Cross-Cancer Type Evaluation of Potential Interstitial Lung Disease Complications of Immune Checkpoint Inhibitors Using JADER

Abstract

Interstitial lung disease (ILD) is a serious adverse event caused by the administration of immune checkpoint inhibitors (ICIs). However, only few large-scale studies have explored the association among ICI use, underlying cancer type, and ILD complications. This study aimed to analyze the association between the primary cancer type and ICI-induced ILD in a cross-sectional manner using the Japanese Adverse Drug Event Report (JADER) database. Nivolumab and pembrolizumab (anti-programmed cell death 1 (PD-1) antibodies) and durvalumab, avelumab, and atezolizumab (anti-programmed cell death ligand 1 (PD-L1) antibodies) were included as ICIs in this study. Adverse events were identified based on the preferred terms of Medical Dictionary for Regulatory Activities (MedDRA) version 27.0/J listed in the Standardized MedDRA Queries (SMQ) “interstitial lung disease.” The reporting odds ratio was calculated to detect the association between ICI use and ILD complications, and a signal was detected if the lower limit of the 95% confidence interval exceeded 1. In the analysis of all cancer types, a signal was detected for all ICIs except avelumab. An association between ICI and ILD was detected for all cancer types with nivolumab. However, pembrolizumab exhibited a signal only in colorectal cancer. In contrast, anti-PD-L1 antibodies displayed signals in five cancer types, excluding head and neck cancer, which was not reported in JADER. Among these cancer types, atezolizumab exhibited a signal only in breast cancer. The results of this study will help guide the safe use of ICIs based on the underlying cancer type in terms of ILD complications.

INTRODUCTION

Interstitial lung disease (ILD), also known as diffuse lung disease, comprises a diverse group of lung diseases with similar clinical, physiological, and pathological features.¹⁾ ILD is generally associated with delayed diagnosis, and patients with ILD over the age of 65 years have an extremely poor prognosis, with a mean survival of 2.54 years even after the diagnosis is confirmed.²⁾ Drug-induced ILD is an adverse drug reaction with an annual incidence of 4.1 to 12.4 cases per million people. Drug-induced ILD has been reported to be caused by the administration of antineoplastics, anti-rheumatic drugs, amiodarone, and antibiotics,³⁾ and recently by immune checkpoint inhibitors (ICIs).⁴⁾ ICIs bind to the inhibitory receptor programmed cell death 1 (PD-1) or its ligand (programmed cell death ligand 1; PD-L1), an immune checkpoint molecule. This releases the brakes of the immunoreactive system and enhances the immune response against tumors, thereby exerting an antitumor effect.⁵⁾ While the clinical use of ICI has expanded with the recent addition of many new indications, immune-related adverse events (irAEs) have become a concern. irAEs are manifestations of autoimmune disease-like symptoms, including colitis and thyroid dysfunction, caused by immune dysregulation and can occur anywhere in the body.⁶⁾ Drug-induced ILD is an irAE that been reported in approximately 3% of ICI users, of which 1% users experience severe outcomes.⁷⁾ Moreover, it has been reported that the incidence of ILD caused by nivolumab, an ICI, is relatively high in lung cancer and renal cancer,⁸⁾ and the incidence of ILD caused by ICIs is expected to vary depending on the underlying cancer type. Therefore, exploring the association among ICI use, underlying diseases, and ILD complications may help guide the safe use of ICIs in clinical practice. However, only few large-scale studies have investigated the association between ICIs and ILD complications across cancer types.

Voluntary adverse event reporting databases have been used in large-scale retrospective studies and are particularly useful for investigating drug safety.⁹⁾ The Japanese Adverse Drug Event Report (JADER) is a database of voluntary adverse event reports published by the Pharmaceuticals and Medical Devices Agency (PMDA). JADER is particularly useful for the post-marketing risk assessment of drugs in Japan because it contains adverse event reported from clinical settings in Japan.^10,11) While the occurrence of ILD due to ICI use is a fatal adverse effect, its incidence is not always high. Therefore, large datasets, such as JADER, are helpful for investigating the association between drugs and rare adverse events. Additionally, the strength of JADER lies in its collection of information on adverse events primarily from the Japanese population, rendering it less susceptible to racial differences.¹²⁾ Thus, this study aimed to investigate the association among the use of ICIs (nivolumab, pembrolizumab, durvalumab, avelumab, and atezolizumab), underlying diseases, and ILD complications using the JADER database.

MATERIALS AND METHODS

Subject of Analysis

JADER data were downloaded from the PMDA website (https://www.pmda.go.jp/ index.html). All reports from April 2004 to March 2024 were included in the analysis to ensure comprehensive analysis.

Anti-PD-1 monoclonal antibodies (nivolumab and pembrolizumab) and anti-PD-L1 monoclonal antibodies (durvalumab, avelumab, and atezolizumab) were included among the ICIs marketed in Japan as of March 2024. Adverse events were identified based on the Medical Dictionary for Regulatory Activities (MedDRA version 27.0/J), and 78 preferred terms (PTs) included in the Standardized MedDRA Queries (SMQ) for “interstitial lung disease” were used in the analysis (Table 1). The following primary cancer types were included in the analysis: esophageal cancer, gastric cancer, colorectal cancer, breast cancer, renal cancer, and head and neck cancer; any drug treatment was covered by health insurance in Japan for these cancers as of March 2024. Cemiplimab, an anti-PD-1 monoclonal antibody, was excluded from the study owing to its early launch. In addition, one of the ICI classes, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, was excluded from the analysis because they are used in combination with other ICIs. Small-cell and non-small-cell lung cancers were also excluded from the analysis because the primary disease itself could be a factor for ILD development.

Table 1. Preferred Terms (PTs) Defined as Interstitial Lung Disease

PT code	PT
10066728	Acute interstitial pneumonitis
10073344	Alveolar lung disease
10001881	Alveolar proteinosis
10001889	Alveolitis
10050343	Alveolitis necrotising
10080701	Autoimmune lung disease
10006448	Bronchiolitis
10083303	Bronchiolitis obliterans syndrome
10086041	Chronic graft versus host disease in lung
10076515	Combined pulmonary fibrosis and emphysema
10085189	Confirmed e-cigarette or vaping product use
10060902	Diffuse alveolar damage
10014952	Eosinophilia myalgia syndrome
10078117	Eosinophilic granulomatosis with polyangiitis
10014962	Eosinophilic pneumonia
10052832	Eosinophilic pneumonia acute
10052833	Eosinophilic pneumonia chronic
10081988	Hypersensitivity pneumonitis
10078268	Idiopathic interstitial pneumonia
10063725	Idiopathic pneumonia syndrome
10021240	Idiopathic pulmonary fibrosis
10085352	Immune-mediated lung disease
10087834	Interstitial lung abnormality
10022611	Interstitial lung disease
10086117	Low lung compliance
10025102	Lung infiltration
10081792	Lung opacity
10070831	Necrotising bronchiolitis
10029888	Obliterative bronchiolitis
10084305	Pleuroparenchymal fibroelastosis
10035742	Pneumonitis
10085188	Probable e-cigarette or vaping product use
10036805	Progressive massive fibrosis
10037383	Pulmonary fibrosis
10058824	Pulmonary necrosis
10061473	Pulmonary radiation injury
10061924	Pulmonary toxicity
10037457	Pulmonary vasculitis
10037754	Radiation alveolitis
10085628	Radiation bronchitis
10037758	Radiation fibrosis-lung
10037765	Radiation pneumonitis
10085517	Rheumatoid arthritis-associated interstitial lung disease
10080547	Small airways disease
10052235	Transfusion-related acute lung injury
10069351	Acute lung injury
10001052	Acute respiratory distress syndrome
10075289	Airway remodelling
10075185	Allergic eosinophilia
10068801	Antisynthetase syndrome
10004795	Biopsy lung abnormal
10010187	Complications of transplanted lung
10078811	Cystic lung disease
10018620	Goodpasture’s syndrome
10072579	Granulomatosis with polyangiitis
10069152	Granulomatous pneumonitis
10069698	Langerhans’ cell histiocytosis
10057261	Lung induration
10051604	Lung transplant rejection
10057481	Lupus pneumonitis
10049459	Lymphangioleiomyomatosis
10089961	Mixed obstructive and restrictive lung disease
10067472	Organising pneumonia
10035745	Pneumonitis chemical
10036024	Polyarteritis nodosa
10037313	Pulmonary alveolar haemorrhage
10086936	Pulmonary bullae rupture
10037382	Pulmonary eosinophilia
10037391	Pulmonary granuloma
10037396	Pulmonary haemosiderosis
10068513	Pulmonary renal syndrome
10037430	Pulmonary sarcoidosis
10086984	Pulmonary septal thickening
10048667	Restrictive pulmonary disease
10039081	Rheumatoid lung
10039486	Sarcoidosis
10042954	Systemic sclerosis pulmonary
10051222	Toxic oil syndrome

Analysis Method

The JADER dataset comprises a case list table (demo), drug information table (drug), adverse drug reaction information table (reac), and primary disease table (hist). All four tables were used in this study, and a database was created and analyzed using the Microsoft Access 2016. The association between ICI use and development of ILD was defined as a signal when the lower limit of the 95% confidence interval (CI) exceeded 1 by calculating the reporting odds ratio (ROR) and 95% CI using the following method⁹⁾:

  

For the analysis within each cancer type, the ROR and 95% CI were calculated after filtering the cancer type using the “hist” table according to the definition provided in the supplementary tables.

RESULTS

Relationship between ICI Use and Development of ILD

The total number of adverse event reports in JADER from April 2004 to March 2024 was 887704, of which 53512 were related to ILDs. Drug induced-ILD associated with the administration of nivolumab and pembrolizumab (anti-PD-1 monoclonal antibodies) was reported in 5018 and 3379 cases, respectively, and that with durvalumab, avelumab, and atezolizumab (anti-PD-L1 monoclonal antibodies) was reported in 2065, 49, and 946 cases, respectively (Fig. 1). ROR (95% CI) for each ICI were as follows: nivolumab 4.53 (4.39–4.68), pembrolizumab 3.56 (3.42–3.70), durvalumab 20.16 (18.90–21.51), avelumab 1.18 (0.88–1.58), and atezolizumab 2.48 (2.31–2.66), indicating signals related to ILD for all drugs except avelumab (Table 2).

Fig. 1. Patient Selection Flow Chart

Table 2. Association of Each Immune Checkpoint Inhibitor with Interstitial Lung Disease (ILD)

Drug category	Drug name	Total number of adverse events	Number of cases of ILD	ROR (95% CI)
Anti PD-1a)	Nivolumab	23639	5018	4.53 (4.39–4.68)
	Pembrolizumab	18895	3379	3.56 (3.42–3.70)
Anti PD-L1b)	Durvalumab	3764	2065	20.16 (18.90–21.51)
	Avelumab	695	49	1.18 (0.88–1.58)
	Atezolizumab	6956	946	2.48 (2.31–2.66)

a) Programmed cell death 1, b) programmed cell death ligand 1.

Relationship between ICI Use and Development of ILD for Each Cancer Type

Table 3 shows the association between ICI use and ILD complications for each cancer type. For anti-PD-1 monoclonal antibodies, ROR (95% CI) for nivolumab was 4.59 (3.75–5.62) for esophageal cancer, 2.33 (2.05–2.65) for gastric cancer, 3.60 (2.57–5.05) for colorectal cancer, 2.27 (1.29–4.01) for breast cancer, 1.74 (1.58–1.92) for renal cancer, and 2.51 (1.84–3.41) for head and neck cancer, indicating signals related to ILD in all six cancer types. For pembrolizumab, a signal was detected only in colorectal cancer (ROR, 2.10; 95% CI, 1.44–3.04). For the anti-PD-L1 monoclonal antibody durvalumab, ROR (95% CI) was 3.99 (1.35–11.24) for esophageal cancer, 25.0 (8.87–70.04) for gastric cancer, 14.23 (4.77–42.40) for colorectal cancer, 8.87 (1.98–39.67) for breast cancer, and 16.22 (2.97–88.64) for renal cancer, indicating that the signals were detected in five of the six cancer types studied. A signal was also detected for atezolizumab in breast cancer (ROR, 2.12; 95% CI, 1.66–2.70). Collectively, signals were detected with nivolumab and durvalumab in esophageal, gastric, breast, and renal cancers, in colorectal cancer along with pembrolizumab, as well as in breast cancer along with atezolizumab.

Table 3. Association between Immune Checkpoint Inhibitors and Interstitial Lung Disease (ILD) in Each Cancer Type

Primary disease	Drug name	Total number of adverse events	Number of cases of ILD	ROR (95% CI)
Esophageal cancer	Nivolumab	1110	256	4.59 (3.75–5.62)
	Pembrolizumab	536	56	0.99 (0.74–1.33)
	Durvalumab	16	5	3.99 (1.35–11.24)
	Atezolizumab	9	2	2.43 (0.50–11.74)
Gastric cancer	Nivolumab	2605	422	2.33 (2.05–2.65)
	Pembrolizumab	145	17	1.26 (0.76–2.10)
	Durvalumab	18	13	25.00 (8.87–70.04)
	Atezolizumab	20	4	2.38 (0.80–7.12)
Colorectalcancer	Nivolumab	201	45	3.60 (2.57–5.05)
	Pembrolizumab	227	33	2.10 (1.44–3.04)
	Durvalumab	13	7	14.23 (4.77–42.40)
	Atezolizumab	12	2	2.43 (0.53–11.10)
Breast cancer	Nivolumab	63	16	2.27 (1.29–4.01)
	Pembrolizumab	918	75	0.58 (0.46–0.74)
	Durvalumab	7	3	8.87 (1.98–39.67)
	Atezolizumab	365	87	2.12 (1.66–2.70)
Renal cancer	Nivolumab	5431	807	1.74 (1.58–1.92)
	Pembrolizumab	1739	146	0.72 (0.60–0.86)
	Durvalumab	6	4	16.22 (2.97–88.64)
	Atezolizumab	4	0	NA
Head and neck cancer	Nivolumab	896	193	2.51 (1.84–3.41)
	Pembrolizumab	328	55	1.00 (0.72–1.39)
	Durvalumab	0	0	NA
	Atezolizumab	0	0	NA

NA, not applicable.

DISCUSSION

In this study, we investigated the association between the use of anti-PD-1 or anti-PD-L1 monoclonal antibodies and ILD complications across cancer types, using the spontaneous adverse event reporting database. In the unrestricted cancer type analysis, signals were detected for all ICIs analyzed in this study (Table 2), suggesting an association between ICI use and ILD complications. These results are consistent with those of previous reports¹³⁾ and suggest the importance of early symptom monitoring and patient education for the early detection of ILDs when ICIs are used.

When the association between ICI use and ILD complications was examined in each cancer type, signals were detected in renal, head and neck, gastric, breast, and esophageal cancers only with nivolumab among anti-PD-1 monoclonal antibodies. These results suggest that for renal, head and neck, gastric, breast, and esophageal cancer types, pembrolizumab is safer than nivolumab in patients with a predisposition to ILDs and prescribed anti-PD-1 monoclonal antibodies. This finding is consistent with a previous report¹⁴⁾ that nivolumab had a higher incidence of all-grade and grade ≥3 irAEs than that of pembrolizumab and may be similarly reflected in this study with respect to ILDs only. However, this study showed a signal for pembrolizumab in addition to nivolumab in colorectal cancer. Anti-PD-1 monoclonal antibodies are thought to exert antitumor activity by suppressing the regulation of cytotoxic T-cells by inhibiting the binding of cytotoxic T-cell PD-1 to tumor cell PD-L1. In contrast, cytotoxic T-cell PD-1 also binds to dendritic cell PD-L2,^15,16) and PD-L2 has been reported to bind to repulsive guidance molecule b (RGMb) in addition to PD-1.¹⁷⁾ RGMb is upregulated in human colorectal cancer tissues compared to control tissues. It has also been shown that RGMb promotes colon cancer cell proliferation, accelerates tumor growth, and acts via the bone morphogenetic protein (BMP) 4-Smad1/5/8 and extracellular signal-regulated kinase (ERK) 1/2 pathways in colon cancer development.¹⁸⁾ In addition, RGMb has been implicated in respiratory immune tolerance and may be involved in the development of lung inflammation by disrupting the balance of PD-L2 binding upon the administration of anti-PD-1 monoclonal antibodies.¹⁷⁾ These findings suggest that pembrolizumab, which is considered to have a lower incidence of irAEs than nivolumab, may also lead to ILD complications only in colorectal cancer.

In this study, atezolizumab, an anti-PD-L1 monoclonal antibody, exhibited signals related to ILD complications only in breast cancer. In an international phase III clinical trial in patients with breast cancer, several cases of ILD were reported as an adverse event in patients treated with atezolizumab, supporting the findings of the present study.¹⁹⁾ In addition, a previous study comparing the incidence of ILD in patients with breast cancer based on the analysis of the Medical Data Vision database reported an increase in ILD with atezolizumab.²⁰⁾ Thus, ILD complications of atezolizumab treatment in patients with breast cancer are a serious concern. The present finding that only pembrolizumab did not exhibit a signal related to ILD complications in breast cancer suggests that pembrolizumab is also safer than atezolizumab and durvalumab, not only compared to nivolumab, in patients with a predisposition to ILDs and in need of treatment with ICI. Additionally, this study comprehensively examined the association between ICI use and ILD complications by cancer type, regardless of insurance coverage. The findings that signals were also detected regardless of insurance coverage (e.g., breast cancer and nivolumab, durvalumab) indicate that the results of this study are not affected by insurance coverage.

This study had several limitations. First, the number of patients administered the target drug was unknown, which is a characteristic of adverse drug reaction reporting databases; therefore, the incidence of adverse drug reactions could not be determined. Second, potential biases, confounding factors, and duplicating reports should also be considered.¹²⁾ In addition, we were unable to assess the complications of ICI and ILD in combination with CTLA-4 inhibitors. However, the study compared the association between ICI use and ILD complications in each cancer type using the voluntary adverse event reporting database and suggested that ILD complications due to ICI use may differ depending on the underlying cancer type. In addition, drug selection that considers the differences based on the site of action, particularly in breast cancer, may contribute to improved safety in terms of ILD complications associated with ICI use. Therefore, the findings of this study are expected to guide safe use of ICIs based on the underlying disease in terms of ILD complications.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

REFERENCES

• 1) King TE Jr. Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am. J. Respir. Crit. Care Med., 172, 268–279 (2005).
• 2) Raghu G, Chen SY, Yeh WS, Maroni B, Li Q, Lee YC, Collard HR. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir. Med., 2, 566–572 (2014).
• 3) Skeoch S, Weatherley N, Swift AJ, Oldroyd A, Johns C, Hayton C, Giollo A, Wild JM, Waterton JC, Buch M, Linton K, Bruce IN, Leonard C, Bianchi S, Chaudhuri N. Drug-induced interstitial lung disease: a systematic review. J. Clin. Med., 7, 356 (2018).
• 4) Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med., 378, 158–168 (2018).
• 5) Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer, 12, 252–264 (2012).
• 6) Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site—when a biomarker defines the indication. N. Engl. J. Med., 377, 1409–1412 (2017).
• 7) Wang PF, Chen Y, Song SY, Wang TJ, Ji WJ, Li SW, Liu N, Yan CX. Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis. Front. Pharmacol., 8, 730 (2017).
• 8) Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol., 2, 1607–1616 (2016).
• 9) Poluzzi E, Raschi E, Piccinni C, Ponti FD. Chapter 12. Data mining techniques in pharmacovigilance: analysis of the publicly accessible FDA adverse event reporting system (AERS). Data mining applications in engineering and medicine. IntechOpen Ltd., London (2012).
• 10) Nawa H, Niimura T, Yagi K, Goda M, Zamami Y, Ishizawa K. Evaluation of potential complication of interstitial lung disease with abemaciclib and palbociclib treatments. Cancer Rep. (Hoboken), 5, e1402 (2022).
• 11) Kyotani Y, Zhao J, Nakahira K, Yoshizumi M. Analysis of appendicitis cases in the Japanese Adverse Drug Event Report (JADER) Database. Biol. Pharm. Bull., 46, 655–660 (2023).
• 12) Sakai T, Wada Y, Kokan A, Tanabe K, Goto N, Ohtsu F. Creating a checklist and a survey on research that used the Japanese adverse drug event report database. Jpn. J. Drug Inform., 22, 7–16 (2020).
• 13) Delaunay M, Cadranel J, Lusque A, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur. Respir. J., 50, 1700050 (2017).
• 14) Wang Y, Zhou S, Yang F, Qi X, Wang X, Guan X, Shen C, Duma N, Vera Aguilera J, Chintakuntlawar A, Price KA, Molina JR, Pagliaro LC, Halfdanarson TR, Grothey A, Markovic SN, Nowakowski GS, Ansell SM, Wang ML. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol., 5, 1008–1019 (2019).
• 15) Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin. Cancer Res., 18, 6580–6587 (2012).
• 16) Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med., 366, 2455–2465 (2012).
• 17) Xiao Y, Yu S, Zhu B, Bedoret D, Bu X, Francisco LM, Hua P, Duke-Cohan JS, Umetsu DT, Sharpe AH, DeKruyff RH, Freeman GJ. RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J. Exp. Med., 211, 943–959 (2014).
• 18) Shi Y, Chen GB, Huang XX, Xiao CX, Wang HH, Li YS, Zhang JF, Li S, Xia Y, Ren JL, Guleng B. Dragon (repulsive guidance molecule b, RGMb) is a novel gene that promotes colorectal cancer growth. Oncotarget, 6, 20540–20554 (2015).
• 19) Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med., 379, 2108–2121 (2018).
• 20) Nishijima S, Sato K, Onoue T, Hashimoto W, Shikano M. Incidence of interstitial lung disease in patients with breast cancer: a nationwide database study in Japan. Future Oncol., 20, 679–690 (2024).