Treatment Response and Safety of Immunotherapy for Advanced Non-Small Cell Lung Cancer With Comorbid Chronic Obstructive Pulmonary Disease

A Retrospective Cohort Study

Kening Zhang; Chengzhi Zhou; Jiabo Gao; Pei Yu; Xinqing Lin; Xiaohong Xie; Ming Liu; Jiexia Zhang; Zhanhong Xie; Fei Cui; Shiyue Li; Francesco Passiglia; Giulia Maria Stella; Yinyin Qin


Transl Lung Cancer Res. 2022;11(11):2306-2317. 

In This Article

Abstract and Introduction


Background: Immunotherapy has provided a novel therapeutic option for lung cancer but studies involving patients with advanced non-small cell lung cancer (NSCLC) coupled with various degrees of comorbid chronic obstructive pulmonary disease (COPD) are limited. Thus, we performed a retrospective cohort study to optimize the use of immunotherapy in this special population.

Methods: We enrolled a total of 99 patients with advanced (stage IIIB/C-IV) NSCLC with comorbid COPD who had received immune checkpoint inhibitors (ICIs) according to the inclusion and exclusion criteria. They were divided into four groups according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline criteria as follows: no COPD group (n1=19), mild COPD group (n2=24), moderate COPD group (n3=31), and severe COPD group (n4=25). Routine blood, imaging characteristics, related cytokines including interleukin (IL)-6, IL-8, IL-10, etc., Krebs Von den Lungen (KL)-6, and corresponding indicators of immune-related adverse events (irAEs), incidence of irAEs, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were recorded and analyzed. Comparability of baseline factors above and clinical characteristics were evaluated.

Results: There were statistically significant differences in the incidence of irAEs among the four groups (P=0.003). The incidence of irAEs in patients with no COPD (n1, 21.1%) and mild to moderate COPD (n2/3, 8.3%, 32.3%) was lower than that in patients with severe COPD (n4, 56.0%) (P=0.003). The median PFS of the mild to moderate COPD group was significantly longer than the severe COPD group (19.0 vs. 8.00 months, log-rank P=0.004). A significant increase of both ORR (P=0.004) and DCR (P=0.037), as well as higher IL-6 (P=0.000), IL-8 (P=0.026), and IL-10 (P=0.010) levels, have been observed in the mild to moderate COPD group compared with severe COPD group. IL-6 level was an independent factor influencing PFS [P=0.007, 95% confidence interval (95% CI): 1.000–1.002] and COPD grading was an independent predictor of irAEs (P=0.037, 95% CI: 1.035–3.039).

Conclusions: Immunotherapy should be selected with caution for advanced NSCLC patients with comorbid severe COPD, considering the limited efficacy and the increased risk of immune-related adverse events related to the immune-checkpoint inhibitors administration in this special population.


Lung cancer and chronic obstructive pulmonary disease (COPD) are two major respiratory diseases affecting the quality of human life. Lung cancer still represents the main cause cancer-related deaths, with non-small cell lung cancer (NSCLC) accounting for about 85% of all types of lung cancers. However, approximately 75% of NSCLC patients are diagnosed at an advanced stage.[1] COPD is already the third leading cause of death worldwide, and its prevalence is expected to rise in the next 40 years. COPD and NSCLC are mutually important causes of death of each other. Recent research has suggested that the incidence of COPD is higher in NSCLC patients,[2] and the incidence of comorbidities in both diseases is not low. Some researchers found that 69% had COPD or emphysema (39% with COPD, 59% with emphysema) in their lung cancer patients studied.[2] Others also found that 50.5% patients with advanced NSCLC had COPD in their study.[3] For this reason, clinicians are gradually paying more attention to this cohort, with relevant content added to the 2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. However, currently little is known about the treatment of advanced NSCLC with comorbid COPD, and there is no consensus on how to optimize treatment for these patients.

In recent years, immune checkpoint inhibitors (ICIs) have become a new standard of care for NSCLC, but evidence in NSCLC patients with comorbid COPD remain lacking. There is currently no uniform conclusion on the correlation between GOLD grading of COPD and the efficacy of immunotherapy. A study by Zhou et al.[4] found that PFS had a tendency to prolong in patients with comorbid moderate to severe COPD compared with no COPD patients, while Shin SH[5] found that PFS is better in patients with mild COPD. Therefore, this study analyzed the efficacy and tolerability of ICIs in advanced NSCLC patients with various degrees of comorbid COPD in order to optimize the use of immunotherapy in this special population. We present the following article in accordance with the STROBE reporting checklist (available at