
==== Front
Cancer Immunol Immunother
Cancer Immunol Immunother
Cancer Immunology, Immunotherapy : CII
0340-7004
1432-0851
Springer Berlin Heidelberg Berlin/Heidelberg

39235641
3792
10.1007/s00262-024-03792-5
Research
Outcome of immune checkpoint inhibitor treatment in non-small cell lung cancer patients with interstitial lung abnormalities: clinical utility of subcategorizing interstitial lung abnormalities
http://orcid.org/0000-0002-0854-3494
Kikuchi Ryota reo1129@tokyo-med.ac.jp

1
Watanabe Yusuke 2
Okuma Takashi 1
Nakamura Hiroyuki 2
Abe Shinji 1
1 https://ror.org/012e6rh19 grid.412781.9 0000 0004 1775 2495 Department of Respiratory Medicine, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-Ku, Tokyo 160-0023 Japan
2 https://ror.org/031hmx230 grid.412784.c 0000 0004 0386 8171 Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
5 9 2024
5 9 2024
11 2024
73 11 21112 5 2024
24 7 2024
© The Author(s) 2024
2024
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Interstitial lung abnormalities (ILAs) are immune checkpoint inhibitor (ICI)-related pneumonitis (ICI-P) risk factors. However, the relationship between imaging patterns and immunotherapy outcomes, and treatment strategies remain unclear in patients with non-small cell lung cancer (NSCLC) and ILAs. We retrospectively evaluated patients with ILAs-complicated NSCLC who received ICI therapy. ILAs were subcategorized as non-subpleural, subpleural non-fibrotic, and subpleural fibrotic (SF) based on the 2020 position paper by the Fleischner Society. We investigated ICI-P incidence, ICI-P risk factors, lung cancer prognosis, and ILAs radiological progression. Of the 481 ICI-treated patients, 79 (16.4%) had ILAs (45 non-SF and 34 SF). The ICI-P cumulative incidence (hazard ratio, 4.57; 95% confidence interval [CI], 1.90–10.98; p = 0.001) and any grade and grade ≥ 3 ICI-P incidences were higher in patients with SF-ILAs than in those with non-SF-ILAs (all grades: 7/45 [15.6%)] vs. 18/34 [52.9%]; p < 0.001; grade ≥ 3: 1/45 [2.2%] vs. 10/34 [29.4%]; p = 0.001). According to multivariate analysis, SF-ILAs independently predicted ICI-P (odds ratio, 5.35; 95% CI 1.62–17.61; p = 0.006). Patients with SF-ILAs had shorter progression-free and overall survival and higher ICI-P-related respiratory failure death rates than those with non-SF-ILAs. Approximately 2.5 times more patients with SF-ILAs showed progression by the 2-year follow-up than those with non-SF-ILAs. SF-ILAs is an independent strong predictor of ICI-P development in patients with NSCLC, may increase ICI-P severity, worsen prognosis, and accelerate ILAs progression. ILAs subcategorization is an important treatment strategy for patients with lung cancer treated with ICIs.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00262-024-03792-5.

Keywords

Immune checkpoint inhibitor-related pneumonitis
Interstitial lung abnormalities
Non-small cell lung cancer
Prognosis
Radiological change
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pmcIntroduction

Interstitial lung abnormalities (ILAs) are interstitial lung diseases (ILD) often found in patients without clinical suspicion [1]. It is reported that 20% of patients with ILA progress in 2 years and 73% in 5 years [2, 3]. Risk factors for ILA progression include chemotherapy, immune checkpoint inhibitor (ICI) use, radiotherapy, and thoracic surgery [1]. Hence, ILAs and lung cancer are closely related. Among ILAs, fibrosis patterns and subpleural lesions are more likely to progress, and patients with these imaging patterns have an increased mortality risk [2–4]. To identify progressive ILAs, the Fleischner Society classifies ILAs into three subtypes: non-subpleural (NS), subpleural non-fibrotic (SNF), and subpleural fibrotic (SF) [1]. However, the relationship between the clinical outcomes and ILA imaging patterns in patients with ILA-complicated lung cancer remains unclear.

Since the advent of ICIs [particularly anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies], drug therapy for advanced non-small cell lung cancer (NSCLC) has markedly changed, prolonging survival compared with conventional chemotherapy [5–7]. ICIs activate and sustain tumor immunity by blocking co-inhibitory molecules that suppress immunity in various immune cells; hence, autoimmune disease-like immune-related adverse events (IrAEs) appear [8]. IrAEs occur most frequently in the skin, gastrointestinal tract, liver, endocrine system, and lungs [9]. According to a meta-analysis, ICI-related pneumonitis (ICI-P) is a clinically serious and often fatal adverse event that accounts for 35% of anti-PD-1 and anti-PD-L1 antibody-related deaths [10].

Risk factors for developing ICI-P include the type of ICI, combination immunotherapy, primary tumor site, radiation history, and baseline lung disease [11, 12]. Despite a conflicting report [13], ILA has been reported to lead to the development of ICI-P [14–17]. In particular, the incidence of ICI-P in patients with pre-existing ILAs is 12.3–52.6%, which is approximately six times higher than that in patients without ILAs [14–17]. The prognosis of lung cancer may worsen after the onset of ICI-P. Although the presence of ILA before starting treatment is associated with lung cancer-related death [18–21], previous studies did not adequately reflect the current reality of lung cancer drug therapy owing to the absence of ICI data. Furthermore, the predictive factors and preventive measures for the development of ICI-P and the natural history of ILAs in patients with lung cancer with ILAs have not been fully evaluated. Consequently, treatment strategies for lung cancer patients with ILAs are considered an important but unresolved question in ILA position papers [1].

Therefore, we investigated the risk factors for ICI-P development, prognosis, and radiological changes in patients with ILAs-complicated lung cancer, focusing on the ILAs imaging patterns.

Materials and methods

Patients

Consecutive patients with cytologically and/or histologically confirmed advanced or recurrent NSCLC and preexisting ILAs who received ICIs (nivolumab, pembrolizumab, or atezolizumab) for the first time at the Tokyo Medical University Hospital or Tokyo Medical University Ibaraki Medical Center between January 2016 and June 2021 were retrospectively enrolled. This study was approved by the Institutional Review Board of the Tokyo Medical University (approval no. TS2021-0175). This study was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki. The need for obtaining informed consent from the patients was waived owing to the retrospective nature of the study. The official website of our institution was used to allow patients to opt out from participation.

All patients received at least one intravenous ICI. The follow-up period lasted until June 30, 2022. The median observation period after receiving ICI was 17.7 months.

Data collection and outcome assessment

Clinical information and follow-up data were obtained from the patients’ medical records and included age at ICI treatment, sex, Eastern Cooperative Oncology Group performance status (PS), smoking history, cancer staging, histology, PD-L1 tumor proportion score (TPS), laboratory findings, development of ICI-P, progression-free survival (PFS), and overall survival (OS). Cancer staging was performed according to the eighth edition of the Tumor, Node, and Metastasis (TNM) classification for lung cancer [22]. The expression of PD-L1 by tumor cells was determined using a PD-L1 immunohistochemistry 22C3 pharmDx assay kit (Dako North America, Carpinteria, CA, USA). Laboratory measurements were performed up to 2 weeks before first ICI administration, including serum neutrophil-to-lymphocyte ratio, absolute monocyte count, lactate dehydrogenase, albumin, and C-reactive protein. ICI-P was diagnosed based on a combination of the following: (1) clinical findings (signs and symptoms); (2) new lung parenchymal abnormalities on chest high-resolution computed tomography (CT) either during or after treatment with ICIs; (3) biological findings, such as sputum and/or blood culture, bronchoalveolar lavage fluid, and laboratory data; and (4) exclusion of pulmonary infectious diseases, heart failure, fluid overload, or cancer progression, including malignant lung infiltration and carcinomatous lymphangiosis [23–25]. The severity grade of ICI-P was evaluated using the Common Terminology Criteria for Adverse Events (version 4.0). Radiologic patterns of ICI-P were classified as non-specific interstitial pneumonia (NSIP) pattern, organizing pneumonia (OP) pattern, hypersensitivity pneumonitis (HP) pattern, diffuse alveolar damage (DAD) pattern, or pulmonary eosinophilia (PEo) pattern according to the drug-related pneumonitis position paper by the Fleischner Society [26]. These patterns were classified as DAD or non-DAD pattern (image features of NSIP, OP, HP or PEo). Progression-free survival was defined as the number of months from the date of initial treatment to the date of progression, date of initial administration of the next treatment, or death. Overall survival was defined as the number of months from the date of initial treatment until death or censoring. Mortality and cause of death were assessed during the 1-year follow-up period after ICI treatment. The causes of death were classified into three categories: cancer-related death, ICI-P-related respiratory failure, and other causes.

Interstitial lung abnormalities evaluation

ILAs were defined as the incidental identification of non-dependent abnormalities affecting over 5% of any lung zone on CT images, according to the Fleischner Society classification [1]. They included ground-glass or reticular abnormalities, lung distortions, traction bronchiectasis, honeycombing, or non-emphysematous cysts. Mild focal or unilateral abnormalities (so-called equivocal for ILAs) and diffuse centrilobular nodular abnormalities were not considered as ILAs. ILAs were classified into three subcategories according to the Fleischner Society [1]: NS-ILAs showed opacities without predominant subpleural localization. Subpleural ILAs were further classified based on the presence or absence of fibrosis. SF-ILAs were defined as those with fibrosis, characterized by architectural distortion with traction bronchiectasis and/or honeycombing, whereas SNF-ILAs were defined as those without fibrosis. These types of ILAs were classified as SF-ILAs or non-SF-ILAs (image features of NS-ILAs or SNF-ILAs) [3, 4]. Patients with NSCLC who received thoracic irradiation before ICI administration were excluded. Serial CT images were independently reviewed by trained pulmonologists (RK, YW, and TO) blinded to patient information. Final decisions were made by a majority, and consensus was achieved through discussion when necessary. These chest image assessment methods have already been utilized and previously reported [27, 28]. Individuals who were followed up for over 2 years after receiving ICIs were divided into progressors or non-progressors. Progressive change was defined as an increase in the lung areas affected by non-dependent ground glass opacities, reticular abnormalities, non-emphysematous cysts, honeycombing, traction bronchiectasis, or the appearance of at least one such abnormality [3].

Statistical analysis

Data are presented as numbers (percentages) or medians (ranges). Categorical variables were analyzed using the chi-square test or fisher's exact test, whereas continuous variables were compared using the Mann–Whitney U test. Risk factors for ICI-P and radiological progression were identified using univariate and multivariate logistic regression analyses. Furthermore, in the multivariate analysis to identify risk factors for the development of ICI-P, we selected covariates based on established factors from previous literature [29]. The following covariates were included: squamous cell carcinoma, preexisting pulmonary emphysema, use of pembrolizumab, high PD-L1 expression, albumin, neutrophil–lymphocyte ratio, and c-reactive protein. PFS, OS, and cumulative incidence of ICI-P were analyzed using the Kaplan–Meier method, and differences were compared using the log-rank test. The hazard ratios were calculated using Cox regression analysis. All statistical analyses were performed using Statistical Package for Social Sciences software (version 26.0; IBM Corp., Armonk, NY, USA), with p < 0.05 indicating statistical significance.

Results

Patient characteristics

Among the 481 patients reviewed, 79 were diagnosed with NSCLC and pre-existing ILAs and received ICIs (nivolumab, pembrolizumab, or atezolizumab), without having undergone prior thoracic radiotherapy (Supplementary Fig. 1). None of the patients had received radiation after ICI administration, had previously received ICIs other than nivolumab, pembrolizumab, or atezolizumab, had received oxygen before ICI administration, or had a history of autoimmune disease. The patients were subcategorized into three groups: NS-ILAs (n = 8), SNF-ILAs (n = 37), and SF-ILAs (n = 34). Furthermore, these ILAs were classified as non-SF- (45 patients with image features of NS-ILAs or SNF-ILAs) and SF- (34 patients) ILAs. Figure 1 shows examples of non-SF- and SF-ILAs. The clinical characteristics of the patients are presented in Table 1. The differences in patients’ age (median age [range] 73.0, [68.0–77.5] vs. 69.0 [63.7–74.2] years; p = 0.023) and emphysema (57.8% vs. 82.4%; p = 0.020) were significant between the non-SF and SF-ILA groups, but none of the other baseline clinical characteristics significantly differed.Fig. 1 Subcategories of interstitial lung abnormalities. a-1 Non-subpleural fibrotic interstitial lung abnormalities. a-2 Follow-up CT image approximately four years later shows increased ground glass opacity. b-1 Subpleural fibrotic interstitial lung abnormalities. b-2 Follow-up CT image approximately three years later shows increase severity and extent of reticulation, traction bronchiectasis and honeycomb cysts

Table 1 Clinical characteristics

ILAs subcategory	Non-SF (n = 45)	SF (n = 34)	p-value	
Age (years, range)	73 (68–77.5)	69 (63.7–74.2)	0.023	
Male (%)	37 (82.2)	30 (88.2)	0.461	
Smoking history (%)			0.630	
 Former or current	42 (93.3)	33 (97.1)		
 Never	3 (6.6)	1 (2.9)		
 Pack years of smoking (range)	49.0 (30.0–71.0)	50.0 (33.0–84.0)	0.434	
PS (%)			0.389	
 0, 1	39 (86.7)	27 (79.4)		
 ≥ 2	6 (13.3)	7 (20.6)		
SpO2 (%, range)	98.0 (96.0–98.0)	97.5 (97.0–98.0)	0.798	
Histology (%)			0.807	
 Adenocarcinoma	29 (64.4)	21 (61.8)		
 Non-adenocarcinoma	16 (35.6)	13 (38.2)		
PD-L1 TPS (%)			0.369	
 < 1%	4 (8.9)	7 (20.6)		
 1–49%	13 (28.9)	7 (20.6)		
 ≥ 50%	16 (35.6)	9 (26.5)		
Unknown	12 (26.7)	11 (32.4)		
Driver mutation (%)	
 EGFR	1 (2.2)	0 (0)	1.000	
 ALK	0 (0)	0 (0)		
Stage (%)			1.000	
 III	2 (4.4)	2 (5.9)		
 IV or recurrent	43 (95.6)	32 (94.1)		
NLR (range)	3.4 (2.1–5.7)	4.6 (2.5–5.6)	0.280	
AMC (× 109 cells/L, range)	476.0 (396.0–636.6)	504.5 (351.6–685.5)	0.937	
LD (U/L, range)	223.0 (187.0–271.0)	217.0 (181.2–346.7)	0.797	
Alb (g/dL, range)	3.6 (3.1–3.9)	3.5 (2.9–3.9)	0.874	
CRP (mg/dL, range)	1.6 (0.4–5.8)	2.6 (0.9–6.2)	0.807	
Prior chemotherapy (%)	22 (48.9)	21 (61.8)	0.255	
ICI agent (%)			0.562	
 Anti-PD-L1	38 (84.4)	27 (79.4)		
 Anti-PD-1	7 (15.6)	7 (20.6)		
Treatment (%)			0.891	
 ICI	35 (77.8)	26 (76.5)		
 Chemo + ICI	10 (22.2)	8 (23.5)		
 Emphysema (%)	26 (57.8)	28 (82.4)	0.020	
ILAs location (%)			1.000	
 Upper lobe predominant	1 (2.2)	0 (0.0)		
 Lower lobe predominant	44 (97.8)	34 (100.0)		
Alb albumin, ALK anaplastic lymphoma kinase, AMC absolute monocyte count, Chemo, chemotherapy, CRP C-reactive protein, EGFR epidermal growth factor-receptor, ICI immune checkpoint inhibitor, ILAs interstitial lung abnormalities, LD lactate dehydrogenase, NLR, neutrophil-to-lymphocyte ratio, PD-1 programmed cell death 1, PD-L1 programmed cell death-ligand 1, PS performance status, SF subpleural fibrotic, SpO2 percutaneous oxygen saturation, TPS tumor proportion score

Immune checkpoint inhibitor-related pneumonitis

The incidence of ICI-P is presented in Fig. 2. ICI-P occurred in 25/79 (31.6%) patients with NSCLC with pre-existing ILAs. Most patients were diagnosed with ICI-P using non-invasive methods such as clinical findings, blood tests, sputum tests, and imaging findings. One patient with SF-ILA was diagnosed with ICI-P by transbronchial lung biopsy and bronchoalveolar lavage fluid. Patients in the SF-ILAs group had a higher frequency of any grade and grade ≥ 3 ICI-P than did those in the non-SF-ILAs group (all grades: 7/45 [15.6%] vs. 18/34 [52.9%], p < 0.001; grade ≥ 3: 1/45 [2.2%] vs. 10/34 [29.4%], p = 0.001). Furthermore, the rate of severe disease (grade ≥ 3) in each type of ICI-P was higher in the SF-ILAs group than in the non-SF-ILAs group (14.3% vs. 55.6%).Fig. 2 Incidence of immune checkpoint inhibitor-related pneumonitis. Comparison of a any grade, b grade ≥ 3 ICI-P and c severity distribution in the patients with and without subpleural fibrotic interstitial lung abnormalities. ILAs, interstitial lung abnormalities; SF, subpleural fibrotic

The cumulative incidence of ICI-P is shown in Fig. 3. Patients in the SF-ILAs group had a significantly higher cumulative incidence of ICI-P than did those in the non-SF-ILAs group (hazard ratio [HR], 4.57; 95% confidence interval [CI] 1.90–10.98; p = 0.001).Fig. 3 Cumulative incidence of immune checkpoint inhibitor-related pneumonitis. Cumulative incidence is shown in patients with (n = 34) and without subpleural fibrotic interstitial lung abnormalities (n = 45). ILAs, interstitial lung abnormalities; SF, subpleural fibrotic

The risk factors of ICI-P are summarized in Table 2. Univariate logistic regression analysis showed that the incidence ICI-P was significantly associated with the albumin level (≥ 3.5 vs. < 3.5) (odds ratio [OR], 2.76; 95% CI 1.04–7.33; p = 0.041) and ILAs subcategory (Non-SF vs. SF) (OR, 6.10; 95% CI 2.13–17.45; p = 0.001). Multivariate analysis showed that SF-ILAs were an independent predictive factor for ICI-P after adjusting for the neutrophil-to-lymphocyte ratio, albumin level, treatment, emphysema, and ILAs subpleural predominant pattern (OR, 5.35; 95% CI 1.62–17.61; p = 0.006). The presence of SF-ILAs remained independently associated with an increased risk of developing ICI-P after adjusting for covariates suggested by previous literature [29] (Supplementary Table 1). Furthermore, SF-ILAs significantly predicted the development of grade ≥ 3 ICI-P after adjusting for age, PS, and histology (OR, 15.77; 95% CI, 1.80–137.74; p = 0.013) (Supplementary Table 2). Table 2 Factors associated with ICI-P following univariate and multivariate analyses

Factors	Univariate analysis	Multivariate analysis	
OR	95% CI	p value	OR	95% CI	p value	
Age, per year increment	0.94	0.87–1.01	0.980				
Sex (female vs. male)	1.46	0.36–5.96	0.593				
Pack years of smoking, per pack increment	1.00	0.98–1.01	0.703				
PS (0, 1 vs. 2–4)	2.12	0.63–7.13	0.225				
Histology (adenocarcinoma vs. non-adenocarcinoma)	1.22	0.46–3.25	0.680				
PD-L1 TPS (< 1 vs. ≥ 1)	0.58	0.14–2.37	0.452				
NLR (< 5 vs. ≥ 5)	2.63	0.97–7.11	0.056	2.01	0.59–6.89	0.263	
AMC (< 600 vs. ≥ 600)	1.90	0.90–5.20	0.209				
LD (< 240 vs. ≥ 240)	1.04	0.39–2.76	0.925				
Alb (≥ 3.5 vs. < 3.5)	2.76	1.04–7.33	0.041	2.07	0.63–6.75	0.227	
CRP (< 1 vs. ≥ 1)	1.01	0.39–2.64	0.970				
ICI agent (anti-PD-L1 vs. anti-PD-1)	1.87	0.47–7.42	0.370				
Treatment (ICI vs. chemo + ICI)	2.07	0.70–6.12	0.189	2.33	0.62–8.70	0.206	
Emphysema (%)	2.35	0.76–7.24	0.136	1.20	0.33–4.39	0.778	
ILAs subcategory (Non-SF vs. SF)	6.10	2.13–17.45	0.001	5.35	1.62–17.61	0.006	
ILAs subpleural predominant (no vs. yes)	4.17	0.49–35.35	0.190	2.02	0.18–21.97	0.563	
Alb albumin, AMC absolute monocyte count, Chemo chemotherapy, CRP C-reactive protein, ICI immune checkpoint inhibitor, ICI-P immune checkpoint inhibitor pneumonitis, ILAs interstitial lung abnormalities, LD lactate dehydrogenase, NLR neutrophil-to-lymphocyte ratio, PD-1 programmed cell death 1, PD-L1 programmed cell death-ligand 1, PS performance status, SF subpleural fibrotic, TPS tumor proportion score

Supplemental Table 3 presents the characteristics for patients with ICI-P. There were no significant differences in terms of time of onset of ICI-P, treatment cycles, discontinuation rate, history of emphysema, or radiologic features. The non-DAD pattern was more common in the non-SF-ILAs group (77.8% vs. 100.0%); however, the DAD pattern was more common in the SF-ILAs group than in the non-SF-ILAs group (0.0% vs. 22.2%). Table 3 Mortality and cause of death during the 1-year follow-up period after receiving ICIs

ILAs subcategory	Non-SF (n = 45)	SF (n = 34)	p value	
Deaths (%)	23/45 (51.1)	22/34 (64.7)	0.199	
Cause of death			0.183	
 Cancer (%)	21/23 (91.3)	17/22 (77.3)		
 ICI-P (%)	0/23 (0.0)	3/22 (13.6)		
 Other (%)	2/23 (8.7)	2/22 (9.1)		
ICI-P immune checkpoint inhibitor pneumonitis, ILAs interstitial lung abnormalities, SF subpleural fibrotic

Other causes included pulmonary artery thromboembolism and arrhythmia

Survival

The Kaplan–Meier survival curves for PFS and OS of patients with non-SF- or SF-ILAs are shown in Fig. 4. Patients with SF-ILAs tended to have shorter PFS and OS than those with non-SF-ILAs (PFS: 5.17 vs. 3.60 months; HR, 1.49; 95% CI 0.91–2.45; p = 0.111; OS: 24.0 vs. 15.7 months; HR, 1.38; 95% CI 0.84–2.27; p = 0.193).Fig. 4 Kaplan–Meier curves. a Progression-free survival and b overall survival of patients with (n = 34) and without subpleural fibrotic interstitial lung abnormalities (n = 45). ILAs, interstitial lung abnormalities; SF, subpleural fibrotic

The association between the incidence of ICI-P and prognosis is shown in Supplementary Figs. 2 and 3. The OS in patients with grade ≥ 3 ICI-P was significantly lower than that in patients without grade ≥ 3 ICI-P (12.1 vs. 23.0 months; p = 0.002), but not in patients with any grade ICI-P than in those without ICI-P (15.7 vs. 20.4 months; p = 0.991).

Mortality and causes of death are summarized in Table 3. Mortality at 1 year after ICI administration tended to be higher in the SF-ILA group than in the non-SF-ILA group (51.1% vs. 64.7%; p = 0.199). Cancer death was more common in the non-SF-ILAs group (77.3% vs. 91.3%); however, respiratory failure owing to ICI-P was more common in the SF-ILAs group than in the non-SF-ILAs group (0.0% vs. 13.6%; p = 0.183). All cases of respiratory failure death owing to ICI-P were grade 5 adverse events caused by ICI administration.

Radiological progression of interstitial lung abnormalities

Among the 79 patients, 18 patients were followed-up for over two years after receiving ICIs (median follow-up period [range] 2.17, [2.07–2.21]). Figure 1 shows examples of radiological progression of non-SF- and SF-ILAs. Supplementary Table 4 shows the changes in the CT findings of the ILAs. Patients with SF-ILAs tended to progress ILA than did those with non-SF-ILAs (30.0% vs. 71.4%; p = 0.193). No patient was diagnosed with ILD during the two-year follow-up. Although the univariate logistic regression analysis did not identify any statistically significant risk factors predicting ILAs progression, it suggested that SF-ILAs might be a candidate risk factor (OR, 5.83; 95% CI, 0.69–48.87; p = 0.104) (Supplementary Table 5).

Discussion

To the best of our knowledge, this is the first study classifying patients with NSCLC and ILAs receiving ICIs according to the Fleischner Society's ILA subtypes and assessing the risk factors for developing ICI-P, prognosis, and radiological changes. Our study revealed the following: First, patients with SF-ILAs had a significantly higher cumulative incidence of ICI-P and an increased incidence of both any grade and grade ≥ 3 ICI-P than did those with non-SF-ILAs. Second, the presence or absence of SF-ILAs was an independent risk factor for the development of any grade and grade ≥ 3 ICI-P. Third, patients with SF-ILAs tended to have shorter PFS and OS and a higher rate of ICI-P-related respiratory failure deaths than did those with non-SF-ILAs. Finally, after two years of follow-up, approximately 2.5 times more patients with SF-ILAs demonstrated radiological ILA progression than did those with non-SF-ILAs, suggesting that SF-ILAs may be a candidate risk factor for ILA progression.

In a previous population-based cohort study, ILAs were observed in 4–9% of smokers and 2–7% of non-smokers [1]. In contrast, we observed ILAs in 16.4% of our patients. This may be because the present study was limited to patients with lung cancer. Smoking, male sex, and older age are known risk factors for ILAs and lung cancer; hence, a synergistic effect may have contributed to their increased frequency. ILAs were observed in 10.7–36.5% of patients with NSCLC in previous studies [13, 14, 16, 17, 19, 30–32], which is comparable to the value in our study. This suggests that the proposed image-evaluation method is reliable.

ICI-P is one of the most common IrAEs, with a reported incidence of 7–19% in patients with lung cancer in clinical practice [12, 24, 25, 33, 34]. Therefore, identifying patients susceptible to ICI-P is clinically important. A prospective study examining the efficacy of atezolizumab in patients with NSCLC and ILD suggested that honeycombing on CT scans may be associated with ICI-P development [35]. Furthermore, retrospective studies showed that fibrotic findings on baseline CT scans are a risk factor for ICI-P development [36, 37]. In this study, the presence of SF-ILAs before starting ICI treatment was associated with an increased risk of ICI-P and was the strongest independent predictor of ICI-P. Although ILAs include various histological patterns [38], most SF-ILAs have definite or probable usual interstitial pneumonia [4]. Therefore, it is possible that patients with SF-ILAs are more likely than those with non-SF-ILAs to develop ICI-P owing to the influence of fibrosis. Even if traction bronchiectasis or honeycombing is mild, caution should be exercised when administering ICIs. Furthermore, for quantitative evaluation of fibrotic changes whether forced vital capacity and carbon monoxide diffusing capacity play an important role in the development of ICI-P needs to be determined. Furthermore, for quantitative evaluation of fibrotic changes, it is necessary to evaluate whether forced vital capacity and carbon monoxide diffusing capacity play an important role in the development of ICI-P.

Previous studies have not demonstrated an association between ICI-P and fibrotic changes in ILAs [13, 14, 32]. These studies included mild focal or unilateral abnormal opacities as ILAs, whereas our study did not classify these findings as ILAs. Furthermore, we excluded patients with a history of thoracic irradiation because such treatment is a risk factor for ICI-P [17, 39]. This may explain why our results differ from those of other studies. To the best of our knowledge, this is the largest study examining the association between ICI-P and definite ILAs in patients with NSCLC. Therefore, our results appear to be more reliable than those of previous studies. We have added new data to this controversial study area by focusing on the subcategorization of ILAs using real-world data. Clinicians should exercise caution when administering ICIs to SF-ILA patients, as those are at an increased risk for developing ICI-P. Alternatively, clinicians are encouraged to use ICIs aggressively in patients with non-SF-ILAs, because the frequency of ICI-P in patients with non-SF-ILAs is similar to that in those without ILAs [24, 25, 33]. Thus, subcategorizing ILAs may be an important strategy to prevent the development of ICI-P in patients with NSCLC with these abnormalities.

In studies of patients with NSCLC without ILAs who received immunotherapy or chemoimmunotherapy, PFS was 5.4–9.0 months and OS 16.7–26.3 months [40–43]. Although ILAs clearly represent a comorbid disease with a poor prognosis in lung cancer patients [20, 21, 44], the survival benefit obtained with ICIs was similar in patients with NSCLC with non-SF-ILAs and those without ILAs. In contrast, patients with SF-ILAs tended to have shorter PFS and OS than those with non-SF-ILAs. This may be owing to differences in the incidence of severe ICI-P among the ILAs subcategories. The incidence of respiratory failure resulting in death caused by ICI-P was unexpectedly high, with three patients dying; all these patients had SF-ILAs. The presence of SF-ILAs remained independently associated with an increased risk of developing grade ≥ 3 ICI-P. Furthermore, the development of grade ≥ 3 ICI-P was associated with a significantly shorter OS. This suggests that ILAs have a significant impact not only on the development of ICI-P but also on the outcomes of lung cancer, which highlights the importance of subcategorizing ILAs for risk assessment when considering ICI treatment.

Among the three ILAs subtypes, SF-ILAs are particularly susceptible to progression and are likely to lead to fatal outcomes [1]. We evaluated the natural history of ILAs in patients with NSCLC, which has not been reported previously. We found that SF-ILAs were more likely to demonstrate radiological progression than were non-SF-ILAs, which is consistent with reports that did not include ICIs [2, 3]. Furthermore, we showed that 30% of non-SF-ILAs and 70% of SF-ILAs progressed within 2 years, which are higher proportions than those reported in previous studies (non-SF: 10.9%, SF: 36.8%) [2]. This suggests that ICI administration may be a risk factor for the progression of fibrosis. On the other hand, there are also reports that PD-L1 may be a new therapeutic target for fibrotic interstitial lung disease. PD-L1-high-expressing fibroblasts promote lung fibrosis compared with PD-L1-negative fibroblasts in a humanized mouse model of interstitial pulmonary fibrosis [45]. Furthermore, PD-L1 may promote pulmonary fibrosis through the SMAD3/β-catenin pathway [46]. Therefore, further research is needed to determine whether PD-1/PD-L1 inhibitors are beneficial or not for the fibrotic pathology underlying IPF and SF-ILAs.

Currently, ICIs are essential drugs for lung cancer treatment. They are widely used in the advanced stage as well as the perioperative period [47–49]. Therefore, ICIs are unlikely to be withheld from all SF-ILA patients simply because of the high risk of ICI-P. When administering ICIs to SF-ILA patients, the risk of ICI-P should be fully explained before administration. In addition, patients need to be informed to seek medical attention immediately if respiratory symptoms appear. After administration, clinicians must carefully examine the patient. Close CT follow-up is also desirable to detect the onset of ICI-P early. These follow-up procedures may sometimes lead to overdiagnosis of ICI-P, thus necessitating investigation of whether asymptomatic, mild ICI-P is associated with lung cancer death.

This study has some limitations. First, the visual assessment method used for ILAs evaluation may have caused a selection bias owing to its subjective nature. However, the diagnosis was made after discussions with multiple experienced pulmonologists; hence, bias seems relatively unlikely. Second, ICI-P treatment was left to the discretion of each physician, which may have affected patient outcomes. Third, the ability to detect risk factors for ILAs progression and the development of grade ≥ 3 ICI-P was limited by the relatively small number of cases. Consequently, some of the CIs were wide. Fourth, this study was retrospective and was conducted in two institutions. Therefore, a prospective study with a larger cohort is required to validate our findings. Finally, in our cohort, the incidence of ICI-P and prognosis of NSCLC in patients without ILA are unknown. Therefore, the incidence of ICI-P and prognosis of NSCLC need to be evaluated in future by comparing patients without ILA with those with non-SF-ILA or SF-ILA.

In conclusion, the presence or absence of SF-ILAs is important in determining the risk of ICI-P development in patients with NSCLC. Compared with non-SF-ILAs patients, those with SF-ILAs develop severe ICI-P, are more likely to progress to ILAs radiologically, and have a worse prognosis. Subcategorizing ILAs is an important treatment strategy for lung cancer patients with these abnormalities, as this may assist clinicians and patients in appropriate shared decision-making.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 158 KB)

Abbreviations

Alb Albumin

AMC Absolute monocyte count

CI Confidence interval

CRP C-reactive protein

CT Computed tomography

HR Hazard ratio

ICI Immune checkpoint inhibitor

ICI-P Immune checkpoint inhibitor-related pneumonitis

ILA Interstitial lung abnormality

ILD Interstitial lung disease

irAE Immune-related adverse events

LD Lactate dehydrogenase

NLR Neutrophil-to-lymphocyte ratio

NSCLC Non-small cell lung cancer

OR Odds ratio

OS Overall survival

PD-1 Programmed cell death 1

PD-L1 Programmed cell death ligand 1

PFS Progression-free survival

PS Performance status

SF Subpleural fibrotic

SNF Subpleural non-fibrotic

TNM Tumor, node, and metastasis

TPS Tumor proportion score

Acknowledgements

The authors are very grateful to Yukiko Hasegawa at the Department of Diabetology and Metabolism, Tokyo Women's Medical University School of Medicine, Japan for providing excellent clinical advice.

Author contributions

R.K designed the study, analyzed and interpreted the data, and prepared the manuscript. Y.W collected and interpreted the data and prepared the manuscript. T.O analyzed and interpreted the data. H.N interpreted the data and participated in the supervision of the study. S. A interpreted the data, wrote the manuscript, and participated in the supervision of the study. All authors reviewed the manuscript draft and critically revised it for intellectual content. All authors read and approved the final manuscript.

All authors reviewed the manuscript draft and critically revised it for intellectual content. All authors read and approved the final manuscript.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

This study was approved by the Institutional Review Board of the Tokyo Medical University (approval no. TS2021-0175). This study was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki.

Consent to participate

An opt-out method was used so that patients and families could refuse to participate in the study.

Consent for publication

All contributing authors agreed to the publication of this article.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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