Treatment Response And Safety Of Immunotherapy For Advanced Non-small Cell Lung Cancer With Comorbid Chronic Obstructive Pulmonary Disease

Background and objectiveLung cancer and chronic obstructive pulmonary disease（COPD）are the two main respiratory diseases that currently affect the quality of human life.Current studies have shown that the incidence of COPD in patients with advanced non-small cell lung cancer（NSCLC）is not low,but there is still a lack of standard treatment.In recent years,immunotherapy has provided a new treatment option for lung cancer patients,and many researchers have explored the clinical characteristics of NSCLC patients with comorbid COPD,the interaction and impact of COPD and lung cancer but the specific mechanism is unknown,and the research involving NSCLC patients with comorbid different degrees of COPD,especially the optimized regimen,response,efficacy and safety of immunotherapy for patients with this special type of severe lung cancer,is still limited.Therefore,this retrospective cohort study was conducted to summarize and analyze the efficacy and safety of immunotherapy,and to improve the clinical attention to such severe lung cancer patients,so as to optimize the application of immunotherapy in this special population.Patients and methodsThis study retrospectively analyzed patients who were admitted to the First Affiliated Hospital of Guangzhou Medical University from January 01,2019 to April30,2021.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.The similarities and differences between patients of advanced NSCLC with and without comorbid COPD,and subgroup patients with comorbid COPD of different degrees were analyzed.The similarities and differences between patients with different degrees of COPD,and the prognostic factors affecting the incidence of irAEs and PFS in such patients were explored.ResultsOf the 99 patients finally included in the study,a total of 30 developed irAEs.Different irAEs have different rates,with fatigue being the highest.There were statistically significant differences in the incidence of irAEs among the four groups（P=0.003）.In subgroup analysis,the incidence of irAEs in patients with no COPD（n₁,21.1%）and mild to moderate COPD(n_2/3,8.3%,32.3%)was lower than that in patients with severe COPD（n₄,56.0%）（P=0.003）.There was a significant difference in the incidence of irAEs between no COPD group and severe COPD group（P=0.024）.There was a significant difference in the incidence of irAEs between the mild to moderate COPD group and severe COPD group（P=0.003）.IL-6（P=0.000）,IL-8（P=0.030）,IL-10（P=0.024）,KL-6（P=0.029）were statistically significant between the four groups（P<0.05）.In the subgroup analysis,there were significant differences in IL-6（P=0.000）,IL-8（P=0.026）,and IL-10（P=0.010）between the mild to moderate COPD group and severe COPD group（P<0.05）.There were statistically significant differences in ORR（P=0.009）and DCR（P=0.016）between the no COPD group（n₁）and severe COPD group（n₄）.In subgroup analysis,there was also a significant difference in ORR（P=0.004）and DCR（P=0.037）between mild to moderate COPD group(n_2/3)and severe COPD group（n₄）.Median follow-up was 42.0 months（17.6 to66.4 months）.The median PFS（mPFS）in the four groups were no COPD（n₁,12.0months）,the mild COPD group（n₂,19.0 months）,the moderate COPD group（n₃,not reached）,and the severe COPD group（n₄,8.00 months）.In subgroup analysis,there was a statistically significant difference in mPFS between no COPD group（n₁）,mild to moderate COPD group(n_2/3),and severe COPD group（n₄）（log-rank P=0.011）,where mPFS was significantly longer in the mild to moderate COPD group than in the severe COPD group（19.0 months vs.8.00 months,log-rank P=0.004）.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）.ConclusionsImmunotherapy is not contraindicated in patients with advanced NSCLC with comorbid COPD.More attention should be paid to the assessment of their lung function before immunotherapy in these patients.In the course of immunotherapy,patients of advanced NSCLC with comorbid mild to moderate COPD had longer PFS than patients of advanced NSCLC with comorbid severe COPD,with a lower incidence of adverse reactions and better immune efficacy.Immunotherapy should be chosen with caution in patients of advanced NSCLC with comorbid severe COPD,as immune checkpoint inhibitor therapy has limited efficacy and an increased risk of immunotherapy-related adverse events in this particular population compared with no COPD patients and patients of advanced NSCLC with comorbid mild to moderate COPD.At the same time,clinical attention should be paid to the independent effects of IL-6 on tumor progression and COPD grade on the occurrence of irAEs.The standardized use of anti-COPD drugs does not increase the toxicity of drug therapy and the incidence of irAEs in patients with advanced NSCLC with comorbid COPD,thus it should be used and treated more strictly for patients with special severe lung cancer to achieve"simultaneous treatment of both cancer and the lung".