Clinical significance of inhaled COPD therapy in advanced or recurrent non-small cell lung cancer in the immune checkpoint inhibitor era: a multicenter retrospective cohort study

Immune checkpoint inhibitors (ICIs) have markedly improved survival in advanced non–small cell lung cancer (NSCLC), potentially modifying the prognostic impact of comorbid chronic obstructive pulmonary disease (COPD). We conducted a multicenter retrospective cohort study across four Japanese institutions including patients with spirometry-confirmed COPD and advanced or recurrent NSCLC, including stage IV disease, postoperative recurrence, recurrence after definitive concurrent chemoradiotherapy, or other advanced/recurrent status documented in the clinical records, treated between January 2007 and December 2020, excluding those with sensitizing EGFR variants or ALK fusions. COPD was diagnosed based on smoking history and airflow limitation, defined as a forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio of less than 70%, in accordance with the Japanese Respiratory Society guidelines and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. COPD treatment was defined as regular use of inhaled bronchodilators and/or inhaled corticosteroids initiated before or at the start of first-line therapy. Overall survival (OS) was measured from treatment initiation to death from any cause. Among 455 eligible patients with spirometry-confirmed COPD, 144 received regular inhaled COPD therapy and 311 did not. Median OS was longer in the COPD-treated group than in the untreated group (23.3 vs. 16.7 months; hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.57–0.93; P = 0.0105). However, patients receiving COPD treatment were more likely to receive ICIs during the disease course than untreated patients (109/144, 75.7% vs. 138/311, 44.4%), and ICI therapy remained a strong independent predictor of OS in conventional multivariable analysis. In an additional time-dependent Cox analysis accounting for the timing of ICI initiation, COPD treatment showed a modest association with longer OS, whereas ICI exposure showed a nonsignificant trend toward improved OS. When patients were stratified by ICI exposure, COPD-treated patients had longer OS than untreated patients in the non-ICI subgroup, whereas OS did not differ meaningfully by COPD treatment status among patients who received ICIs. These findings indicate that the survival association between COPD treatment and OS should be interpreted with careful consideration of the timing and line of ICI exposure in the ICI era.