Efficacy and safety of immune checkpoint inhibitors in advanced non-small cell lung cancer with idiopathic interstitial pneumonia or interstitial lung abnormalities: NJLCG2301

Introduction

The global incidence of lung cancer is on the rise, and it remains a leading cause of cancer-related mortality (1). Individuals with interstitial lung disease (ILD) face a heightened risk of developing lung cancer (2). Additionally, growing evidence suggests that patients with interstitial lung abnormalities (ILA)—incidental findings on computed tomography (CT) scans that may indicate underlying ILD in individuals without a prior clinical suspicion—are also at increased risk of developing treatment-related pneumonitis (3,4). Furthermore, patients diagnosed with both lung cancer and ILD tend to have poorer survival outcomes compared to those with lung cancer alone, even after accounting for cancer stage (5). In recent years, treatment options for advanced non-small cell lung cancer (NSCLC) have notably improved. The introduction of immunotherapy, in particular, has significantly transformed the therapeutic landscape of advanced NSCLC. Phase 3 clinical trials have demonstrated that inhibitors targeting programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) significantly extend overall survival (OS) when compared to docetaxel monotherapy (6-9). Moreover, several phase 3 trials have reported that incorporating immune checkpoint inhibitors (ICIs) into platinum-based doublet chemotherapy leads to superior OS and progression-free survival (PFS) compared to chemotherapy alone (10-14). However, patients with NSCLC who also have idiopathic interstitial pneumonia (IIP)were excluded from these studies, highlighting a significant gap in clinical evidence for this population.

Only two prospective phase 2 studies have assessed the safety of ICI monotherapy in patients with previously treated NSCLC and IIPs (15,16). Evidence regarding the use of combined chemotherapy and ICIs in the first-line setting remains limited and inconclusive. Although ICIs have demonstrated the potential for prolonged survival and are a key component in improving OS in advanced NSCLC, their safety and efficacy in patients with IIPs—particularly in relation to achieving long-term survival—have not been adequately explored. Accordingly, we examined the current use of ICI therapy for NSCLC associated with IIPs in real-world clinical practice and evaluated its safety and efficacy, including outcomes related to long-term survival. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-783/rc).

Methods

Study design

This was a multicenter retrospective cohort study conducted across 11 institutions affiliated with the North Japan Lung Cancer Study Group (NJLCG). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Hirosaki University Graduate School of Medicine (approval number: 2022-145-3). Informed consent was waived in this retrospective study. All participating hospitals were informed and agreed with the study. Patients were provided with the option to decline participation through a notice posted on the official website of each institution.

Patient selection

We reviewed the medical records of patients who received either ICI monotherapy or a combination of ICI and chemotherapy (chemo-ICI) between December 2015 and March 2020. The study included consecutive patients with advanced NSCLC—defined as stage IIIB/IIIC deemed unsuitable for definitive radiation therapy, stage IV, or postoperative recurrence based on the eighth edition of the TNM classification—who also had IIPs or ILA, as diagnosed at each participating institution. Patients were excluded if they had a history of acute exacerbation of IIPs before ICI treatment, if they were receiving systemic corticosteroids at doses exceeding 10 mg/day of prednisolone or equivalent immunosuppressive agents, or if they had autoimmune diseases.

Data collection and outcome assessment

Clinical and follow-up data were extracted from patients’ medical records and included the following variables: age at the time of ICI initiation, sex, Eastern Cooperative Oncology Group performance status (ECOG-PS), smoking history, cancer stage, histological subtype, PD-L1 tumor proportion score, laboratory test results, use of anti-fibrotic agents, % predicted value for forced vital capacity (%FVC), and % predicted value for diffusing capacity for carbon monoxide (%DL_CO), line of therapy and ICI regimen, treatment response to ICI, occurrence of immune-related adverse events—including pneumonitis—PFS, and OS. PD-L1 expression was assessed using the PD-L1 immunohistochemistry 22C3 pharmDx assay kit (Dako North America, Carpinteria, CA, USA). Adverse events were documented based on the Common Terminology Criteria for Adverse Events (version 5.0) (17).

Evaluation of IIPs and ILA

Preexisting IIPs and ILA were identified using high-resolution CT (HRCT) at each participating institution. These findings were then reviewed at a central institution by two radiologists (F.T. and S.K.) and two pulmonologists (H.T. and S.T.), all of whom were blinded to the patients’ clinical information. The presence of IIPs was categorized into four levels of diagnostic confidence for the usual interstitial pneumonia (UIP) pattern based on HRCT findings: UIP, probable UIP, indeterminate for UIP, and alternative diagnosis (18). ILAs were defined according to the Fleischner Society as incidental, nondependent abnormalities involving more than 5% of any lung zone detected on CT imaging (4). Based on the same classification system, ILAs were further divided into three subtypes: non-subpleural ILAs, characterized by opacities without predominant subpleural distribution; subpleural ILAs without fibrosis; and subpleural fibrotic ILAs, which exhibit fibrotic features such as architectural distortion with traction bronchiectasis and/or honeycombing (4). There are currently no imaging criteria that can definitively distinguish IIPs from ILAs. In this study, ILAs were defined as incidental CT findings showing minor interstitial abnormalities involving more than 5% of the lung fields.

Statistical analysis

All statistical analyses were conducted using EZR software, version 1.52 (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Data are reported as either numbers (percentages) or medians (ranges). Univariate and multivariate logistic regression analyses were used to identify risk factors for the development of pneumonitis and radiological disease progression. Radiographic tumor responses were assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (19). PFS and OS were estimated using the Kaplan-Meier method, and differences between groups were evaluated using the log-rank test. A P value less than 0.05 was considered statistically significant.

Results

Patient characteristics

The patient selection process and study consort diagram are presented in Figure 1. A total of 79 patients who received ICI monotherapy, with or without chemotherapy, for advanced NSCLC accompanied by IIPs or ILA were identified. Of these, 53 patients with IIPs and 18 with ILA were subjected to the analysis, following the exclusion of 1 patient determined to have no IIPs and 7 with ILAs based on central institutional review. Baseline characteristics for the 53 patients with IIPs are summarized in Table 1. The characteristics and outcomes of the 18 patients with ILAs are presented separately in “Results in patients with the ILA cohort”. The median age was 71 years (range, 55–84 years), and 50 patients (94.3%) were male. The majority (96.2%) were either current or former smokers. Squamous cell carcinoma was the most frequently observed histological type, present in 50.9% of cases. Eight patients (15.1%) had an ECOG-PS of 2. Based on HRCT findings, 18 patients were classified as having a definite UIP pattern, 28 as probable UIP, 6 as indeterminate for UIP, and 1 as an alternative diagnosis. The median %FVC was 94% (range, 41.9–142%), and the median %DL_CO was 49.8% (range, 5.4–97%). Complete pulmonary function testing was performed in 32 patients (55%). Treatment regimens are detailed in Table S1. Among patients receiving combination therapy, pembrolizumab plus chemotherapy was the most commonly used regimen, while nivolumab was the most frequently selected agent for ICI monotherapy.

Figure 1 Consort diagram of the study. ICI, immune checkpoint inhibitor; IIPs, idiopathic interstitial pneumonias; ILA, interstitial lung abnormalities; IP, interstitial pneumonia; NSCLC, non-small cell lung cancer.

Efficacy

The data cutoff was set for December 31,2022. Kaplan–Meier survival curves illustrating the PFS for patients treated with chemo-ICI and ICI monotherapy are presented in Figure 2A. The ICI monotherapy group was further subdivided into patients receiving treatment as the first-line therapy and those receiving it as the second-line or later. The median PFS was 5.1 months [95% confidence interval (CI): 1.2–not available (NA)] in the chemo-ICI group, 7.3 months (95% CI: 0.5–12.6) in the first-line ICI monotherapy group, and 5.7 months (95% CI: 2.5–10.1) in the second-line or later ICI monotherapy group. The 12- and 24-month PFS rates were 28.1% and 9.4% in the first-line ICI monotherapy group and 29.8% and 13.2% in the second-line or later group, respectively. No patients in the chemo-ICI group achieved PFS of 12 months or longer. The objective response rate was 66.6% in the chemo-ICI group and 31.9% in the ICI monotherapy group (Table S2). Results from univariate and multivariate analyses for PFS are shown in Table 2. In the univariate analysis, PS 2 was identified as a statistically significant prognostic factor for shortened PFS (P=0.01). However, the multivariate analysis did not identify any independent factors associated with extended PFS.

Figure 2 Progression-free survival (A) and overall survival (B) in patients with NSCLC and IIPs treated with ICI. CI, confidence interval; ICI, immune checkpoint inhibitor; IIPs, idiopathic interstitial pneumonias; NA, not available; OS, overall survival; PFS, progression-free survival.

The Kaplan-Meier curves for OS in patients treated with chemo-ICI and ICI monotherapy are presented in Figure 2B. The median OS was 5.4 months (95% CI: 3.2–NA) in the chemo-ICI group, 10.0 months (95% CI: 1.2–26.9) in the first-line ICI monotherapy group, and 15.4 months (95% CI: 8.0–22.1) in the second-line or later group. The 12- and 24-month OS rates were 16.7% and 0% in the chemo-ICI group, 44.0% and 26.4% in the first-line ICI monotherapy group, and 52.9% and 32.1% in the second-line or later group, respectively. Univariate and multivariate analyses for OS are shown in Table 3. In the univariate analysis, PS 2 (P=0.02) and treatment with ICI monotherapy (P=0.04) were significant prognostic factors for shorter OS. However, the multivariate analysis did not identify any factors independently associated with longer OS.

Safety

Data regarding pneumonitis by imaging pattern and treatment details are summarized in Table 4. The overall incidence of pneumonitis was 28.3% (15 out of 53 patients) for all grades, with grade 3 or 4 pneumonitis occurring in 9 (17.0%). There were no cases of grade 5 pneumonitis reported. The median time from the start of treatment to pneumonitis onset was 42 days. The rate of treatment discontinuation due to pneumonitis was 24.5%. Univariate and multivariate analyses did not identify any independent predictors for pneumonitis or high-grade pneumonitis (Tables 5,6). Immune-related adverse events (irAE) other than pneumonitis are listed in Table S3. Most adverse events were grade 1 or 2, with high-grade events observed in two patients (33.3%) in the chemo-ICI group and six patients (12.8%) in the ICI monotherapy group. Among the five long-term responders with IIPs—defined as patients without disease progression for at least 2 years—four did not develop pneumonitis during ICI treatment (Table S4).

Results in patients within the ILA cohort

Although the primary focus of this study was on NSCLC patients with IIPs, we also performed an exploratory analysis with ILA. The baseline characteristics of the 18 patients with ILA are detailed in Table S5. Most patients (66.6%) received ICI therapy as first-line treatment, and five patients (27.8%) were treated with chemo-ICI. Regarding radiological patterns, the subpleural fibrotic pattern was the most common, observed in 77.8% of cases; two patients (11.0%) had a subpleural non-fibrotic pattern, and another two (11.0%) exhibited a non-subpleural pattern. The median PFS was 9.9 months (95% CI: 5.1–NA) in the chemo-ICI group, 3.1 months (95% CI: 0.7–NA) in the first-line ICI monotherapy group, and 5.8 months (95% CI: 1.6–NA) in the second-line or later ICI monotherapy group. The 12- and 24-month PFS rates were 40.0% and 20.0% for the chemo-ICI group and 33.3% and 16.7% for the second-line or later ICI monotherapy group, respectively (Figure S1A). Median OS was 27.0 months (95% CI: 5.7–NA) in the chemo-ICI group, 8.4 months (95% CI: 1.6–21.7) in the first-line ICI monotherapy group, and 20.3 months (95% CI: 7.5–NA) in the second-line or later ICI monotherapy group. The OS rates at 12 and 24 months were 80.0% and 60.0% in the chemo-ICI group, 28.6% and 14.3% in the first-line ICI monotherapy group, and 66.7% and 44.4% in the second-line or later ICI monotherapy group (Figure S1B). Kaplan-Meier curves for PFS and OS stratified by radiological pattern are shown in Figure S2A,S2B. The objective response rate was 40.0% in the chemo-ICI group and 53.8% in the ICI monotherapy group (Table S6).

Data on pneumonitis in the ILA cohort are presented in Table S7. The overall incidence of pneumonitis was 22.2% (4 out of 18 patients). Grade 1 or 2 pneumonitis occurred in 11.1% (2/18), and grade 3 or 4 pneumonitis also occurred in 11.1% (2/18). The median time to pneumonitis onset was 21 days (range, 5–172 days).

Treatment was discontinued due to pneumonitis in 16.7% (3/18) of patients. In a subgroup analysis by imaging pattern, pneumonitis developed in 21.4% (3/14) of patients with subpleural fibrotic ILA, with grade 3 or 4 pneumonitis seen in 14.3% (2/14). Regarding treatment type, no pneumonitis cases were observed in the chemo-ICI group, while the incidence was 30.7% (4/13) in the ICI monotherapy group, including grade 3 or 4 events in 15.4% (2/13). Discontinuation of treatment due to pneumonitis occurred in 23.1% (3/13) of patients receiving ICI monotherapy.

Discussion

In everyday clinical practice, deciding on the treatment for NSCLC patients with IIPs remains a critical issue. Although ICI therapy is now considered standard treatment, its role in improving long-term survival for NSCLC patients with IIPs is still uncertain. Our findings indicate that ICI therapy is linked to long-term survival outcomes in NSCLC patients with IIPs, both in the first-line and in the subsequent treatment settings. In this study, pneumonitis occurred in 50% of patients receiving chemo-ICI, with 33.3% experiencing severe pneumonitis, which may have contributed to the shorter OS. The 12- and 24-month OS rates were also low (16.7% and 0%) in the chemo-ICI group, suggesting that, considering the toxicity, avoiding chemo-ICI might be preferable. In the second-line or later treatment setting, the median PFS was 5.8 months, and the 12- and 24-month OS rates were 52.9% and 32.1%, respectively. Phase 3 trials have reported 2-year OS rates with nivolumab of 23% in squamous NSCLC (CheckMate 017 trial) and 29% in non-squamous NSCLC (Checkmate 057 trial) (20). Our results demonstrated higher 2-year OS rates. Interestingly, in our cohort, second-line or later ICI monotherapy exhibited numerically longer OS and slightly better PFS compared with first-line ICI monotherapy in patients with IIPs, and favorable outcomes in those with ILAs. This counterintuitive result may be explained by patient selection bias, in which only patients who remained eligible for second-line treatment following previous therapy may represent a favorable subset. Moreover, attrition of early progressors may have enriched the second-line group with long-term responders. Differences in histology, performance status, or comorbidities may also have contributed. As data on PD-L1 expression was limited, we could not fully assess its contribution. Therefore, these results should be interpreted cautiously and warrant confirmation in larger prospective studies. The proportion of NSCLC patients achieving long-term survival was not different between those with IIPs and those without. However, the incidence of pneumonitis during ICI monotherapy was 25.5%, with 14.9% experiencing grade 3 pneumonitis, which is higher than the incidences previously reported in patients without IIPs (21-24). There are only two small prospective phase 2 trials evaluating the safety of ICI monotherapy for previously treated NSCLC in patients with IIPs. Fujimoto et al. conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab in previously treated NSCLC patients with mild IIPs (15). The objective response rate (ORR) was 39% and the PFS was 7.4 months. However, OS data were limited, with only 33% of events recorded at the data cutoff. Pneumonitis occurred in 2 out of 18 cases (11%). Another phase 2 trial, TORG1936/AMBITIOUS, examined the safety and efficacy of atezolizumab in previously treated NSCLC patients with IIPs (16,25). The ORR was 6.3 %, with a PFS of 3.2 months and a 1-year OS rate of 53.3%. This trial was prematurely stopped because pneumonitis developed in 5 of 17 patients (29%), including 4 cases of grade 3 or higher (23.5%) and 1 fatal case (grade 5). The incidence rate of pneumonitis differed notably between these two studies, potentially due to the differences in the number of patients with honeycomb lung and the minimum %FVC values on inclusion. The AMBITIOUS trial included a high proportion of patients with honeycomb lung (44%). In our study, 47% of patients had honeycomb lung. Furthermore, we included patients with %FVC less than 70%, which may have contributed to the higher pneumonitis incidence compared to previous nivolumab studies (15).

Poor lung function has been reported as a risk factor for pneumonitis. In our study, low %FVC was not found to be a significant risk factor for pneumonitis, although this might be affected by the low rate of pulmonary function test implementation. Treatments for idiopathic pulmonary fibrosis (IPF), particularly antifibrotic agents, such as pirfenidone and nintedanib, reduce the risk of acute exacerbation in IPF (26,27). In the present study, only one patient received nintedanib at the time of ICI initiation, which prevented a meaningful subgroup analysis. Whether antifibrotic drugs can suppress the development of ICI-related pneumonitis remains unclear. Recently, Yamaguchi et al. described four cases of patients with NSCLC and IIPs treated with atezolizumab and nintedanib (28). One patient developed asymptomatic grade 1 pneumonitis. They suggested that the absence of severe pneumonitis indicates that antifibrotic therapy mitigates immune-related lung toxicity. Although our data are limited, antifibrotic treatments may play a protective role and warrant further evaluation in prospective studies combining ICIs with antifibrotic agents.

We also performed an exploratory analysis of ILA patients with imaging patterns centrally reviewed to ensure consistent and reliable diagnoses. Because of the small number of cases and the distinct pathogenesis compared with IIPs, the results should be considered hypothesis-generating, rather than confirmatory. Nevertheless, some patients achieved durable responses and long-term survival, particularly in the chemo-ICI group, which exhibited favorable PFS and OS rates. Pneumonitis occurred in >20% of the patients, primarily in those receiving ICI monotherapy, whereas no events were observed in the chemo-ICI group. Although the number of patients was small, this may be related to the milder extent of lung abnormalities in ILA compared with those in the IIPs, and possibly to an immunomodulatory effect of chemotherapy in reducing immune-related lung toxicity. This is consistent with previous studies suggesting a safer profile when ICIs are combined with chemotherapy (29,30). The predominance of the subpleural fibrotic pattern may explain, in part, the higher risk of lung toxicity in some ILA patients. Taken together, these results should be interpreted with caution, and further prospective studies are needed to clarify the role of ICIs in NSCLC patients with ILA.

Our study has several limitations. First, it was retrospective, which introduced treatment selection bias, and the timing of tumor assessments varied across study sites. Second, since the primary aim was to evaluate long-term survival with ICI therapy in NSCLC patients with IIPs, patients who had not undergone pulmonary function tests were included, resulting in many cases lacking these tests. This absence of pulmonary function data may have hindered the identification of previously reported pneumonitis risk factors, complicating the interpretation of results. Finally, only a small number of cases were classified as ILA by central review, limiting the conclusions that can be drawn about the ILA cohort.

Conclusions

ICI therapy for NSCLC with IIPs may result in long-term survival; however, the rate of adverse events related to ILD was high. Further prospective studies are warranted to better define the safety and efficacy of ICIs in this population.

Acknowledgments

We express our gratitude to the patients and investigators who contributed to this study. The authors also thank Enago (www.enago.jp) for the English language review.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-783/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-783/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-783/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-783/coif). H.T. reported receiving lecture fees from AstraZeneca K.K, Chugai Pharmaceutical Co., Boehringer-Ingelheim Japan Inc., Ono Pharmaceutical Co., Pfizer Japan Inc., and Bristol-Meyers Squibb. R.M. reported receiving consulting fee from AstraZeneca K.K and Daiichi Sankyo, honoraria from AstraZeneca K.K, Bristol-Meyers Squibb, Eli Lilly, Chugai Pharmaceutical Co., MSD K.K, Takeda Pharmaceutical Co., Amgen, and Daiichi Sankyo. M.I. reported receiving honoraria from AstraZeneca K.K, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Eli Lilly Japan K.K, Takeda Pharmaceutical Company Limited, MSD K.K, and Boehringer Ingelheim Japan Co. J.S. reported receiving honoraria from AstraZeneca K.K, MSD K.K, Chugai Pharmaceutical Co., and Kyowa Kirin. The other 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Hirosaki University Graduate School of Medicine (approval number: 2022-145-3). Informed consent was waived in this retrospective study.

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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