Accepted: 20 October 2022

DOI: 10.1111/1759-7714.14718

ORIGINAL ARTICLE

Clinical significance of interstitial lung abnormalities and immune
checkpoint inhibitor-induced interstitial lung disease in patientswith non-small cell lung cancer
Daiki Murata 1| Koichi Azuma 1| Goushi Matama 1 | Yoshiaki Zaizen 1 |Norikazu Matsuo 1 | Kenta Murotani 2 | Takaaki Tokito 1| Tomoaki Hoshino 1
1
Division of Respirology, Neurology, andRheumatology, Department of Internal Medicine,
Kurume University School of Medicine, Kurume,Japan
2
Biostatistics Center, Kurume University School of
Medicine, Kurume, Japan

Correspondence
Koichi Azuma, Division of Respirology,
Neurology, and Rheumatology, Department ofInternal Medicine, Kurume University School of
Medicine, 67 Asahi-machi, Kurume, Fukuoka
830-0011, Japan.
Email: azuma@med.kurume-u.ac.jp

Abstract
Background: Interstitial lung abnormalities (ILAs) are known to be a risk ofdrug-induced pneumonitis. However, there are few reports on the relationshipbetween ILAs and immune checkpoint inhibitor-related interstitial lung disease (ICIILD). We retrospectively investigated the clinical significance of ILAs in patients with
non-small cell lung cancer (NSCLC) receiving ICIs.
Methods: We defined ILAs as nondependent abnormalities affecting more than 5% of
any lung zone, including ground-glass or diffuse centrilobular nodularities, traction
bronchiectasis, honeycombing, and nonemphysematous cysts. Early-onset ICI-ILD
was defined as developing within 3 months after the initiation of ICI administration.
Results: Of 264 patients with advanced NSCLC, 57 patients (21.6%) had ILAs
(43 fibrotic and 14 nonfibrotic ILAs). The difference between the incidence of
ICI-ILD in patients with or without ILAs was not significant. Of 193 patients treatedby ICI monotherapy, 18 (9.3%) developed early-onset ICI-ILD. Among patients
receiving ICI monotherapy, the incidence of early-onset ICI-ILD was significantly
higher in patients with than in patients without nonfibrotic ILAs.
Conclusion: The presence of nonfibrotic ILAs is a significant risk for early-onset ICI-ILD
in patients with NSCLC undergoing ICI monotherapy. Clinicians should be aware of
ILAs, especially nonfibrotic ILAs, before administering ICIs to lung cancer patients.
KEYWORDS
ICI-ILD, ILA, NSCLC, PD-1 inhibitor

INTRODUCTION
The immune-checkpoint inhibitor (ICI) is the latest therapeutic breakthrough in several types of advanced tumors
such as lung cancer, melanoma, head and neck tumors,
bladder cancer, and lymphoma.1–5 Safety is a major concern
as the number of patients receiving these new drugs
increases. Although ICIs provide an overall favorable riskto-benefit profile, they are known to cause unique toxicities
named immune-related adverse events (irAEs), due to theirmechanisms of action. Although irAEs are typically manageable, uncommon fatal irAEs have been reported, which tend

to occur early in ICI treatment. Clinicians should recognize
and manage these types of immune-mediated events early
on, as they can be severe or fatal. Interstitial lung disease(ILD) induced by ICI treatment has been observed to be aclinically serious and fatal toxicity.6,7 The majority of episodes of ILD occur within 3 months of the induction of
immunotherapy, and the onset tends to be particularly earlyin patients with non-small cell lung cancer (NSCLC).6–8
Some studies have found that the risk of ICI-related ILD(ICI-ILD) was associated with pre-existing ILD.9 However,
ICI-ILD is also frequently clinically developed in patients
without pre-existing ILD.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.
Thorac Cancer. 2022;1–8.

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Received: 17 September 2022

Interstitial lung abnormalities (ILA) are specific findings
on computed tomography (CT) that may be compatible
with ILD in patients without clinical manifestations. ILAs
that occur with normal aging are increasingly recognized tobe common features on CT scans of the elderly. With theincreasing use of CT for various purposes, ILAs will increasingly be observed on CT scans. These abnormalities are risk
factors for increased mortality and complications from surgery and chemotherapy. Thus, these changes on chest CT
scans have prognostic value and should be reported.10–12
ILAs seen in patients before they undergo treatment forcancer have been associated with cancer-related mortality.11,13 The exact reason for increased mortality is unclear,but the risks of lung injury due to ILAs and cancer therapy
have been speculated.11 However, results of the studies on
the association of ILAs and lung cancer treatments remain
unclear. To our knowledge, only two reports have examined
the relationship between pre-existing ILAs and ICIILDs.14,15 Thus, we retrospectively investigated the clinicalsignificance of ILAs on the incidence, subcategories, andonset of ICI-ILD in patients with NSCLC who received
immunotherapy at our hospital.

METHODS
Study design
We retrospectively screened patients with pathologically confirmed advanced or recurrent NSCLC who had been treatedwith ICIs at our institution between February 2016 andMarch 2021. There were no pre-existing ILDs among patients
who received ICI treatment. First-line treatment was definedas either primary chemotherapy or immunotherapy. Prior
treatment with molecular targeted drugs were not counted in
the treatment line. PD-L1 expression by tumor cells on preparations of the archived biopsy specimens was assessed by the
PD-L1 IHC 22C3 pharmDx assay (Agilent). This study was
performed in accordance with the provisions of the Declaration of Helsinki and was approved by the Institutional Review
Board of the Kurume University Hospital (IRB No 20100).

Evaluation of high-resolution CT (HRCT)
findings
We investigated the presence of abnormal findings, which
included pre-existing ILAs, on the HRCT scans of the study
patients. ILAs were defined based on the report of Hatabu et al,11
as follows: nondependent abnormalities affecting more than 5%of any lung zone, including ground-glass or diffuse centrilobular
nodularities, traction bronchiectasis, honeycombing, and nonemphysematous cysts. These types of ILAs were classified into
two broad subcategories as fibrotic and nonfibrotic ILAs.
As previous reports and a position paper from the
Fleischner Society,11,16 fibrotic ILA was defined by the presence of pulmonary parenchymal architectural distortion

TABLE 1

Patient characteristics

Variables

N = 264 (%)
No.

%

Age
Median

70

Range

63–75

Gender
Male

196

74.2

Female68

25.8

Past or current

202

76.5

Never

62

23.5

Adenocarcinoma

164

62.1

Squamous

71

26.9

NSCLC

26

9.8

Smoking status

Histology

LCNEC

3

1.1

57

21.6

Fibrotic ILAs

43

16.3

Nonfibrotic ILAs

14

5.3

≥50

73

27.7

1–49

78

29.5

<1

59

22.3

Not tested

54

20.5

41

15.5

EML4-ALK fusion

4

1.5

RET fusion

1

0.4

Negative

218

82.6

EGFR-TKI

41

15.5

ALK-TKI4

1.5

Others00

ICI monotherapy

193

73.1

Combination therapy

71

26.9

1

111

42

2,3

118

44.7

≥4

35

13.3

ILA

PD-L1 tumor proportion score (%)

Driver mutation
EGFR mutation

Prior molecular targeted drugs

TreatmentLine of ICI therapy

Abbreviations: ALK, anaplastic lymphoma kinase, EGFR, epidermal growth factor
receptor, EML4-ALK, echinoderm microtubule-associated protein-like 4 - anaplastic
lymphoma kinase, ICI, immune-checkpoint inhibitors, ILA, interstitial lungabnormalities, ILD, interstitial lung disease, LCNEC, large cell neuroendocrine
carcinoma, NSCLC, non-small cell lung cancer, PD-L1, programmed death-ligand 1,
RET, rearranged during transfection, TKI, tyrosine kinase inhibitor.

(e.g., traction bronchiectasis, honeycombing) consistent witha fibrotic lung disease (definite fibrosis), which is not limited
to those whose imaging pattern is consistent with a usual

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MURATA ET AL.

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3

F I G U R E 1 (a) Chest computed tomography images of interstitial lung abnormalities. (a, b) Patients with nonfibrotic interstitial lung abnormalities. (c,d) Patients with fibrotic interstitial lung abnormalities. (b) Flow diagram of the study population. In total, 264 patients were enrolled. Of the 264 patients,
57 had interstitial lung abnormalities (ILAs); 14 had fibrotic ILAs and 43 had nonfibrotic ILAs. There were 51 patients treated with a programmed death-1(PD-1) inhibitor, five treated with a programmed death-ligand 1 (PD-L1) inhibitor, one patient was treated with both a PD-1 and PD-L1 inhibitor. Of the
57 ILA patients, seven developed immune checkpoint inhibitor-induced interstitial lung disease (ICI-ILD); four had fibrotic ILAs and three had nonfibrotic
ILAs. There were six patients treated with a PD-1 inhibitor and one treated with a PD-L1 inhibitor. Of the seven ILA patients with ICI-ILD, 4 had early-onset
disease; three cases had fibrotic and one had nonfibrotic ILAs. There were three patients treated with a PD-1 inhibitor and one treated with a PD-L1 inhibitor

interstitial pneumonia or probable usual interstitial pneumonia pattern. Nonfibrotic ILA was defined as ILA not
included in fibrotic ILA.
A CT system was used to obtain HRCT data (1–10 mm
slice thickness), which were obtained at the end of inspiration with the patient in the supine position. HRCT was usedwhich was taken closest before ICI administration. The
HRCT scans were reviewed by two independent pulmonologists. Final decisions were made by consent of two independent pulmonologists.

Diagnosis of ICI-induced ILD
ICI-ILD was diagnosed as follows: (1) occurring during
treatment with an ICI, (2) new ground-glass attenuation(GGA) or consolidations in the bilateral lung fields of CT
scan, (3) exclusion of pulmonary infection, and (4) exclusionof heart failure.13,16–19 Pulmonary infections were ruled out
by sputum culture and antibiotic efficacy, and heart failure
was excluded by clinical examination and echocardiography.
The radiographic patterns of the ILD were classified according to the American Thoracic Society/European Respiratory
Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) international multidisciplinary classification of interstitial pneumonias.20 ILD
was evaluated according to the National Cancer InstituteCommon Terminology Criteria for Adverse Events, version
4.0. Early-onset ICI-ILD was defined as ILD developing
within 3 months after the start of immunotherapy.

Statistical analysis
The Pearson χ2 test or Mann–Whitney U test was used forcomparison of the two groups. Risk factors for ICI-ILD were
examined using univariate and multivariate logistic regression models. Multivariate analysis was performed using
fibrotic and nonfibrotic ILD as covariates to evaluate which
ILD finding was an independent risk factor for ICI-ILD. A
two-tailed p-value of <0.05 was considered statistically significant. Statistical analyses were conducted using JMP version 16.0 software (SAS Institute Inc.).

RESULTS
Patient characteristics
A total of 264 patients were enrolled in this study. Table 1
shows the clinical characteristics of the patients. The medianage of patients was 70 years (63–75 years). Male patients(74.2%) were predominant. Many patients (76.5%) had a smoking history. Adenocarcinoma and squamous cell carcinoma

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MURATA ET AL.

TABLE 2

Characteristics of patients with and without ICI-ILD

All patients

ICIILD + n = 32

ICIILD-n = 232

Gender

0.334

Male

26

170

Female662

Smoking status

0.263

Past or current

27

175

Never

5

57

PD-L1 tumor proportion
score (%)

0.377

≥50

13

60

1–49

8

70

<1

6

53

Not tested

549

Prior thoracic radiation
therapy+

p-value

0.786
7

46

25

186

EGFR-TKI

3

38

0.305

ALK-TKI

1

3

0.427

monotherapy and seven (2.7%) patients who received a
combination of ICI therapy and chemotherapy developed
ICI-ILD. The differences between the baseline characteristics
of study patients with and without ICI-ILD were notsignificant.
Figure 1b shows a flow diagram of the various categories
of patients with/without various iterations of ILA, ILD, ICIILD, and fibrotic and nonfibrotic disease, and numbers ofpatients in each category within the study population. Of
the 264 patients, 32 (12.1%) developed ICI-ILD. Amongthe 32 patients with ICI-ILD, seven (21.9%) had ILAs,
four (12.5%) had fibrotic ILAs, and three (9.3%) had
nonfibrotic ILAs.
Figure 2a shows examples of HRCT scans of patents
with ILAs who developed ILD after ICI monotherapy.
Figure 2b shows the time to the onset of ICI-ILD after thestart of immunotherapy. Seven (2.7%) of 264 patients
underwent thoracic radiation therapy before the occurrenceof ICI-ILD. The difference between the proportion ofpatients with and without ILA who developed ICI-ILD was
not significant (p = 0.967).

Prior molecular targeted
drugs

ILA

7

50

0.967

Fibrotic ILAs

4

39

0.536

Nonfibrotic ILAs

3

11

0.273

Treatment

0.495

ICI monotherapy

25

168

Combination therapy

764accounted for 62.1 and 26.9%, of the cases, respectively. A
driver mutation was harbored in 17.4% of patients, and an epidermal growth factor receptor (EGFR) mutation in 15.5%, anaplastic lymphoma kinase (ALK) fusion gene was 1.5%, and arearrangement during transfection fusion was 0.4%. All patientswith harbored EGFR and ALK mutations had been previously
treated with tyrosine kinase inhibitors (TKIs), respectively. PDL1 tumor proportion scores of ≥50%, 1%–49%, and <1% wereseen in 27.7, 29.5, and 22.3% of patients, respectively. HRCT
revealed ILAs in 57 (21.6%) patients, of whom 16.3 and 5.3%
had fibrotic ILAs and nonfibrotic ILAs, respectively. Figure 1ashows examples of the CT scans of patients with ILAs. A totalof 73.1% were treated by ICI monotherapy and 26.9% weretreated by a combination of an ICI and chemotherapy. The
median follow-up term was 8.8 months (0.2–61.3 months) for
the ICI monotherapy group and 10.7 months (0.4–29.6 months)
for the combined group, respectively.

Proportions and characteristics of patients withand without ICI-ILD
Table 2 shows the prevalence of ICI-ILD in the 264 study
patients. Of the 264 patients, 25 (9.5%) who received ICI

Proportion and characteristics of patients withearly-onset ICI-ILD
Table 3 shows that 21 (8.0%) of 264 patients developed
early-onset ICI-ILD. Among the 21 patients with early-onset
ICI-ILD, four (19.0%) had ILAs; one patient (4.8%) had
fibrotic ILAs and three (14.3%) had nonfibrotic ILAs. Eighteen (9.3%) of 193 patients who received ICI monotherapy
and three (4.2%) of 71 patients who received ICI and chemotherapy developed early-onset ICI-ILD. Seven patients(2.7%) underwent thoracic radiation therapy before theoccurrence of early-onset ICI-ILD. Differences between thebaseline characteristics of patients with and without earlyonset ICI-ILD were not significant. The difference between
the proportions of patients with and without ILA who developed early-onset ICI-ILD was not significant (p = 0.765).

Proportions and characteristics of patients with/without early-onset ICI-ILD who received ICI
monotherapy
Table 4 shows the proportion of patients with early-onset
ICI-ILD among the 193 patients who received ICI monotherapy. Of the 193 patients, 18 (9.3%) developed
early-onset ICI-ILD. Among the patients with early-onset
ICI-ILD, three (16.7%) had ILAs, one (5.6%) had fibrotic
ILAs, and two patients (11.1%) had nonfibrotic ILAs. Seven(3.6%) patients underwent thoracic radiation therapy before
the occurrence of ICI-ILD. ICI-ILD did not develop inpatients who had previously received molecularly-targeteddrugs. The differences between the baseline characteristics
of patients with and without early-onset ICI-ILD were notsignificant. The difference between the proportions of17597714, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1759-7714.14718 by Kurume University/Kurume Daigaku, Wiley Online Library on [15/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

MURATA ET AL.

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5

F I G U R E 2 (a) A patient with nonfibrotic interstitial lung abnormalities leading to immune checkpoint inhibitor-related interstitial lung disease. The
patient was a 67-year-old man with squamous cell carcinoma. (a)–(c) Chest computed tomography (CT) scans before the administration of immunotherapy.
The scans show nonfibrotic subpleural interstitial lung abnormalities (ILAs). (d)–(f) Chest CT scans 2 months after the initiation of nivolumab monotherapy.
CT showed consolidations in both peripheral lungs fields. The shadows are predominantly distributed in the right lower lobe. (b) Graph of the onset of
immune checkpoint inhibitor-induced interstitial lung disease in study patients. There were 32 patients who developed immune checkpoint inhibitor-related
interstitial lung disease; seven patients had ILAs and 25 did not have ILAs. Early onset cases accounted for 57.1% of the patients with ILAs and 64% of thepatients without ILAs

patients with and without ILAs who developed early onset
ICI-ILD was not significant (p = 0.694). In contrast, theincidence of early-onset ICI-ILD was significantly higher inpatients with nonfibrotic ILAs than in patients with fibrotic
ILAs (p = 0.040).

DISCUSSION
This study revealed that the presence of pre-existing nonfibrotic ILAs was an independent risk factor of early-onset
ICI-ILD induced by ICI monotherapy. To the best of ourknowledge, this is the first study to report on the relationship between a subcategory of ILAs and the onset time of
ICI-ILD. In the present study, ILAs accounted for 21.6%(57/264) of study patients. Fibrotic ILAs accounted for
16.3% and nonfibrotic ILAs accounted for 5.3% of the study
patients. Before administering ICIs to patients with ILAs, weshould estimate their risk of developing ICI-ILD. Estimating
the risk of ICI-ILD is especially important for patients with
nonfibrotic ILAs.
Previous studies determined that the presence of GGAs,
not including fibrotic area, was a risk for conventional chemotherapy and immunotherapy-related ILD.13,14,21 We also
found that the presence of nonfibrotic ILAs was an independent risk factor for early-onset ICI-ILD. GGA reflects
inflammation by lymphocytes in the interstitium, and ICIs
exert antitumor effects via activation of lymphocytes.13,14,21

These results may explain why GGAs were involved withICI-ILD.13,14,21
Nonfibrotic ILAs are known to have a better prognosis
compared to fibrotic ILAs because fibrotic ILAs are associated with risk of progression on CT imaging and death.16
For this reason, nonfibrotic ILAs are less emphasized thanfibrotic ILAs in clinical practice. However, nonfibrotic ILAs
were significantly associated with the risk of developing
early onset ICI-ILD in this study, while fibrotic ILAs were
not. Since ICI-ILDs are sometimes fatal, it is important to becareful about the presence of nonfibrotic ILAs in patientstreated with cancer immunotherapy.
This study found that the combination of an ICI and
chemotherapy did not lead to early-onset ICI-ILD, even inpatients with nonfibrotic disease. This is the first report on
the combination of ICI and chemotherapy, as previous
reports have only focused on ICI monotherapy.14,15 The
combination of ICI and chemotherapy may be less likely toresult in ICI-ILD, even in patients with pre-existing ILAs,
compared to ICI monotherapy alone. We previously
reported that the incidence of irAEs, especially pneumonitis,
during the first 3 months after the start of treatment was significantly higher in patients receiving ICI monotherapy thanin the patients receiving a combination of ICI and
chemotherapy.22
The mechanism by which chemotherapy suppresses thedevelopment of ICI-ILD remains unclear. The reduced rateof ICI-ILD might be accounted for by the steroids

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MURATA ET AL.

TABLE 3
ICI-ILD

Characteristics of patients with and without early-onset

All patients

Early-onset
ICI-ILD(+) N = 21

Early-onset
ICI-ILD( ) N = 243

GenderICI
monotherapy
p-value
0.464

Male

17

179

Female464

Smoking status
18

184

Never

3

59

PD-L1 tumor
proportion score(%)

Early-onset ICIILD (+) N = 18

Early-onset ICIILD ( ) N = 175

Male

15

127

Female3

48

Past or current

15

130

Never

3

45

Gender

0.201

0.398

PD-L1 tumor
proportion
score (%)
≥50

0.341

9

52

≥50

10

63

1–49

4

44

1–49

5

73

<1

2

36

<1

3

56

Not tested

343

Not tested

351

Prior thoracic radiation
therapy
+

0.114
7

46

14

197

0.101

Prior thoracic
radiationtherapy+

p-value
0.324

Smoking status
0.300

Past or current

T A B L E 4 Characteristics of patients with and without early-onset ICIILD who received ICI monotherapy

7

38

11

137

Prior moleculartargeted drugs

Prior moleculartargeted drugs
EGFR-TKI

0

41

0.041

EGFR-TKI

0

39

0.025

ALK-TKI

0

4

0.554

ALK-TKI

0

3

0.576

4

53

0.768

3

36

0.694

Fibrotic ILAs

1

42

0.136

Fibrotic ILAs

1

32

0.172

Nonfibrotic ILAs

3

11

0.056

Nonfibrotic
ILAs

2

4

0.040

ICI monotherapy

18

175

Combination therapy

3

68

ILA

Treatment

0.174

Abbreviations: ALK, anaplastic lymphoma kinase, EGFR, epidermal growth factor
receptor, ICI, immune-checkpoint inhibitors, ILAs, interstitial lung abnormalities,
ILD, interstitial lung disease, PD-L1, programmed death-ligand 1, TKI, tyrosine kinase
inhibitor.

administered during chemotherapy. Steroids are the mostcommon basic treatment for ICI-ILD. In addition, the myelosuppression induced by chemotherapy could suppress
inflammation through the regulation of soluble immune
mediators.
In older individuals (>60 years of age) the prevalence of
ILAs has been reported to be 4%–9% of smokers and 2%–
7% of nonsmokers.10 However, in patients with lung cancer,
the prevalence of ILAs has been reported to be 14%–22%.13,23–26 In this study, 57 patients (21.6%) had ILAs,
which is consistent with the prevalence reported in previous
studies.13,23–26 Based on the above, just as idiopathic pulmonary fibrosis and other ILDs,26–28 patients with ILAs may beprone to complications from lung cancer. Additionally, thepresence of nonfibrotic ILAs was seen in 5.3% of all of ourstudy patients (264 patients). Nonfibrotic ILAs account for
24.6% of the total ILAs. Other studies have reported that the

ILA

Abbreviations: ALK, anaplastic lymphoma kinase, EGFR, epidermal growth factor
receptor, ICI, immune-checkpoint inhibitors, ILAs, interstitial lung abnormalities,
ILD, interstitial lung disease, PD-L1, programmed death-ligand 1, TKI, tyrosine kinase
inhibitor.

presence of nonfibrotic ILAs accounted for 53.8% to 67.6%
of all the patients with ILAs,13,14 results that are muchhigher than observed in our study. It should be noted thatlung cancer tends to be a complication of ILAs, and it
includes nonfibrotic ILA, which is a risk for ICI-ILD.
Male and smoking history have been reported as clinicalrisk factors for ILA.11 In this study, being male was not associated with ILA, but smoking history was significantly associated with ILA (Table S2). Smoking history was alsosignificantly associated with both fibrotic and nonfibrotic
ILA. In addition, smoking history was not associated withICI-ILD. Although smoking history is not directly related to
ICI-ILD, it is involved in the development of ILA. Therefore,
the presence of ILA should be confirmed at the start ofimmunotherapy in lung cancer patients with smoking
history.
The present study had some limitations. First, ICI-ILD
was not diagnosed by histopathological examinations. Second, this study was a retrospective single-center study.

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MURATA ET AL.

6

Third, patients included in our study received heterogeneous
regimens. Fourth, the number of ILA patient was small
within the ICI-ILD group. A prospective multicenter study
is warranted to validate the present findings. In conclusion,
the presence of nonfibrotic ILAs was a significant risk factor
for early-onset ICI-ILD in patients about to undergo ICI
monotherapy. The presence of ILAs is more likely to be
associated with lung cancer then the absence of ILAs, andearly-onset ICI-ILD can interfere with the treatment of lungcancer and can be life-threatening. Clinicians should bear inmind the possible presence of ILAs, especially nonfibrotic
ILAs, in patients with lung cancer, before they decide toadminister ICIs.

7

7.

8.

9.

10.

ACKNOWLEDGMENTS
We would like to thank the participating patients for theircontributions to this study.

11.

CONF LICT OF IN TEREST
KA reports receiving personal fees from AstraZeneca, MSD,
Bristol Myers Squibb, Ono Pharmaceutical, Takeda Pharmaceutical, Pfizer and Chugai Pharmaceutical. NM reports
receiving personal fees from AstraZeneca, Bristol Myers
Squibb, Ono Pharmaceutical and Chugai Pharmaceutical.
TT reports receiving personal fees from AstraZeneca, Bristol
Myers Squibb, MSD, Novartis and Chugai Pharmaceutical.
The remaining authors have no conflicts of interest to
disclose.

12.

13.

14.

15.

ORCID
Daiki Murata https://orcid.org/0000-0002-4295-5046
Koichi Azuma https://orcid.org/0000-0001-5040-5856
Takaaki Tokito https://orcid.org/0000-0002-8429-2287
16.

R EF E R EN C E S
1.

2.

3.

4.

5.

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9906062

SU PP O RT I NG IN FO RM A T I ON
Additional supporting information can be found online in
the Supporting Information section at the end of this article.
How to cite this article: Murata D, Azuma K,
Matama G, Zaizen Y, Matsuo N, Murotani K, et al.
Clinical significance of interstitial lung abnormalities
and immune checkpoint inhibitor-induced interstitiallung disease in patients with non-small cell lungcancer. Thorac Cancer. 2022. https://doi.org/10.
1111/1759-7714.14718

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