based on manual chart review were recorded for all lung cancer patients with and without pre-ICI COPD from the 12 months preceding ICI treatment and from ICI initiation to 6 months following ICI discontinuation or to when the patient was deceased (Figure 1). If systemic steroid utilization or hospitalizations were not for respiratory symptoms, they were not recorded.

Evaluation of chronic obstructive pulmonary disease burden
Among patients with COPD prior to ICI initiation, COPD medications were collected at ICI start and compared to the time period after ICI initiation to 6 months after ICI discontinuation. PFTs, COPD exacerbations, and COPD-related hospitalizations were recorded from the 12 months preceding ICI treatment and from ICI initiation to 6 months following ICI discontinuation or to when the patient was deceased (Figure 1). The following COPD medications were recorded if they were present on patients’ medication lists: short-acting beta agonist, long-acting muscarinic antagonist, long-acting beta agonist, inhaled steroid, oxygen supplementation, roflumilast, theophylline, chronic azithromycin, chronic systemic steroids utilized only for COPD, and nocturnal noninvasive positive pressure ventilation (NIPPV) utilized for chronic hypercapnic respiratory failure from COPD. We defined refractory COPD medications as roflumilast, theophylline, chronic azithromycin, chronic systemic steroids utilized for COPD, and nocturnal NIPPV utilized for chronic hypercapnic respiratory failure from COPD. COPD exacerbations were recorded if all criteria were met: 1). Documentation of a COPD exacerbation by the treating provider 2). Treatment with systemic steroids 3). Lack of another more convincing etiology of dyspnea or respiratory failure, including CIP. Similarly, hospitalizations were attributed to COPD if all the following were present: 1). COPD exacerbation documented by treating provider 2). Treatment with systemic steroids 3). Lack of another more convincing etiology of dyspnea or respiratory failure, including CIP.

Evaluation of pulmonary function tests
PFTs were examined before and after ICI treatment. If more than one set of PFTs was available, the PFTs closest to ICI initiation were utilized as pre-treatment PFTs, and the PFTs closest to ICI discontinuation were assigned as post-treatment PFTs. Spirometry (FEV1, FVC, FEV1/FVC ratio), lung volumes (total lung capacity [TLC], RV), diffusing capacity for carbon monoxide (DLCO), and DLCO corrected for hemoglobin were recorded by the study team. Testing that did not meet the American Thoracic Society guidelines was excluded.15 All values were recorded as raw values (liters for FEV1, FVC, TLC, and RV and mmol/min/mmHg for DLCO and DLCO corrected for hemoglobin) or pp adjusted for a patient’s sex, height, age, and race.

Statistical analysis
Descriptive statistics were used to compare baseline characteristics between patients with and without COPD using Fisher’s exact test for categorical variables and two-sampled t-tests (for normally distributed data) or the Mann-Whitney U Test (for non-normally distributed data) for continuous variables. Among patients with pre-ICI COPD, COPD disease severity (number of medications, number of COPD exacerbations, number of COPD-related hospitalizations) was compared before and after ICI initiation using linear mixed models (for continuous variables) or generalized mixed models (for categorical variables) with random intercepts for each participant. These models were adjusted for receiving chemotherapy or chemoradiation within 12 months of ICI treatment, cancer type, age, BMI, sex, smoking status, type of ICI treatment (monotherapy vs combination), and number of ICI doses. In order to determine whether COPD disease burden varied by absolute eosinophil count before ICI treatment, an interaction term was included in the mixed models. Additionally, among COPD patients with pre and post PFTs, PFT measures were compared before and after ICI initiation using paired t-tests (for normally distributed data) and Wilcoxon signed-rank tests (for non-normally distributed data). The date of ICI initiation and date of death or loss to follow-up were used to calculate OS. Unadjusted and adjusted survival curves were plotted by pre-ICI COPD status. The Kaplan-Meier method was used for the unadjusted OS and a log-rank test was used to compare OS between patients with and without pre-ICI COPD. Adjusted OS curves were obtained from Cox regression models controlling for line of therapy and cancer type. Statistical significance was defined as alpha <0.05. All statistical analyses were performed using SAS, version 9.4 (Caryn, NC).

Results
The following flowchart summarizes included patients, number of patients with and without pre-ICI COPD, and a list of variables analyzed among patients with pre-ICI COPD (Figure 2).

Demographics
In total, there were 1083 patients with lung cancer who received ICIs between 2011–2021. Most patients received ICIs as first line therapy (68.4%) with a PD-1 inhibitor (70.1%). Of the total patients, 585 (54.0%) had COPD before ICI initiation. The majority of patients were diagnosed with COPD based on the presence of emphysema on chest imaging (53.9%), and 33.3% of patients with pre-ICI COPD were followed at OSU for at least 12 months prior to ICI start (Supplementary Table S1). Patients with lung cancer and COPD were older (p = 0.012), more often male (p = 0.017), more often classified as current users of tobacco at time of ICI initiation (p < 0.001), and a higher proportion received radiation treatment for their lung cancer within one year of ICI treatment (p < 0.001) compared to patients with lung cancer without COPD. Demographic data of lung cancer patients with and without COPD are summarized in Table 1.

Steroid courses and respiratory related hospitalizations among lung cancer patients with and without COPD
Lung cancer patients with COPD were prescribed more systemic steroids for respiratory symptoms (45.8% vs 8.2%, p < 0.001) and had more respiratory related hospitalizations compared to those without co-morbid COPD (53.2% vs 26.7%, p < 0.001). Patients with COPD also received systemic steroids for respiratory symptoms sooner after ICI initiation (median 2.7 vs 4.6 months, p = 0.025) compared to those without COPD, while no difference was appreciated in the time to first respiratory related hospitalization between the two groups (2.8 vs 2.8 months, p = 0.987, Supplementary Table S2).

COPD disease severity before and after ICI treatment
The median time of ICI treatment for patients with COPD was 4.37 months (interquartile range (IQR) [1.05, 11.73]). After initiation of ICI treatment, patients with COPD were prescribed more COPD medications (3 [1, 4] vs 1 [0, 3], p < 0.001, Supplementary Figure S1 and Supplementary Table S3), had more COPD exacerbations (38.3% vs 25.8%, p < 0.001, Supplementary Table S3), and had more COPD-related hospitalizations (27.9% vs 16.9%, p < 0.001, Supplementary Table S3) compared to before ICI treatment. There was an increase in the proportion of patients with greater than or equal to one COPD medication, COPD exacerbation, and COPD hospitalization after ICI treatment (Figure 3). Following exclusion of short-acting beta agonists and oxygen supplementation, we found that COPD patients still required more COPD medications (1 [0, 2] vs 0 [0, 2], p < 0.001, Supplementary Table S3) after ICI treatment. These results remained statistically significant after excluding patients who were not followed at OSU for at least 12 months prior to ICI initiation (3 [1, 4] vs 2 [0, 3], p < 0.001 for COPD medications, 44.0% vs 31.4%, p = 0.006 for COPD exacerbations, and 33.0% vs 17.3%, p = 0.001 for COPD hospitalizations, Supplementary Table 4), those with a clinical diagnosis of COPD (3 [1, 4] vs 2 [0, 3], p < 0.001 for COPD medications, 39.3% vs 26.6%, p < 0.001 for COPD exacerbations, and 29.4% vs 17.2%, p < 0.001 for COPD hospitalizations, Supplementary Table S5), and those with a diagnosis of CIP (3 [1, 4] vs 2 [0, 3], p < 0.001 for COPD medications, 38.3% vs 25.1%, p < 0.001 for COPD exacerbations, and 27.6% vs 16.9%, p < 0.001 for COPD hospitalizations, Supplementary Table S6). Furthermore, COPD disease severity before and after ICI treatment was independent of a patient’s eosinophil count before ICI initiation (Supplementary Table S7).

Fifty-one patients (9.0%) with COPD had both pre-treatment and post-treatment PFTs. FEV1, FVC, TLC, and DLCO were all lower after ICI treatment. There was no statistically significant difference in the FEV1/FVC ratio, RV, or RVpp after ICI initiation (Supplementary Table 8).

Mixed models for COPD disease severity before and after ICI treatment
Mixed models were utilized to account for potential confounders of worsening COPD and incorporated significant findings from the univariate analysis along with other variables of interest by controlling for the following: patients who received chemotherapy or chemoradiation within 12 months of ICI treatment, cancer type, age, gender, BMI, smoking status, ICI type, and number of ICI doses. After accounting for these factors, we found that lung cancer patients with COPD were on more COPD medications (increase by 0.73 [0.63, 0.83], p < 0.001, Table 2), were more likely to be on refractory COPD medications (OR 4.01 [1.96, 8.22], p < 0.001), had more COPD exacerbations (OR 1.83 [1.42, 2.36], p < 0.001), and were more likely to have at least one COPD-related hospitalization (OR 1.96 [1.47, 2.61], p < 0.001, Table 3) after ICI treatment.

Overall survival
Among lung cancer patients treated with an ICI, patients with COPD had longer median OS compared to those without COPD (14.55 vs 9.99 months, p = 0.018, Supplementary Figure S2). However, once adjusted for line of therapy and cancer stage there was no statistically significant difference between the two groups (p = 0.160, Supplementary Figure S3).

Discussion
In this large, single-center, retrospective cohort study of consecutive lung cancer patients treated with ICIs, we found that after starting treatment with ICIs, patients with COPD were prescribed more COPD medications, required more systemic steroids for COPD exacerbations, and were hospitalized more frequently for COPD exacerbations compared to before ICI initiation. These findings persisted after controlling for patients who received chemotherapy or chemoradiation within 12 months of ICI treatment. COPD patients treated with ICIs may have improved survival compared to lung cancer patients without COPD, but this was not statistically significant once adjusted for line of therapy and cancer stage. Our study provides a comprehensive evaluation on the impact of ICI treatment on co-morbid COPD disease severity in patients with lung cancer.
While some have evaluated the impact of COPD on the efficacy of ICI treatment in those with lung cancer,16,17 as well as the impact of COPD medications on CIP,18 little is known about whether ICIs affect the underlying clinical course of COPD. There have been two studies to date focused on COPD post-ICI treatment. Nair et al described a series of six patients with pre-ICI COPD who had minimal disease burden before ICI initiation but developed worsening symptoms post-ICI treatment.19 It is unknown whether these patients were on other forms of cancer treatment during the pre-ICI period when their COPD was well controlled. Zarogoulidis et al. found that concurrent treatment with ICIs and chest radiation increased COPD medication burden compared to pre-ICI treatment, which corroborates our findings.20 However, the study was small (82 total patients), was unable to differentiate whether radiation alone or ICIs increased COPD medication burden, and did not examine the impact on COPD exacerbations and COPD-related hospitalizations. In our study, we found that ICI treatment increased COPD disease severity (medications, exacerbations, and hospitalizations) compared with the time period before ICI therapy. This change in COPD control persisted after accounting for patients who received chemotherapy or chemoradiation preceding ICIs, suggesting ICIs have a uniquely detrimental impact on COPD compared to other forms of cancer treatment.
We found that our lung cancer patients with COPD received ICIs for a median of 4.37 months, and the COPD evaluation window pre-ICI treatment (12 months) and post-ICI treatment (10.37 months) were similar, suggesting the increase in exacerbations and hospitalizations are not likely due to differences in the duration of evaluation. We also found that COPD medications, excluding short-acting beta agonists and oxygen supplementation, and refractory COPD therapies were higher following ICI treatment. Refractory COPD therapies are rarely utilized for non-COPD diseases and further illustrate that COPD disease burden worsens after ICI initiation. Furthermore, worsened COPD control after ICI treatment persisted when evaluating only patients treated at OSU for at least 12 months before ICI therapy and excluding those with a clinical diagnosis of COPD and with CIP, suggesting the detrimental impact of ICIs on COPD disease burden was not related to lack of available documentation on COPD status before ICI treatment or misattribution to an alternate diagnosis.
Lung cancer patients treated with ICIs frequently experience dyspnea, and these symptoms are often attributed to infection, cancer progression, or drug-related (i.e. ICI, targeted treatment) pneumonitis. Establishing the impact of ICIs on COPD will help clinicians better identify COPD as the etiology of worsening dyspnea if chest imaging is not suggestive of alternate etiologies. Avoiding misattribution of symptoms to infection, cancer progression, and pneumonitis will prevent premature discontinuation of ICIs, avoid unnecessary antibiotics, and allow for prompt optimization of COPD treatment.
There are several reasons why COPD may worsen following treatment with ICIs. One possible mechanism is the enhancement and revitalization of cytotoxic CD8+ T-cells following ICI initiation. Cytotoxic CD8+ T-cells are abundant in the alveolar walls in patients with emphysema as well as in the small airways in patients with COPD,21–23 and ICI treatment increases the number of CD8+ T-cells in COPD patients, which can be cytotoxic to epithelial airway cells.24,25 Treatment with ICIs and the subsequent boost to CD8+ T-cells may exacerbate the preexisting small airway and alveolar damage in patients with pre-ICI COPD, leading to worsening respiratory symptoms and increased COPD exacerbations. Another possible mechanism surrounds the PD-1 pathway and its impact on the large airways. PD-1 typically limits the viability of type-2 innate lymphoid cells, which are a potent source of T-helper 2 (Th2) cytokines that promote airway hyperreactivity and lung inflammation.26 Blocking the PD-1 pathway may promote and increase type-2 innate lymphoid cells and subsequent release of Th2 cytokines, leading to bronchospasm, COPD exacerbations, and COPD hospitalizations. Lastly, treatment with ICIs increases the levels of IL-17, IL-6, TNF-α, and TGF-β in patients with NSCLC and COPD.27 TGF-β is known to stimulate fibroblast proliferation, which could increase fibrosis in the small airways, while TNF-α and IL-6 are known to increase inflammation and mucous hypersecretion.28 Thus, after ICI treatment, it is possible that increased cytotoxic CD8+ T cells and inflammatory cytokines (such as IL-6, TNF-α, and TGF-β) result in further damage and inflammation of the airways, resulting in more COPD exacerbations and hospitalizations.
Several studies found either longer progression free and/or overall survival following ICI treatment in patients with lung cancer and co-morbid COPD; though, repeated chronic systemic steroid use during ICI treatment is associated with increased risk of death or cancer progression.17,29–34 In our study, we found that lung cancer patients with COPD required more courses of systemic steroids for respiratory-related symptoms compared to those without underlying COPD, and we found no difference in survival between COPD patients and those without COPD after adjusting for line of therapy and cancer stage. This suggests that while ICIs are an effective treatment for lung cancer patients with concurrent COPD, close monitoring of respiratory symptoms are needed while on ICI treatment and aggressive management of COPD should be considered to avoid cancer treatment interruptions from systemic corticosteroid administration for COPD exacerbations. Though pre-ICI peripheral cytokines and markers of T-cell activation may be predictive of immune-related adverse events, there are currently no studies examining potential pre-ICI biomarkers identifying patients at high risk for increased COPD severity following ICI treatment.35 Further studies are needed to identify biomarkers predictive of poor COPD control following ICI treatment.
We previously reported that PFTs are not routinely done before ICI treatment.36 There were no physiologic signs of worsening COPD (obstruction by FEV1/FVC, hyperinflation [TLC], or air trapping [RV]) after ICI treatment, but only 9.0% of the patients in our study had both pre-ICI and post-ICI PFTs. Bao et al37 found that DLCO was increased following neoadjuvant ICI-chemotherapy treatment in stage II-IIIA lung cancer but found no difference in FEV1 following ICI treatment. Future studies are needed to quantify whether physiologic declines in lung function accompany the clinical worsening of COPD observed in our study. Especially given the recent introduction of neoadjuvant immunotherapy approaches,38,39 a better understanding of the impact of ICIs on pulmonary function and surgical outcomes is needed.
There are several limitations to our study. First, this is a single center study at a tertiary referral center, so the results may not apply to all lung cancer patients with COPD. Second, as this is a retrospective study, there is a possibility of unrecognized confounders that may misclassify the relationship between ICI treatment and COPD disease control, and causality is unable to be determined with confidence. Also, once patients begin anticancer treatment, they are typically followed very closely for treatment toxicities – often every 2–3 weeks – and this increased visit frequency may lead to a higher rate of diagnosis of COPD exacerbations. Finally, our recording of pre-ICI COPD did not require spirometry, leading to potential misdiagnosis of COPD. We attempted to address this by evaluating patients with “objective” findings of COPD (emphysema on chest imaging or obstruction/air trapping on PFTs) and found that worsened COPD disease burden following ICI treatment persisted in this subgroup of patients. Furthermore, lack of spirometry in the diagnosis of COPD is a common and real-world issue,40,41 and the prevalence of COPD in our study is in line with the prevalence of COPD reported in larger studies,11,12 suggesting generalizability of our results.

Conclusion
Lung cancer patients with COPD have worsened COPD disease burden following ICI treatment, and lung cancer patients with COPD had similar overall survival compared to those without COPD. Close monitoring of respiratory symptoms is needed to allow for prompt and aggressive management of COPD in lung cancer patients with co-morbid COPD on ICI therapy. Further studies are needed to clarify the mechanisms linking lung cancer, COPD, and ICI treatment.

Supplementary Material

Supplementary_Table_8.docx

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