Serial KL-6 Changes in PD-1/PD-L1 Inhibitor-Related Pneumonitis in Non-small Cell Lung Cancer: A Single-Center Prospective Pilot Study

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Tuberc Respir Dis. 2026;89(2):257-265

Publication date (electronic) : 2025 December 12

doi : https://doi.org/10.4046/trd.2025.0133

Jae Kyeom Sim¹, Juwhan Choi¹, Sung Won Chang¹, Sang Hyuk Kim¹, Jee Youn Oh¹, Kyung Hoon Min¹, Gyu Young Hur¹, Hwan Seok Yong², Jae Jeong Shim¹, Sung Yong Lee^,1

¹Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea

²Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea

Address for correspondence Sung Yong Lee Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea E-mail syl0801@korea.ac.kr

Received 2025 August 7; Revised 2025 October 3; Accepted 2025 December 11.

Abstract

Introduction

The role of immunotherapy in cancer treatment is continually growing. It works by reactivating and enhancing the patient's immune system, particularly cytotoxic T-cell responses. Among the various immunotherapeutic strategies, immune checkpoint inhibitors (ICIs) have become some of the most commonly used. ICIs are widely applied in managing non-small cell lung cancer (NSCLC) across different stages and clinical contexts [1,2].

ICIs can lead to distinct inflammatory side effects known as immune-related adverse events [3]. Immune-related adverse events can occur in various anatomical locations, with their distribution influenced by the therapeutic agent and the type of underlying cancer. A recent analysis of VigiBase data found that pneumonitis has a prevalence of 18.5%, making it the second most commonly reported immune-related adverse event [4]. Pneumonitis is more commonly observed in patients receiving programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors, particularly in those diagnosed with lung cancer [5]. PD-1/PD-L1 inhibitor-related pneumonitis can lead to life-threatening complications. A meta-analysis found that the fatality rate associated with this condition was 10%, with pneumonitis accounting for 35% of all deaths attributed to these therapies [6].

Although the overall incidence of pneumonitis is generally considered low, a recent study from Korea reported an incidence rate as high as 13% [7]. In addition, investigations conducted in Korea and Japan reported that the mortality rate for pneumonitis in patients with NSCLC was approximately 20% [7,8]. Consequently, identifying factors that influence the development, diagnosis, and prognosis of PD-1/PD-L1 inhibitor-related pneumonitis has potential to substantially inform cancer treatment decisions and improve patient care.

Krebs von den Lungen-6 (KL-6) is a high-molecular-weight glycoprotein primarily found in type 2 pneumocytes and the respiratory bronchial epithelium, and it can also be detected in serum. In interstitial lung diseases, the heightened regeneration of type 2 pneumocytes and increased permeability of the alveolar-capillary barrier lead to elevated serum KL-6 levels. For example, elevated serum KL-6 levels have been noted in idiopathic pulmonary fibrosis and connective tissue disease-associated interstitial lung diseases, making it a valuable biomarker for both diagnosis and prognosis [9]. Additionally, increased serum KL-6 levels are also associated with radiation pneumonitis and drug-induced interstitial lung disease in patients with lung cancer [10,11]. Accordingly, we performed this study to determine the associations between baseline serum KL-6 levels and the occurrence of PD-1/PD-L1 inhibitor-related pneumonitis, as well as between serial changes in serum KL-6 levels and pneumonitis.

Materials and Methods

Results

A total of 22 patients initially consented to participate in the study. One individual withdrew soon after providing informed consent, and another three did not commence PD-1/PD-L1 inhibitor therapy. As a result, the study analyzed data from 18 patients, with pneumonitis occurring in 11 of them (Figure 1).

Fig. 1.

Flow chart. PD-1/PD-L1: programmed cell death 1/programmed cell death ligand 1.

1. Baseline characteristics

The median ages were 69 years for the pneumonitis group and 73 years for the non-pneumonitis group. All patients in the pneumonitis group (n=11) were male, while five of the seven patients in the non-pneumonitis group were male. The prevalence of smoking history and underlying lung disease was similar in both groups. In the pneumonitis cohort, squamous cell carcinoma was the predominant histologic type (n=6, 54.5%), whereas adenocarcinoma was more common in the non-pneumonitis group (n=5, 71.4%). Stage III disease was observed more frequently in the pneumonitis group (n=7, 63.6%), while stage IV disease was more prevalent in the non-pneumonitis group (n=6, 85.7%). The diffusion capacity of the lungs for carbon monoxide was numerically higher in the pneumonitis group (61% vs. 53%, p=0.791). Although baseline KL-6 levels appeared higher in the non-pneumonitis group, this difference was not statistically significant (261 U/mL vs. 373 U/mL, p=0.375). Further baseline details are provided in Table 1.

Table 1.

Baseline characteristics

Patients in the pneumonitis group were more likely to have received prior chemotherapy or radiotherapy, although these differences did not reach statistical significance (81.8% vs. 42.9%, p=0.141; 72.7% vs. 42.9%, p=0.332). In the pneumonitis group, the median duration from the latest chemotherapy or radiotherapy to the onset of pneumonitis was 126 and 121 days, respectively. Durvalumab was the most frequently used PD-1/PD-L1 inhibitor in the pneumonitis group (63.6%), while pembrolizumab was predominantly administered in the non-pneumonitis group (57.1%). In the non-pneumonitis group, two patients underwent combination chemotherapy with PD-1/PD-L1 inhibitors, whereas no patients in the pneumonitis group did (Table 2).

Table 2.

Treatment history and KL-6 measurement intervals

2. Serial changes of KL-6

Changes in serum KL-6 levels exhibited distinct patterns between the two groups (Figure 2 and Supplementary Figure S1). In the pneumonitis group, serum KL-6 levels generally showed an upward trend. In contrast, the non-pneumonitis group did not exhibit a clear overall change, with some patients experiencing reductions while others showed increases. In the linear mixed-effects model, the time × group interaction for log-transformed KL-6 did not reach statistical significance (p=0.113). Additionally, an exploratory receiver operating characteristic analysis evaluating the predictive value of KL-6 changes for pneumonitis also failed to yield statistically significant results (Supplementary Figure S2). The KL-6 levels for each individual patient in both groups are detailed in Supplementary Tables S1, S2.

Fig. 2.

Serial change of Krebs von den Lungen-6 (KL-6) levels after programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitor therapy in the pneumonitis group (A) and in the non-pneumonitis group (B). Each line represents an individual patient, and the numbers displayed to the right of each trajectory correspond to patient identifiers.

3. Clinical profile of PD-1/PD-L1 inhibitor-related pneumonitis

KL-6 measurements at the onset of pneumonitis were available for five of the 11 patients, with a median value of 412 U/mL. All these patients showed an increase in KL-6 compared to their baseline levels at pneumonitis onset. The median duration from the initiation of PD-1/PD-L1 inhibitor therapy to pneumonitis onset was 48 days. Among these patients, eight experienced mild to moderate pneumonitis, while three had severe or life-threatening cases. CT imaging patterns were analyzed in 10 patients. Five of these patients exhibited localized infiltrates and all had previously received concurrent chemoradiotherapy before PD-1/PD-L1 inhibitor treatment (durvalumab). Among this group, four had main clinically relevant cancer lesions located in the right upper lobe, left lower lobe, right upper lobe, and right middle lobe, respectively, with their pneumonitis infiltrates corresponding to these lobes. The remaining patient had mediastinal lymph nodes (left subaortic and lower paratracheal nodes) as the main cancer site, while localized pneumonitis infiltrates were observed in both upper lobes. The other five patients presented with diffuse infiltrates: two were classified as having an acute interstitial pneumonia pattern, one as an organizing pneumonia pattern, and two as a nonspecific interstitial pneumonia/organizing pneumonia pattern (Figure 3). Both patients with nonspecific interstitial pneumonia/organizing pneumonia pattern had previously undergone radiotherapy. The main clinically relevant cancer lesions were located in the right lower lobe and left upper lobe, respectively. The patient with right lower lobe lesion showed infiltrates affecting the entire right lung, while the other with left upper lobe lesion primarily exhibited infiltrates in both lower lobes. Corticosteroid therapy was administered to seven patients, and four required hospitalization. One patient ultimately died after developing pneumonitis and undergoing mechanical ventilation. However, the primary cause of death was likely liver failure due to PD-1/PD-L1 inhibitor-related liver injury (Table 3).

Fig. 3.

Interstitial lung disease pattern on chest computed tomography. (A) Acute interstitial pneumonia pattern. (B) Organizing pneumonia pattern. (C) Nonspecific interstitial pneumonia/organizing pneumonia pattern.

Table 3.

Clinical profile of PD-1/PD-L1 inhibitor-related pneumonitis

Discussion

In this study, we compared KL-6 levels between patients who developed PD-1/PD-L1 inhibitor-related pneumonitis and those who did not. Baseline KL-6 levels were similar in both groups. However, serial evaluations revealed a progressive increase in KL-6 levels in the pneumonitis group. While the results did not achieve statistical significance, the study’s strength lies in its prospective design, which involved a cohort of patients treated with PD-1/PD-L1 inhibitors, monitored the incidence of pneumonitis, and assessed changes in KL-6 over time. Conflicting reports have addressed the relationship between baseline KL-6 levels and the subsequent development of pneumonitis. For instance, a study conducted in Korea found no correlation between baseline KL-6 levels and drug-induced pneumonitis, although it lacked detailed information about the specific drugs used [13]. Another investigation from Japan found no significant difference in the incidence of ICI-related pneumonitis between groups with high and low baseline KL-6 levels [14]. In contrast, research involving patients with different types of cancer found that baseline KL-6 levels were predictive of ICI-related pneumonitis [15]. Furthermore, in patients treated with ICI after radiotherapy, baseline KL-6 levels were correlated with the severity of pneumonitis [16]. It should be noted that KL-6 levels are influenced by a variety of factors. Prior studies indicated that both histologic subtype and cancer stage affect baseline KL-6 levels [13,14]. In our cohort, baseline KL-6 levels were numerically higher in the group without pneumonitis, which had a larger proportion of adenocarcinoma and stage IV cases. These findings suggest that baseline KL-6 levels may have limited predictive value for the onset of PD-1/PD-L1 inhibitor-related pneumonitis.

A key finding of this study is that changes in KL-6 levels over time varied based on the development of PD-1/PD-L1 inhibitor-related pneumonitis. There has been limited research on the relationship between fluctuations in KL-6 levels and ICI-related pneumonitis. A retrospective analysis of 118 patients with NSCLC showed a significant increase in KL-6 levels following the onset of ICI-pneumonitis [17]. Additionally, a cohort study involving 631 patients with solid tumors, including 174 with lung cancer, found that the increase in KL-6 levels from baseline was more pronounced in patients who developed pneumonitis compared to those who did not [18]. Conversely, another study found that KL-6 levels did not significantly increase after the onset of pneumonitis; however, the small sample sizes limited the study’s interpretability [19]. Therefore, monitoring serial changes in KL-6 levels may help facilitate the early identification of pneumonitis.

This study has several limitations. First, the small sample size hindered our ability to identify statistical significance and conduct comprehensive subgroup analyses. This limitation also restricted further exploration of potential clinical factors, such as disease stage, histologic subtype, and treatment differences (e.g., prior radiotherapy or type of ICI). Second, there were significant missing values during follow-up, and onset KL-6 values were available for only five of the 11 patients. These issues, combined with the limited sample size, further constrained our analysis and interpretation of the relationship between KL-6 changes and pneumonitis. Consequently, our conclusions should be regarded as preliminary and serve as a foundation for future research. Third, a considerable number of patients had previously received radiotherapy, likely reflecting the high prevalence of stage III disease in the cohort. Specifically, six patients in the pneumonitis group received durvalumab after concurrent chemoradiotherapy, five of whom exhibited localized infiltrates, making it challenging to exclude the possibility of radiation pneumonitis. However, for patients exposed to multiple therapies, distinguishing between drug-induced and radiation-induced pneumonitis based solely on localized radiological findings proves to be difficult [20,21]. Fourth, in the pneumonitis group, KL-6 levels were measured every 1–2 weeks, which may have resulted in an overestimation of changes. In contrast, the non-pneumonitis group had longer measurement intervals, limiting the ability to detect variations in KL-6 levels. Despite this, the overall upward trend of KL-6 in the pneumonitis group suggests a possible link to the development of pneumonitis.

In conclusion, our data indicate that baseline KL-6 levels may not be reliable predictors of PD-1/PD-L1 inhibitor-related pneumonitis. However, an increase in KL-6 values from baseline appears to occur in patients who develop pneumonitis. Therefore, evaluating serum KL-6 levels before the initiation of PD-1/PD-L1 inhibitors, and comparing them with levels obtained at the onset of respiratory symptoms and pulmonary infiltrates may provide valuable insight for diagnosing of PD-1/PD-L1 inhibitor-related pneumonitis. Further large-scale, prospective studies with rigorous methodology are necessary to validate the hypothesis suggested by our current findings.

Supplementary Material

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