Identifying risk factors for refractory tyrosine kinase inhibitor-induced interstitial lung disease in patients with non-small cell lung cancer

Introduction

In the landscape of lung cancer treatment, molecular targeted therapy has emerged as a pivotal strategy in managing non-small cell lung cancer (NSCLC), particularly among patients harboring epidermal growth factor receptor (EGFR) mutations. Tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, afatinib, and the third-generation agent osimertinib, have markedly improved patient prognosis and quality of life owing to their impressive therapeutic efficacy.

However, alongside these remarkable advancements, the utilization of TKIs presents challenges. Among the adverse effects linked to TKI therapy, TKI-induced interstitial lung disease (TKI-ILD) stands out as a severe and potentially life-threatening complication (1). Despite its relatively low incidence rate, estimated at around 1% to 5% (2-4), TKI-ILD can manifest with a spectrum of clinical presentations, ranging from mild interstitial changes to acute and diffuse lung injury (5,6), thereby posing a significant risk to patient safety.

Of particular concern are instances where patients with TKI-ILD exhibit a poor response to initial low or intermediate doses of corticosteroid treatment. For refractory TKI-ILD cases, timely administration of ultra-high doses of corticosteroids is crucial for managing pneumonitis to prevent further deterioration or even life-threatening outcomes (7,8). Therefore, early identification of refractory TKI-ILD patients is of paramount importance. Potential risk factors contributing to refractory TKI-ILD may include tumor biological characteristics, drug factors, and blood biomarkers, among others.

So far, no research has specifically focused on the risk factors associated with refractory TKI-ILD. Identifying refractory TKI-ILD prior to corticosteroid treatment poses a challenge in clinical practice. Given these challenges, this study aims to retrospectively analyze the characteristics of TKI-ILD, with a specific focus on refractory cases exhibiting poor response to standard corticosteroid therapy. Through comprehensive data collection and in-depth analysis, we seek to elucidate the factors associated with the development of refractory TKI-ILD and explore optimized therapeutic strategies to improve clinical outcomes for this distinct patient population. We present this article in accordance with the STROBE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-56/rc).

Methods

Patients

We retrospectively analyzed data from lung cancer patients diagnosed with TKI-ILD and treated at Guangdong Provincial People’s Hospital from January 2014 to December 2022. All patients had histopathologically confirmed NSCLC and exhibited driver gene mutations, such as EGFR mutation or anaplastic lymphoma kinase (ALK) rearrangement, among others. TKIs were administered based on the specific mutated genes, either as adjuvant therapy for early-stage NSCLC or as first-line and subsequent-line treatments for advanced NSCLC.

A multidisciplinary team comprising specialists in medical oncology, radiation oncology, and radiology managed all TKI-ILD cases. Diagnosis of TKI-ILD was established based on the following criteria: (I) a history of TKI treatment; (II) respiratory symptoms including cough, dyspnea, and fever; and (III) characteristic and diverse radiographic findings indicative of interstitial pneumonitis observed on chest computed tomography (CT). Management of TKI-ILD followed therapeutic consensus guidelines (9). For grade 1 TKI-ILD (asymptomatic), TKI therapy could be continued with close symptom monitoring. If symptoms worsened, patients were classified as grade 2–4. Patients with grade 2 TKI-ILD were instructed to discontinue TKI therapy immediately and initiate systemic methylprednisolone treatment (0.5–1.0 mg/kg daily). Failure to improve within 48–72 h of steroid initiation warranted classification as grade 3 TKI-ILD. For grade 3 TKI-ILD, methylprednisolone treatment commenced at a dose of 1.0–2.0 mg/kg daily, along with empirical antibiotic therapy. If symptoms persisted after 48–72 h, patients were categorized as grade 4. For grade 3 TKI-ILD, methylprednisolone was initiated at a dose of 500–1,000 mg daily for 3 days followed by methylprednisolone at 1.0–2.0 mg/kg daily. Steroids were tapered over a minimum of 6 weeks upon symptom improvement. Refractory TKI-ILD was defined as pneumonitis unresponsive to initial steroid therapy according to the aforementioned guideline.

Data collection

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the ethics board of Guangdong Provincial People’s Hospital (No. KY-Z-2021-418-01). As it is a retrospective study, informed consents are not required. Clinical data of patients were retrieved from digital medical records. Baseline characteristics, including age, smoking status, underlying diseases, tumor histology, and gene mutation status at the initiation of TKI treatment, were documented. Additionally, information on TKI treatment response, as well as prior history of surgery and chemotherapy before TKI initiation, was recorded.

TKI-ILD grading at the patient’s initial visit for ILD and during ILD treatment was assessed by a multidisciplinary team using the Common Toxicity Criteria for Adverse Events (version 5.0). Time to TKI-ILD onset was defined as the duration from initial TKI administration to the onset of TKI-ILD. Data regarding symptoms, initial corticosteroid dosage, antibiotic usage, and immunosuppressive drug administration were collected. Blood parameters, including blood routine, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels at baseline and upon TKI-ILD onset, were documented. Changes in blood parameters from baseline to TKI-ILD onset were calculated using the formula [(parameter value at TKI-ILD onset) − (parameter value at baseline)]/(parameter value at baseline).

Chest CT images acquired at TKI-ILD onset underwent meticulous review by a senior radiologist. Radiological features, such as carcinomatous lymphangitis, TKI-ILD involvement of lung parenchymal lobes and areas, and radiographic patterns, were documented. Radiographic patterns of TKI-ILD were categorized as cryptogenic organizing pneumonia (COP)-like pattern, hypersensitivity pneumonitis (HP)-like pattern, nonspecific interstitial pneumonia (NSIP)-like pattern, or diffuse alveolar damage (DAD)-like pattern (10). Survival periods from the onset of TKI-ILD were recorded. The last follow-up date was May 1, 2023.

Statistical analysis

Categorical data were compared using Fisher’s exact test or Yates’ correction. For data meeting the criteria of normal distribution and homogeneity of variance, two-group comparisons were conducted using t-tests, while three-group comparisons were performed using one-way analysis of variance (ANOVA). In cases where the data met the normal distribution assumption but violated the homogeneity of variance assumption, two-group comparisons were carried out using Welch’s t-test, and three-group comparisons were performed using Welch’s one-way ANOVA. For data not meeting the normal distribution assumption, two-group comparisons were made using the Wilcoxon test, and three-group comparisons were conducted using the Kruskal-Wallis test. Risk factors for refractory TKI-related ILD were evaluated through logistic regression analyses, including both univariate and multivariable assessments. All statistical analyses were performed using SPSS version 20 (IBM Corp., Armonk, NY, USA). A significance level of P<0.05 was considered statistically significant.

Results

Baseline characteristics

In total, 71 patients were diagnosed with TKI-ILD. Table 1 summarizes the baseline characteristics of patients with non-refractory and refractory TKI-ILD. The majority of TKI-ILD patients were female (60.0%) and >65 years old (59.2%). Adenocarcinoma was diagnosed in 95.8% of patients, with EGFR mutation being the most common (69.0%). Among TKI-ILD patients, 10 (14.1%) had refractory TKI-ILD. There were no significant differences between non-refractory and refractory TKI-ILD patients regarding gender, age, Eastern Cooperative Oncology Group (ECOG) performance status, smoking status, history of chronic obstructive pulmonary disease, histology, tumor staging, treatment line, best response to TKI, or proportion of prior surgery, chemotherapy, or immunotherapy. However, a significant difference was observed in gene mutation distribution (P=0.02), with ALK rearrangement being more common in the refractory group than in the non-refractory group (40.0% vs. 9.8%).

Clinical features and treatment of TKI-ILD

Table 2 outlines the clinical features and treatment of TKI-ILD. The median time from TKI administration to ILD onset was 90 [40, 167] days for all TKI-ILD patients. There were no differences in ILD onset time between non-refractory and refractory TKI-ILD groups [16.57 (6.82–28.14) vs. 7.43 (2.71–19.1) days, P=0.27], as illustrated in Figure 1. The Common Terminology Criteria for Adverse Events (CTCAE) grade of ILD differed significantly between the two groups (P<0.001), with 90% of refractory TKI-ILD patients experiencing grade 3 pneumonitis. Cough was the most common symptom in TKI-ILD patients, while shortness of breath (100% vs. 55.7%, P=0.02) and dyspnea (60% vs. 11.5%, P=0.001) were more prevalent in the refractory group. Other symptoms, including cough, expectoration, fever, and chest pain, were present in some patients but lacked specificity in the refractory group. The majority of TKI-ILD patients exhibited two or more symptoms at pneumonitis onset (Figure 2). Pneumonia occurred more frequently in the refractory group (60.0% vs. 27.9%, P=0.11), leading to increased antibiotic use (90.0% vs. 52.5%, P=0.06). Regarding treatment, there were no significant differences between groups in the initial dose of equivalent methylprednisolone or the use of other immunosuppressive agents.

Figure 1 Time from initiation of TKI treatment to onset of TKI-ILD in non-refractory TKI-ILD and refractory TKI-ILD patients. TKI-ILD, tyrosine kinase inhibitor-induced interstitial lung disease.

Figure 2 Symptoms presented in patients with (A) non-refractory TKI-ILD and (B) refractory TKI-ILD. TKI-ILD, tyrosine kinase inhibitor-induced interstitial lung disease.

Peripheral blood biomarkers in patients with TKI-ILD

Table 3 presents the blood parameters at baseline, at the onset of TKI-ILD, and changes from baseline to ILD onset. No significant differences between groups were observed in white blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count, absolute eosinophil count (AEC), NLR, and PLR at baseline. However, at the onset of TKI-ILD, WBC [10.58 (8.21, 15.38) vs. 6.94 (5.06, 10.29) ×10⁹/L, P=0.04] and ANC [9.67 (5.71, 13.36) vs. 4.53 (3.13, 7.85) ×10⁹/L, P=0.04] were significantly high in the refractory TKI-ILD group. Additionally, LDH levels detected in the refractory group were significantly higher than those in the non-refractory group [422.00 (311.50, 518.50) vs. 279.00 (206.00, 332.00) U/L, P=0.03] (Figure 3). Furthermore, WBC and ANC markedly decreased from baseline to TKI-ILD onset in the non-refractory group [−17.0% (−46.1%, 12.6%), −19.7% (−40.9%, 28.9%)], while they increased in the refractory group [42.3% (8.5%, 108.5%), 51.4% (17.4%, 171.1%)]. Hence, the changes in WBC and ANC from baseline to TKI-ILD onset differed significantly between the two groups (P=0.006; P=0.01). Notably, although AEC did not differ between the two groups, it significantly decreased from baseline to the onset of TKI-ILD in the non-refractory group.

Figure 3 Peripheral blood biomarkers in patients with TKI-ILD. Blood routine parameters in non-refractory and refractory groups at baseline and at the onset of TKI-ILD, including (A) white blood cell count, (B) absolute neutrophil count and (C) absolute eosinophil count were showed. (D) The lactate dehydrogenase level at two groups were only at the onset of TKI-ILD were showed. *, P<0.05. TKI-ILD, tyrosine kinase inhibitor-induced interstitial lung disease.

Radiological features in patients with TKI-ILD

Table 4 displays the radiological features in patients with TKI-ILD. Carcinomatous lymphangitis was uncommon in these patients (8.5%). More than 50% of the lung parenchyma was involved in 90.0% and 42.6% of refractory and non-refractory TKI-ILD patients, respectively (P=0.02). Additionally, 90.0% of refractory group patients exhibited involvement of more than three lobes, while 49.2% in the non-refractory group (P=0.04). Regarding radiographic patterns, a significant difference was observed between the two groups (P<0.001). COP and NSIP were the most common patterns in overall patients (38.0% and 36.6%) and in the non-refractory group (42.6% and 41.0%), respectively, while the DAD pattern was predominant in the refractory group (80.0%). Figure 4 illustrates typical radiological manifestations of TKI-ILD.

Figure 4 The radiographic manifestation of TKI-ILD. (A) COP-like pattern, showed multiple patchy alveolar opacities. (B) HP-like pattern, showed poorly defined small centrilobular nodules, bilateral GGO, lobular areas of decreased attenuation and vascularity. (C) NSIP-like pattern, showed subpleural GGO and diffused reticulation at the right lower lobe. (D) DAD-like pattern, showed patchy and confluent GGO, bilateral consolidation. COP, cryptogenic organizing pneumonia; DAD, diffuse alveolar damage; GGO, ground glass opacity; HP, hypersensitivity pneumonitis; NSIP, nonspecific interstitial pneumonia; TKI-ILD, tyrosine kinase inhibitor-induced interstitial lung disease.

Risk factors for refractory TKI-ILD

Gene mutation with ALK rearrangement, dyspnea, WBC >10×10⁹/L, ANC >9×10⁹/L, LDH >420 U/L at onset of TKI-ILD, DAD radiographic pattern, and >50% area of lung involvement were significantly associated with an increased risk of developing refractory TKI-ILD (Table 5). Multivariable logistic analysis identified dyspnea (OR, 27.683; 95% CI: 1.938–395.499; P=0.01), LDH >420 U/L at onset of TKI-ILD (OR, 17.117; 95% CI: 1.369–213.954; P=0.03), and DAD radiographic pattern (OR, 57.517; 95% CI: 2.810–1,177.471; P=0.009) as independent risk factors for refractory TKI-ILD.

Clinical course and outcomes of refractory TKI-ILD

All TKI-ILD patients received treatment according to established guidelines combined with physicians’ expertise. Notably, 10 patients did not experience symptom relief after commencing steroid therapy, categorizing them as refractory TKI-ILD cases. Upon the lack of improvement within the initial 72-h period, steroid dosage was escalated (Figure 5). As salvage therapy, all refractory TKI-ILD patients received high doses of methylprednisolone ranging from 500 to 1,000 mg daily (Table 6). Following this intensified regimen, six patients achieved symptom resolution; however, the condition of four patients deteriorated, ultimately leading to fatality. Among the six refractory patients whose TKI-ILD was brought under control, one patient (patient No. 8) experienced disease recurrence. Despite re-administration of high-dose steroids, this patient succumbed to TKI-ILD eventually. Overall, the mortality rate of refractory TKI-ILD was 50% (5/10). All refractory TKI-ILD patients passed away within 84 days from ILD onset. Among them, four patients with unmanageable TKI-ILD progression died within 16 days. Additionally, five other patients, whose TKI-ILD was eventually controlled, succumbed to lung cancer progression within a 3-month period.

Figure 5 Clinical course and outcomes of patients with refractory TKI-ILD. TKI-ILD, tyrosine kinase inhibitor-induced interstitial lung disease.

Discussion

In recent decades, TKIs designed to target various gene mutations in NSCLC have gained widespread application. Research has explored the risk factors associated with TKI-ILD, particularly in the context of EGFR-TKI and ALK-TKI therapies (2,3,11,12). However, there remains a lack of information regarding therapeutic strategies and clinical outcomes specific to TKI-ILD, especially among patients demonstrating refractoriness to corticosteroid treatment. This study scrutinized the clinical characteristics, peripheral blood biomarkers, radiological features, risk factors, and outcomes of refractory and non-refractory TKI-ILD in a cohort of 71 patients. To the best of our knowledge, this is the first study to investigate the risk factors for refractory TKI-ILD.

As our findings revealed, 14.1% of TKI-ILD patients were refractory to initial corticosteroid therapy. Among the baseline characteristics, a notable observation was the higher prevalence of ALK rearrangement in refractory TKI-ILD patients (40.0%) than in non-refractory patients (9.8%), suggesting a potential association with refractoriness. Some studies have reported fatal cases of ALK-TKI-related ILD (13,14). For instance, Zhao et al. (12) reported that ALK-TKI-associated ILD led to hospitalization in 55.77% of patients and resulted in death or life-threatening outcomes in 43.03%. Although subsequent logistic regression analysis did not identify ALK rearrangement as an independent risk factor for refractory TKI-ILD, heightened vigilance is warranted for patients receiving ALK-TKI therapy.

Different TKI regimens are associated with varying incidences of TKI-ILD. For EGFR-TKIs, erlotinib has been linked to a low incidence of TKI-ILD (15), albeit with potential fatal outcomes (16). Osimertinib exhibits the strongest association with TKI-ILD among first to third-generation EGFR-TKIs (6). In our study, patients were treated with various TKI regimens; however, owing to the limited sample size, statistical analysis correlating TKI regimens with TKI-ILD incidence was challenging. Previous pulmonary fibrosis has also been recognized as a risk factor for TKI-ILD (6,17,18); however, owing to its low incidence within our study group, we did not analyze its relationship with refractory TKI-ILD. Older patients have been identified as a risk factor for TKI-ILD in some studies (3,11) but not in our analysis focusing on refractory TKI-ILD.

Regarding clinical features, patients with refractory TKI-ILD exhibited severe manifestations, with 90% presenting with grade 3 pneumonitis, along with a high prevalence of shortness of breath and dyspnea. Further multivariate analysis confirmed that dyspnea was an independent risk factor for refractory TKI-ILD. Dyspnea may indicate compromised gas exchange capacity in the lungs, resulting in a poor treatment response.

The onset time of TKI-ILD varied among patients and TKI regimens (6,12). A case report (19) and a retrospective study (6) demonstrated that early-onset TKI-ILD is associated with fatal outcomes. Unexpectedly, in our study, the median onset time for refractory TKI-ILD was longer than that for non-refractory TKI-ILD. However, owing to the small sample size, drawing definitive conclusions is challenging.

Low baseline serum albumin levels (1) and interleukin-6 (IL-6) levels (20) appeared to be associated with the development of TKI-ILD. Serum KL-6 levels have been proposed as potential diagnostic biomarkers for life-threatening EGFR-TKI-induced ILD (18,21). However, the standardized detection and commercialization of KL-6 have not been achieved, limiting its clinical utility. In our study, we selected blood routine and LDH levels as potential diagnostic biomarkers. WBC, ANC, and LDH levels at the onset of TKI-ILD were significantly elevated in refractory patients, indicating a more pronounced systemic inflammatory response. Moreover, in the refractory TKI-ILD group, the ANC was significantly upregulated from baseline to the onset of ILD, suggesting possible concurrent bacterial infection.

The median LDH level in the refractory group was 422 U/L, suggesting that 420 U/L may serve as a potential cutoff value for predicting refractory TKI-ILD. Further multivariable logistic analysis confirmed that LDH levels >420 U/L were an independent risk factor for refractory TKI-ILD. Elevated LDH levels are commonly associated with lung injury and autoimmune pneumonia (22,23). Lin et al. (24) reported a significant increase in LDH levels from baseline to the onset of checkpoint inhibitor-related pneumonitis (CIP). Another study on CIP indicated that an LDH level >320 U/L at CIP onset is independently associated with refractory CIP (25). These findings suggest that LDH could serve as a risk factor for refractory drug-related interstitial lung injury, although the underlying mechanisms remain unclear. Although elevated levels of LDH may serve as a potential risk factor for the development of refractory TKI-ILD, it is important to note that these elevated LDH levels can also arise as a consequence of the progression of lung cancer itself, reflecting the complex interplay between cancer progression and treatment-related complications.

Different TKI regimens can result in varying radiological manifestations in TKI-ILD. Endo et al. (26) analyzed the imaging findings of gefitinib-related ILD and found that nonspecific areas with ground-glass attenuation were the most common pattern. Conversely, ILD associated with ALK-TKI is predominantly presented as an OP pattern (11), but may also involve a mixture of radiological patterns (27). In our study, refractory patients exhibited more extensive lung involvement and a higher prevalence of DAD pattern than non-refractory patients. The presence of a DAD pattern appeared to be indicative of poor prognosis, as evidenced by a significantly higher mortality rate among patients with this pattern than that with other patterns in gefitinib-related ILD (26). DAD may signify a widespread inflammatory state in the lungs. Controlling inflammation with low to medium doses of steroids may prove challenging, potentially leading to life-threatening TKI-ILD.

After initial corticosteroid treatment, symptoms in refractory TKI-ILD patients worsened, reaching life-threatening levels (grade 4–5). These patients promptly received high doses of methylprednisolone, administered at 500 or 1,000 mg daily for a minimum of 3 days. While six patients showed improvement following high-dose methylprednisolone therapy, four patients experienced deteriorating conditions leading to death. One patient, initially responsive to high-dose steroids, suffered a recurrence of TKI-ILD and eventually succumbed. The mortality rate attributed to TKI-ILD in this study was 7.0% (5/71) due to ILD-related complications. Comparatively, reported fatality rates for erlotinib-induced ILD ranged around 35.54% (6), while ALK-TKI-induced ILD exhibited rates between 13.08% to 37.42% (12). The observed mortality rate of TKI-ILD in this study was notably lower than that in other studies, possibly due to sampling errors inherent in single-center retrospective analyses. Five patients who initially managed their TKI-ILD ultimately succumbed to rapid lung cancer progression within 3 months. All the patients discontinued TKI drug usage, with some opting for chemotherapy as subsequent treatment; however, tumor control was not achieved. Some studies have demonstrated that the readministration of EGFR-TKI, following the onset of EGFR-TKI-ILD, may be a viable treatment option, showcasing a notably successful readministration rate of 81.9% (28), which suggests early recovery from TIK-ILD may enable re-treatment with TKIs and improve survival. These findings suggest that patients who experience refractory TKI-ILD face a grim prognosis. Early detection of refractory TKI-ILD and timely administration of high-dose corticosteroid therapy may help mitigate the risk of life-threatening outcomes or death.

This study has several limitations. First, its retrospective nature resulted in incomplete clinical records, including missing CT images and blood parameters. Additionally, the varied TKI drug regimens among patients hindered the analysis of their relationship with refractory ILD incidence. Secondly, the relatively small sample size may introduce statistical bias into the results. Thus, a multicenter study is warranted to include a larger patient cohort for result verification. Nevertheless, the study identifies potential risk factors for refractory TKI-ILD and highlights the importance of early identification and effective management strategies for this condition.

Conclusions

Refractory TKI-ILD poses a significant risk to patient survival and well-being. Early identification of refractory TKI-ILD upon its onset is imperative. Dyspnea, LDH >420 U/L at the onset of TKI-ILD, and the presence of a DAD radiographic pattern have emerged as independent risk factors for refractory TKI-ILD. Future research endeavors should focus on validating these risk factors in larger cohorts to enhance our understanding and management of this challenging condition.

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-56/rc

Data Sharing Statement: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-56/dss

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-56/prf

Funding: This study was supported by Guangzhou Science and Technology Plan Foundation (No. 2024A04J10022), National Natural Science Foundation of China (Nos. 82203963, 82172671, and 81972970), GDPH Supporting Fund for NSFC Program (Nos. 8210120361 and 8220120190), and GDPH High-level Full-time Talent Introduction Supporting Research Funds (No. KY 0120220119). The funding sources had no involvement in the conduct of the study.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-56/coif). The 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the ethics board of Guangdong Provincial People’s Hospital (No. KY-Z-2021-418-01). As it is a retrospective study, informed consents are not required.

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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