ABSTRACT
The objective of this study was to investigate the clinical and imaging features of tepotinib‐induced interstitial lung disease (ILD) using real‐world data obtained during routine clinical use of tepotinib in Japan. The study was conducted as a voluntary safety‐monitoring activity and targeted cases reported during the period from 1st June 2020 (the launch date of tepotinib in Japan) to 31st December 2023. An ILD adjudication committee, composed of external respiratory and radiology experts, assessed the clinical and imaging features of the ILD. The committee expertly identified 35 patients with tepotinib‐induced ILD, with an estimated reported incidence of 2.9% (35/1190 patients). The estimated reported incidence of the fatal ILD was 0.9% (11/1190 patients). More than half of the ILDs were classified as ≤grade 2 (19/35 patients), with the predominant imaging pattern of organizing pneumonia (OP) (15/19 patients), followed by hypersensitivity pneumonitis (HP) and diffuse alveolar damage (DAD) patterns (3 and 1/19 patients, respectively). In contrast, among the ≥grade 3 ILDs (15/35 patients), DAD was the most frequently observed pattern (7/15 patients), followed by OP and HP patterns (6 and 2/15 patients, respectively). The median time to onset of the 35 ILDs from the start of tepotinib administration was 50.0 days (range: 4–205 days). Fatal outcomes occurred more frequently in patients with pre‐existing ILD/interstitial lung abnormality (ILA) (8/12 patients), whereas most patients without pre‐existing ILD/ILA experienced better outcomes of recovered/resolving (19/23 patients). These findings highlight the importance of close monitoring for ILD occurrence during the real‐world clinical use of tepotinib.
Keywords: clinical and imaging features, interstitial lung disease, Japan, post‐marketing setting, tepotinib
This article reports on the clinical and imaging features of tepotinib‐induced interstitial lung disease (ILD), which were evaluated by an ILD adjudication committee composed of external respiratory and radiology experts, and the committee expertly identified 35 patients with tepotinib‐induced ILD from spontaneous adverse event reports accumulated in the company's pharmacovigilance database in Japan. There were no notable differences in the characteristics of tepotinib‐induced ILDs, such as the incidence, onset timing, imaging features, patterns, treatment response, and prognosis, compared with previously reported characteristics of EGFR and ALK tyrosine kinase inhibitors‐induced ILDs.
Abbreviations
- ADR
adverse drug reaction
- ALK
anaplastic lymphoma kinase
- CTCAE
Common Terminology Criteria for Adverse Events
- DAD
diffuse alveolar damage
- EGFR
epidermal growth factor receptor
- GVP
Good Vigilance Practice
- HP
hypersensitivity pneumonitis
- ICI
immune checkpoint inhibitor
- ILA
interstitial lung abnormality
- ILD
interstitial lung disease
- NSCLC
non‐small cell lung cancer
- NSIP
non‐specific interstitial pneumonia
- OP
organizing pneumonia
- PMS
post‐marketing surveillance
- SD
standard deviation
- TKI
tyrosine kinase inhibitor
1. Introduction
Genomic aberrations in EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, NTRK and HER2 have been characterized as oncogenic drivers for non‐small cell lung cancer (NSCLC), and the therapeutic use of tyrosine kinase inhibitors (TKIs) targeting these drivers has been developed and commercialized, leading to a paradigm shift in NSCLC treatment [1]. Among oncogenic drivers, MET exon 14 skipping occurs in 3%–4% of patients with NSCLC [2, 3].
Tepotinib, a potent, highly selective, orally available, once‐daily type Ib MET TKI, has demonstrated durable antitumor activity in patients with advanced NSCLC harboring MET exon 14 skipping, with a low frequency of treatment discontinuation in a pivotal, global phase II VISION study [4, 5]. Subgroup analyses of Japanese patients in the VISION study also showed robust and durable clinical efficacy of tepotinib, along with a manageable safety profile [6, 7]. Tepotinib received regulatory approval for the treatment of unresectable, advanced or recurrent NSCLC with MET exon 14 skipping alterations in March 2020 [8], and launched in June 2020 in Japan ahead of other countries and regions.
Interstitial lung disease (ILD), such as pneumonitis and pulmonary fibrosis, is considered to be relatively rare, but occasionally seen as a fatal drug‐induced complication of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) TKIs used for the treatment of NSCLC [9, 10, 11]. The MET tyrosine kinase receptor and its ligand, hepatocyte growth factor, are involved in tissue remodeling, and MET signaling exerts trophic activity that attenuates tissue damage and promotes organ regeneration [12]. Therefore, inhibition of MET signaling by tepotinib has been suggested as a mechanism for MET TKI‐induced ILD. At the time of approval application in Japan, the incidence of ILD‐related events including pneumonitis, ILD, and acute respiratory failure in the VISION study was 5/130 patients in the overall population, and 2/17 patients in the Japanese subgroup [13]. ILD is considered a key risk factor associated with tepotinib and is included in the Japanese Risk Management Plan.
Immediately after the launch of tepotinib in Japan, the incidence of ILD in general clinical practice was reported as 7.5% of patients in post‐marketing surveillance (PMS) of tepotinib [14]. However, the clinical and imaging features of MET TKI‐induced ILD, including tepotinib, remain unclear. Therefore, to ensure the appropriate use of tepotinib, an ILD adjudication committee, composed of external respiratory and radiology experts, was established as a voluntary safety‐monitoring initiative to assess these features of tepotinib‐induced ILD in a post‐marketing setting in Japan.
2. Materials and Methods
2.1. Study Design and Patients
The objective of this study was to investigate the clinical and imaging features of tepotinib‐induced ILD using real‐world data obtained during the routine clinical use of tepotinib in Japan. The study was conducted as a voluntary safety‐monitoring activity and targeted cases reported during the period from 1st June 2020 (the launch date of tepotinib in Japan) to 31st December 2023 (3.5 years after the launch). This study included post‐marketing cases of ILD in Japan, identified through spontaneous reports following tepotinib administration, for which both radiological images and supplementary clinical information were available. The data were based on spontaneous adverse event reports accumulated in the company's pharmacovigilance database under the Good Vigilance Practice (GVP) in Japan.
2.2. Study Assessments
An expert analysis of tepotinib‐induced ILD was voluntarily performed by an ILD Adjudication Committee composed of two respiratory and two radiology experts. The committee was established to evaluate the appropriateness of the diagnosis and its causal relationship with tepotinib. The ILD Adjudication Committee comprehensively assessed individual patient data, including chest imaging, with suspected ILD‐like events reported by local physicians. The assessment was based on clinical course, symptoms, and laboratory tests, as well as imaging findings at baseline, onset and most recently, at outcome. These data were comprehensively reviewed to determine the appropriateness of the diagnosis and its causal relationship with tepotinib. The committee also graded the severity of each ILD according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 [15], and evaluated the response to steroid treatment. Radiographic imaging patterns of ILD were classified as diffuse alveolar damage (DAD), organizing pneumonia (OP), hypersensitivity pneumonitis (HP), non‐specific interstitial pneumonia (NSIP) or other patterns, in accordance with the Japanese guidelines for the management of drug‐induced lung disease [16]. The definitions of outcomes for tepotinib‐induced ILD were as follows: Recovered: symptoms fully resolved, new abnormal shadows on chest CT fully disappeared, and only slight shadows were present but considered not to affect respiratory function, Resolving: symptoms fully resolved or improved, and new abnormal shadows on chest CT were still present but improved, Fatal: death caused by ILD or pneumonitis [17]. The data for each patient were summarized, and the clinical and imaging features of tepotinib‐induced ILD were analyzed. Pre‐existing ILD/interstitial lung abnormality (ILA) before the start of tepotinib administration was defined as the ILD history and comorbidity reported by local physicians as well as the interstitial changes at baseline computed tomography assessed by the ILD Adjudication Committee.
2.3. Statistical Analysis
Descriptive statistics were used to summarize the findings because of the spontaneous reporting nature of the data and the small sample size. The mean, standard deviation (SD), median, minimum, and maximum were calculated for continuous variables, and the frequency number and proportion were calculated for categorical variables. The data was tabulated using Microsoft Excel.
3. Results
3.1. Patient Disposition
Forty‐three patients with ILD‐like events were reported by local physicians as part of voluntary safety monitoring activities from 1st June 2020 to 31st December 2023. Among them, 35 patients were expertly identified as having tepotinib‐induced ILD by the ILD Adjudication Committee, as shown in Figure 1. An estimated 1190 patients were treated with tepotinib during this period, assuming that they were the same population enrolled in the PMS (all‐case survey) of tepotinib in Japan [14] from June 2020 to September 2023. Therefore, the estimated reported incidence of tepotinib‐induced ILD was 2.9% (35/1190 patients) (Figure S1).
FIGURE 1.
Flow diagram to identify patients with tepotinib‐induced ILD. aThe number of patients enrolled in the post‐marketing survey of tepotinib in Japan from June 2020 to September 2023. ILD, interstitial lung disease.
3.2. Characteristics of Patients With ILD
Among the 35 patients identified with tepotinib‐induced ILD, 65.7% were male, and the median age was 76 years. Many patients had clinical characteristics such as an Eastern Cooperative Oncology Group performance status of 2 or 3 (40.0%), smoking history (65.7%), and 1st line treatment with tepotinib (62.9%). Prior immune checkpoint inhibitor (ICI) treatment had been administered to 22.9% of the patients. Interstitial changes at baseline CT were assessed by the ILD Adjudication Committee, and eight patients had abnormalities (Table 1), including seven patients with an imaging pattern of ILA and one patient with NSIP.
TABLE 1.
Characteristics of patients with ILD.
| Characteristic | Classification | Statistics/n (%) | |
|---|---|---|---|
| Number of patients with ILD | 35 | ||
| Sex | Male | 23 | (65.7) |
| Female | 12 | (34.3) | |
| Age, years | Median (min–max) | 76 (60–87) | |
| < 75 | 16 | (45.7) | |
| ≥ 75 | 19 | (54.3) | |
| ECOG PS | 0 | 7 | (20.0) |
| 1 | 14 | (40.0) | |
| 2 | 7 | (20.0) | |
| 3 | 7 | (20.0) | |
| Smoking history | No | 12 | (34.3) |
| Yes | 23 | (65.7) | |
| Treatment line | 1st | 22 | (62.9) |
| ≥ 2nd | 12 | (34.3) | |
| Unknown | 1 | (2.9) | |
| Prior ICI treatment | Yes a | 8 | (22.9) |
| History of thoracic radiotherapy | No | 27 | (77.1) |
| Yes | 8 | (22.9) | |
| Pre‐existing ILD/ILA b | No | 23 | (65.7) |
| Yes | 12 | (34.3) | |
| ILD history/comorbidity | No | 28 | (80.0) |
| Yes | 7 | (20.0) | |
| Interstitial changes at baseline CT | No | 27 | (77.1) |
| Yes | 8 | (22.9) | |
Abbreviations: CT, computed tomography; ECOG PS, Eastern Cooperative Oncology Group performance status; ICI, immune checkpoint inhibitor; ILA, interstitial lung abnormality; ILD, interstitial lung disease; max, maximum; min, minimum.
Includes 3 patients with combined ICI and chemotherapy.
Pre‐existing ILD/ILA before the start of tepotinib administration was defined as the ILD history and comorbidity reported by local physicians as well as the interstitial changes at baseline CT assessed by the ILD Adjudication Committee.
3.3. ILD Severity and Imaging Pattern
The ILD Adjudication Committee evaluated the severity of tepotinib‐induced ILD using the CTCAE grade for the most severe ILD event, and the radiographic imaging pattern for the ILD. The number of patients with each ILD imaging pattern is stratified according to disease severity, as shown in Figure 2. More than half of the ILDs were classified as grade 2 or lower (19/35 patients), with the predominant imaging pattern of OP (15/19 patients), followed by HP and DAD patterns (3 and 1/19 patients, respectively). In contrast, among the ILDs classified as grade 3 or higher (15/35 patients), the DAD pattern was most frequently observed (7/15 patients), followed by OP and HP patterns (6 and 2/15 patients, respectively). No NSIP or other patterns were observed.
FIGURE 2.
ILD severity and imaging pattern. aOne fatal case was not evaluable for the ILD severity by the ILD Adjudication Committee, because an exacerbation of the primary disease was significant, and ILD (grade 2, non‐serious at the onset) was unlikely to be the cause of death. DAD, diffuse alveolar damage; HP, hypersensitivity pneumonitis; ILD, interstitial lung disease; OP, organizing pneumonia.
3.4. ILD Outcomes
The outcomes of tepotinib‐induced ILD were evaluated in 35 patients over a median follow‐up period of 35.0 days (range: 6–127 days). The outcomes were recovered or resolving in 23 patients, and fatal in 11 patients (Table 2). The estimated reported incidence of the fatal ILD was 0.9% (11/1190 patients) (Figure S1).
TABLE 2.
ILD outcomes.
| Outcome | n |
|---|---|
| Number of patients with ILD | 35 |
| Recovered | 12 |
| Resolving | 11 |
| Fatal | 11 |
| Not evaluable a | 1 |
Abbreviation: ILD, interstitial lung disease.
One death was not evaluable for the ILD outcome by the ILD Adjudication Committee, because an exacerbation of the primary disease was significant, and ILD (grade 2, non‐serious at the onset) was unlikely to be the cause of death.
3.5. Time to Onset of ILD and Outcome
Among the 35 patients with ILD, the median time to onset of the ILD from the start of tepotinib administration was 50.0 days (range: 4–205 days). The time to onset was within 4 and 8 weeks in 12 and 23 patients, respectively (Figure 3). Of the 11 patients with a fatal outcome, 7 and 9 patients developed the ILD within 8 and 12 weeks, respectively.
FIGURE 3.
Time to onset of ILD, and outcome. aOne fatal case was not evaluable for the ILD outcome by the ILD Adjudication Committee, because an exacerbation of the primary disease was significant, and ILD (grade 2, non‐serious at the onset) was unlikely to be the cause of death. ILD; interstitial lung disease.
3.6. ILD Imaging Patterns and Outcomes
The number of patients with each outcome (Table 2) was stratified according to imaging pattern, as shown in Figure 4. The worst outcome frequently occurred in patients with the DAD pattern, with 5/8 patients experiencing a fatal outcome. Otherwise, patients with OP and HP patterns had better outcomes of recovered/resolving frequently in 16/22 patients and 4/5 patients, respectively. The median time to onset of the ILD from the start date of tepotinib administration was 59.5, 49.5, and 66.0 days in patients with DAD, OP, and HP patterns, respectively. The median time to recovered/resolving was 31.0, 69.5, and 46.5 days in patients with DAD, OP, and HP patterns, respectively.
FIGURE 4.
ILD imaging patterns, and outcomes. aOne fatal case was not evaluable for the ILD outcome by the ILD Adjudication Committee, because an exacerbation of the primary disease was significant, and ILD (grade 2, non‐serious at the onset) was unlikely to be the cause of death. DAD, diffuse alveolar damage; HP, hypersensitivity pneumonitis; ILD, interstitial lung disease; OP, organizing pneumonia.
3.7. ILD Severity and Outcomes
The number of patients with each outcome (Table 2) was stratified by ILD severity at the time of the worst outcome, as shown in Figure 5. Grade 4 or lower ILDs were observed in 23/35 patients, and the outcome in all 23 patients was resolving or recovered.
FIGURE 5.
ILD severity, and outcomes. aOne fatal case was not evaluable for the ILD outcome by the ILD Adjudication Committee, because an exacerbation of the primary disease was significant, and ILD (grade 2, non‐serious at the onset) was unlikely to be the cause of death. The severity of the ILD was graded at the time of the worst. ILD, interstitial lung disease.
3.8. Pre‐Existing ILD/ILA at Baseline and ILD Outcome
Among the 35 patients with ILD, the number of patients with each outcome was stratified by pre‐existing ILD/ILA confirmed by local physicians and/or the committee, as shown in Figure 6. Patients with pre‐existing ILD/ILA had worse outcomes, with fatal events occurring frequently in 8/12 patients. Among these 12 patients, eight patients had interstitial changes at baseline CT, which were assessed by the ILD Adjudication Committee (Table 1). The outcomes of these eight patients were fatal in 5/7 patients with imaging pattern of ILA and 1/1 patient with NSIP. The other four patients had no interstitial changes at baseline CT, but had an ILD history and comorbidity reported by local physicians, with a fatal outcome in 2/4 patients. In contrast, patients without pre‐existing ILD/ILA had better outcomes, with recovered/resolving events occurring frequently in 19/23 patients.
FIGURE 6.
Pre‐existing ILD/ILA at baseline and ILD outcome. aOne fatal case was not evaluable for the ILD outcome by the ILD Adjudication Committee, because an exacerbation of the primary disease was significant, and ILD (grade 2, non‐serious at the onset) was unlikely to be the cause of death. Pre‐existing ILD/ILA before the start of tepotinib administration was defined as the ILD history and comorbidity reported by local physicians as well as the interstitial changes at baseline CT assessed by the ILD Adjudication Committee. CT, computed tomography; ILA, interstitial lung abnormality; ILD, interstitial lung disease.
3.9. Typical Radiographic ILD Imaging Pattern
Typical radiographic images of DAD, OP, and HP patterns of tepotinib‐induced ILD are shown in Figure 7A–E. Diffuse ground‐glass opacities were observed in both lungs with the DAD pattern, accompanied by traction bronchiectasis in the left upper lobe and worsening lymphangiosis carcinomatosa in the left lower lobe (A). More widespread ground‐glass opacities were present bilaterally throughout the lungs, with internal reticular opacities and traction bronchiectasis in another patient (B). In the OP pattern, the tumor in the left lung shrank, pleural effusion decreased, and consolidation and ground‐glass opacities were observed in the peripheral zones of the right lower lobe (C). Patchy consolidations and ground‐glass opacities were observed bilaterally in the peripheral zones in another patient (D). In the HP pattern, widespread ground‐glass opacities were observed in the right lung, and the tumor had shrunk (E).
FIGURE 7.
Typical radiographic ILD imaging pattern. DAD, diffuse alveolar damage; HP, hypersensitivity pneumonitis; OP, organizing pneumonia.
3.10. Corticosteroid Treatment and ILD Outcome
Tepotinib‐induced ILD required corticosteroid treatment and the outcomes by ILD imaging pattern are shown in Table 3. Corticosteroids were administered to all 8 patients with DAD‐pattern ILD and to 20/27 patients with OP/HP‐pattern ILD. Methyl prednisolone infusions were administered to 7/8 patients with DAD‐pattern ILD, and 5/7 patients had fatal outcomes. In 7 patients with tepotinib‐induced ILD who did not receive corticosteroids, all outcomes were recovered/resolving without additional treatment.
TABLE 3.
Corticosteroid treatment and ILD outcome.
| Treatment | ILD outcomes | DAD pattern n | OP/HP patterns n |
|---|---|---|---|
| Number of patients with ILD | 8 | 27 | |
| Oral PSL only | Recovered | 1 | 5 |
| Resolving | 0 | 6 | |
| Not evaluable a | 0 | 1 | |
| mPSL infusion only | Fatal | 1 | 1 |
| mPSL infusion + oral PSL | Recovered | 0 | 1 |
| Resolving | 2 | 1 | |
| Fatal | 4 | 5 | |
| No corticosteroids | Recovered | 0 | 5 |
| Resolving | 0 | 2 |
Abbreviations: DAD, diffuse alveolar damage; HP, hypersensitivity pneumonitis; ILD, interstitial lung disease; mPSL, methyl prednisolone; OP, organizing pneumonia; PSL, prednisolone.
One death was not evaluable for the ILD outcome by the ILD Adjudication Committee, because an exacerbation of the primary disease was significant, and ILD (grade 2, non‐serious at the onset) was unlikely to be the cause of death.
3.11. Re‐Administration of Tepotinib in Patients With Tepotinib‐Induced ILD
Although re‐administration of tepotinib after ILD onset is not recommended [18], 4 of the 35 patients with tepotinib‐induced ILD were re‐treated, and the committee evaluated ILD recurrence after re‐administration (Table 4). In all four patients, the outcomes of the ILD prior to re‐administration had been recovered/resolving, with ILD severity of grade 1 or 2, and no ILD recurrence was observed after re‐administration.
TABLE 4.
Re‐administration of tepotinib in patients with tepotinib‐induced ILD.
| ILD outcomes | Grade in severity | Seriousness a | Time to re‐administration from the outcome evaluation | Duration of re‐administration | ILD recurrence b |
|---|---|---|---|---|---|
| Resolving | 2 | No | 0 day | Unknown | No |
| Resolving | 1 | No | 1 day | 4 months | No |
| Resolving | 2 | Yes | 8 days | 3 months | No |
| Recovered | 1 | No | 101 days | 8 months | No |
Abbreviation: ILD, interstitial lung disease.
Assessed by local physicians based on International Conference on Harmonization standards.
Assessed by the ILD Adjudication Committee.
4. Discussion
Recently, the importance of spontaneous reporting initiatives in PMS for suspected adverse drug reactions (ADRs) of medicines has been highlighted [19]. ADR reports from pharmaceutical companies, including spontaneous reports, are utilized in various situations to implement safety measures for the reported ADR. Additionally, analysis of spontaneous reports of rare ADRs may further contribute to a deeper understanding of these events, thereby promoting the appropriate use of medicines. Tepotinib, a potent, highly selective, orally available, once‐daily type Ib MET TKI, was approved in March 2020 in Japan as a therapeutic option for patients with advanced NSCLC harboring MET exon 14 skipping mutations. However, MET TKIs may be associated with the risk of developing ILD, a relatively rare but potentially fatal drug‐induced complication, as reported for other TKIs [9, 10, 11]. An ILD adjudication committee composed of external respiratory and radiology experts was established as a voluntary safety monitoring initiative for tepotinib. The committee investigated the clinical and imaging features of tepotinib‐induced ILD and its estimated reported incidence in real‐world clinical practice in Japan.
In real‐world clinical use of tepotinib from June 2020 to December 2023, the committee voluntarily collected data from 43 patients with ILD‐like events reported by local physicians, and expertly identified 35 patients with tepotinib‐induced ILD. During almost the same period, registration forms were collected for 1190 patients in the PMS (all‐case survey) of tepotinib. Therefore, the estimated reported incidence of tepotinib‐induced ILD was 2.9% (35/1190 patients), although interpretive attention should be paid to the possibility that the estimated reported incidence may have been underestimated due to limited spontaneous reporting. In the pivotal phase II VISION study of tepotinib, the incidence of ILD‐related events has been reported to be 3.8% (5/130 patients) in the global population, and 11.8% (2/17 patients) in the Japanese subgroup at the time of new drug application for tepotinib in 2019 in Japan [13]. Le X et al. later updated the ILD incidence to 2.4% (6/255 patients) by analyzing a clinically relevant subgroup in the global population of the VISION study in 2022 [20]. In 2024, Morise M et al. report tepotinib‐induced ILD in 10.5% (4/38 patients) of Japanese patients enrolled in the VISION study and followed‐up for over 18 months [7]. Thus, in spontaneous safety monitoring of tepotinib‐induced ILD, the estimated reported incidence in real‐world clinical settings did not substantially exceed that reported in the phase II clinical trial of tepotinib.
Previously reported incidences of EGFR and ALK TKIs‐induced ILD vary widely across published studies and investigated TKIs. The incidence of ILD with EGFR TKIs such as gefitinib, erlotinib, and osimertinib has been reported at 3%–18% of Japanese patients, which is substantially higher than that in Caucasians [21, 22, 23, 24]. According to reports from the FDA's Adverse Event Reporting System from 2011 to 2023, ILD is reported in 3.2% (range: 1.8%–4.4%) of users of the 5 ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib) [25]. Gemma, A et al. report that the incidence of ILD associated with crizotinib therapy is 5.77% among Japanese patients with NSCLC [26]. Thus, the estimated reported incidence of tepotinib‐induced ILD in real‐world clinical settings was not notably different from that previously reported for other TKIs such as EGFR and ALK TKIs. However, careful caution is required when interpreting comparisons of the ILD incidences among MET, EGFR, and ALK TKIs. The population with MET exon 14 skipping is reported to have patient characteristics associated with higher risks of ILD incidence than those with EGFR mutation and ALK rearrangement, presenting that the median age is 72, 57–64, and 50–56 years; median proportion of ever smoker is 53%, 7%–37%, and 35%–38% in population with MET exon 14 skipping, EGFR mutation, and ALK rearrangement, respectively [27, 28]. Consistent with these findings, median age in 35 patients was 76 years and 65.7% had a smoking history in our study, although we need to note that the incidence of tepotinib‐induced ILD in our study may have been underestimated due to limited spontaneous reporting. While some consideration must be given to these differences in patient characteristics, at least, it can be interpreted that the estimated reported incidence of tepotinib‐induced ILD does not notably exceed the incidence of ILD for EGFR and ALK TKIs. Other MET TKIs, including capmatinib and gumarontinib, may also pose an ILD induction risk based on clinical trial findings of these drugs although the data are limited [29, 30].
A database study of 20,516 patients with NSCLC in the FDA's Adverse Event Reporting System database reveals a higher incidence of interstitial pneumonitis in those treated with ICI, nivolumab in combination with EGFR TKI than that in those treated with either drug alone [31]. The authors emphasize the need to better understand the risks associated with combining ICIs with different classes of antitumor agents, whether administered concomitantly or sequentially. Although the committee did not evaluate risk factors for tepotinib‐induced ILD in this study, prior ICI treatment was received in 22.9% of the patients with the ILD. The PMS result of tepotinib indicates that the incidence of ILD is similar regardless of the presence and absence of prior ICI treatment (10.5%; 6/57 patients vs. 5.6%; 5/90 patients) [14]. However, a previous real‐world study on osimertinib‐induced ILD suggests that a history of nivolumab use may be a risk factor for developing ILD [32], and nivolumab itself has also been reported to cause potentially fatal ILD [33]. One case report describes ILD development after sequential treatment with tepotinib after ICI treatment with durvalumab [34]. Although further data accumulation is needed to determine whether a prior ICI treatment is a risk factor for tepotinib‐induced ILD, tepotinib should be administered with caution in patients with a history of ICI treatment. Among patients with tepotinib‐induced ILD, those with pre‐existing ILD/ILA had a worse outcome of fatal frequently in 8/12 patients, in contrast, those without such characteristics had better outcomes of recovered/resolving frequently in 19/23 patients. These findings suggest that pre‐existing ILD/ILA may be a factor in poor prognosis. The PMS of tepotinib reports that pre‐existing ILD and concurrent complication are risk factors for the development of ILD, with 7/11 patients with ILD ADR having ILD as a condition or complication [14]. Thus, careful assessment for interstitial changes in lung is essential before initiating tepotinib treatment.
The committee evaluated the severity, radiographic imaging patterns, and outcomes of tepotinib‐induced ILD in 35 patients. The worst outcome occurred most frequently in patients with the DAD pattern, with 5/8 patients experiencing a fatal outcome. In contrast, patients with non‐DAD, OP, or HP patterns more frequently had favorable outcomes, with 20/27 patients experiencing outcomes of recovered/resolving. This prognostic trend of tepotinib‐induced ILD stratified by imaging pattern (DAD vs. non‐DAD) aligns with the descriptions in the Japanese guidelines for the management of drug‐induced lung disease [16]. A previously reported real‐world study of crizotinib‐induced ILD shows that 17/32 patients (53.1%) with the DAD pattern had fatal outcomes, compared with 3/54 patients (5.6%) with the non‐DAD patterns [26]. Similarly, a real‐world report on osimertinib‐induced ILD indicates that a higher proportion of patients with a DAD imaging pattern experienced fatal outcomes (14 of 25 patients [56.0%]) compared with those who had a non‐DAD pattern (8 of 178 patients [4.5%]) [32]. Thus, the prognostic impact of imaging patterns in tepotinib‐induced ILD is consistent with that reported for other TKIs.
In the analysis of the time to onset of tepotinib‐induced ILD, ILD occurred within 8 weeks of treatment initiation in 23/35 patients, and fatal ILD occurred within 12 weeks in 9/11 patients. These findings indicate that tepotinib‐induced ILDs, including fatal outcomes, tend to develop early after treatment initiation. This tendency is similar to that seen with other TKIs such as ALK TKIs and osimertinib in patients with lung cancer. According to FDA database analyses, the median time to onset of ILD associated with ALK TKIs of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib is 53 days, with over 70% of ILD cases occurring within the first 2 months [25]. A real‐world study in Japan also reports that 69.2% of crizotinib‐induced ILD cases occur within 8 weeks, and 82.6% of fatal outcomes develop within 10 weeks [26]. Similarly, real‐world data on osimertinib indicate median ILD onset time of 63.0 days [32]. These data suggest that, as with other TKIs, close monitoring for ILDs is particularly important during the early stages of tepotinib treatment.
Corticosteroids were administered to all 8 patients with tepotinib‐induced ILD who had the DAD pattern; however, five of these patients experienced fatal outcomes, indicating a poor prognosis associated with this imaging pattern. According to the committee, tepotinib was confirmed to be re‐administered after ILD onset in four patients who had ILD outcomes of recovered/resolving and ILD severity of grade 1 or 2, and no recurrence of ILD was observed in all four patients. Although the package insert of tepotinib stipulates that when ILD develops after the start of tepotinib treatment, the drug administration should be discontinued, regardless of the severity of the ILD [18], tepotinib was re‐administered in some patients with better outcomes of ILD in real‐world clinical practice. However, the data are limited in this study and more details will become clear in the future as additional data accumulate.
As for the limitation of this study, tepotinib‐induced ILD was evaluated by an organized expert committee based on safety data spontaneously reported by local physicians in real‐world clinical practice. Therefore, all possible cases of tepotinib‐induced ILD may not be included in this study. For reference, transition of ILD incidence based on the internal PMS data of tepotinib provided by Merck Biopharma Co. Ltd. is shown in Figure S1. To estimate incidence, the number of patients registered in PMS until September 2023 was used as the denominator, and the number of patients for which spontaneous ILD‐like events were reported was used as the numerator. Not all ILD occurring in post‐marketing may be covered, possibly leading to underestimation of the incidence. Continued monitoring of tepotinib‐induced ILD is therefore essential in the future. The follow‐up period for evaluating outcomes of tepotinib‐induced ILD was short in this study, with a median follow‐up period of 35.0 days. Long‐term outcome evaluation is warranted in the future study.
In conclusion, an ILD adjudication committee composed of external respiratory and radiology experts was established as a voluntary safety monitoring initiative for tepotinib, and the committee expertly identified 35 patients with tepotinib‐induced ILD in the post‐marketing setting of tepotinib use. The estimated reported incidence of the ILD was 2.9% (35/1190 patients), and that of the fatal ILD was 0.9% (11/1190 patients). There were no notable differences in the characteristics of tepotinib‐induced ILDs, such as estimated reported incidence, onset timing, imaging features, patterns, treatment response, and prognosis, compared with previously reported characteristics of EGFR and ALK TKIs‐induced ILDs. Pre‐existing ILD/ILA may be factors in poor prognosis. As ILD is designated as an “important identified risk” in the Risk Management Plan for tepotinib, continuous monitoring for ILD is essential in real‐world clinical use of tepotinib in the future.
Author Contributions
Terufumi Kato: conceptualization, methodology, investigation, validation, writing – review and editing. Tomohisa Baba: conceptualization, methodology, investigation, validation, writing – review and editing. Masahiro Endo: conceptualization, methodology, investigation, validation, writing – review and editing. Shehla Endo: conceptualization, methodology, validation, writing – review and editing, data curation. Eisuke Horii: conceptualization, methodology, validation, formal analysis, writing – review and editing, data curation. Masahiko Kusumoto: conceptualization, methodology, investigation, validation, writing – review and editing.
Funding
This study was sponsored by Merck Biopharma Co. Ltd., Tokyo, Japan, an affiliate of Merck KGaA (https://ror.org/0292awh62).
Ethics Statement
The study data is based on spontaneous adverse event reports accumulated in the company's pharmacovigilance database under Good Vigilance Practice (GVP) in Japan. Under this local regulation, the patients' data are anonymized. This retrospective study was conducted based on this database and under the conditions with no ethical problems in the Japanese regulatory framework.
Consent
The authors have nothing to report.
Conflicts of Interest
Terufumi Kato has received lecture and advisor fees from Merck Biopharma Co. Ltd., Tokyo, Japan, an affiliate of Merck KGaA, grants for clinical research from AbbVie, Amgen, Arrivent, AstraZeneca, Bayer, BeiGene, BluePrint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Haihe, Johnson & Johnson, Merck Biopharma Co. Ltd., Tokyo, Japan, an affiliate of Merck KGaA, MSD, Novartis, Novocure, Pfizer, Regeneron, and Takeda, consulting fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Merck Biopharma Co. Ltd., Tokyo, Japan, an affiliate of Merck KGaA, MSD, and Novocure, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Bristol Myers Squibb, Chugai, Eli Lilly, Novartis, Ono, Pfizer, and Takeda, and his spouse is employed at Eli Lilly. Tomohisa Baba has received lecture and advisor fees from Merck Biopharma Co. Ltd., Tokyo, Japan, an affiliate of Merck KGaA, consulting fees from Daiichi Sankyo and AstraZeneca, and honoraria for lectures from Daiichi Sankyo, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Bristol Myers Squibb, and Taiho Pharmaceutical. Masahiro Endo has received lecture and advisor fees from Merck Biopharma Co. Ltd., Tokyo, Japan, an affiliate of Merck KGaA. Shehla Endo and Eisuke Horii are employees of Merck Biopharma Co. Ltd., Tokyo, Japan, an affiliate of Merck KGaA. Masahiko Kusumoto has received grants or contracts from Canon Medical Systems Corporation, and consulting fees from Daiichi Sankyo.
Supporting information
Figure S1: Transition of ILD incidence in post‐marketing period in Japan.
Acknowledgments
The authors would like to thank all the physicians and healthcare professionals who cooperated with the survey and data collection. The authors also thank Mr. Akihiko Uegaki of Medical Professional Relations Inc for medical writing and editorial support with the fund from Merck Biopharma Co. Ltd., Tokyo, Japan, an affiliate of Merck KGaA.
Data Availability Statement
Any requests for data by qualified scientific and medical researchers for legitimate research purposes will be subject to Merck's Data Sharing Policy. All requests should be submitted in writing to Merck's data sharing portal (https://www.merckgroup.com/en/research/our‐approach‐to‐research‐and‐development/healthcare/clinical‐trials/commitment‐responsible‐data‐sharing.html). When Merck has a co‐research, co‐development, or co‐marketing or co‐promotion agreement, or when the product has been out‐licensed, the responsibility for disclosure might be dependent on the agreement between parties. Under these circumstances, Merck will endeavor to gain agreement to share data in response to requests.
References
- 1. Herrera‐Juárez M., Serrano‐Gómez C., Bote‐de‐Cabo H., and Paz‐Ares L., “Targeted Therapy for Lung Cancer: Beyond EGFR and ALK,” Cancer 129, no. 12 (2023): 1803–1820, 10.1002/cncr.34757. [DOI] [PubMed] [Google Scholar]
- 2. Rosell R. and Karachaliou N., “Large‐Scale Screening for Somatic Mutations in Lung Cancer,” Lancet 387, no. 10026 (2016): 1354–1356, 10.1016/S0140-6736(15)01125-3. [DOI] [PubMed] [Google Scholar]
- 3. Reungwetwattana T., Liang Y., Zhu V., and Ou S. I., “The Race to Target MET Exon 14 Skipping Alterations in Non‐Small Cell Lung Cancer: The Why, the How, the Who, the Unknown, and the Inevitable,” Lung Cancer 103 (2017): 27–37, 10.1016/j.lungcan.2016.11.011. [DOI] [PubMed] [Google Scholar]
- 4. Paik P. K., Felip E., Veillon R., et al., “Tepotinib in Non‐Small‐Cell Lung Cancer With MET Exon 14 Skipping Mutations,” New England Journal of Medicine 383, no. 10 (2020): 931–943, 10.1056/NEJMoa2004407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Mazieres J., Paik P. K., Garassino M. C., et al., “Tepotinib Treatment in Patients With MET Exon 14‐Skipping Non‐Small Cell Lung Cancer: Long‐Term Follow‐Up of the VISION Phase 2 Nonrandomized Clinical Trial,” JAMA Oncology 9, no. 9 (2023): 1260–1266, 10.1001/jamaoncol.2023.1962. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Sakai H., Morise M., Kato T., et al., “Tepotinib in Patients With NSCLC Harbouring MET Exon 14 Skipping: Japanese Subset Analysis From the Phase II VISION Study,” Japanese Journal of Clinical Oncology 51, no. 8 (2021): 1261–1268, 10.1093/jjco/hyab072. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Morise M., Kato T., Matsumoto S., et al., “Long‐Term Experience With Tepotinib in Japanese Patients With MET Exon 14 Skipping NSCLC From the Phase II VISION Study,” Cancer Science 115, no. 4 (2024): 1296–1305, 10.1111/cas.16107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Markham A., “Tepotinib: First Approval,” Drugs 80, no. 8 (2020): 829–833, 10.1007/s40265-020-01317-9. [DOI] [PubMed] [Google Scholar]
- 9. Dy G. K. and Adjei A. A., “Understanding, Recognizing, and Managing Toxicities of Targeted Anticancer Therapies,” CA: A Cancer Journal for Clinicians 63, no. 4 (2013): 249–279, 10.3322/caac.21184. [DOI] [PubMed] [Google Scholar]
- 10. Shah R. R., “Tyrosine Kinase Inhibitor‐Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic Dilemmas,” Drug Safety 39, no. 11 (2016): 1073–1091, 10.1007/s40264-016-0450-9. [DOI] [PubMed] [Google Scholar]
- 11. Costa R. B., Costa R. L. B., Talamantes S. M., et al., “Systematic Review and Meta‐Analysis of Selected Toxicities of Approved ALK Inhibitors in Metastatic Non‐Small Cell Lung Cancer,” Oncotarget 9, no. 31 (2018): 22137–22146, 10.18632/oncotarget.25154. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Trusolino L., Bertotti A., and Comoglio P. M., “MET Signaling Principles and Functions in Development, Organ Regeneration and Cancer,” Nature Reviews. Molecular Cell Biology 11, no. 12 (2010): 834–848, 10.1038/nrm3012. [DOI] [PubMed] [Google Scholar]
- 13. Merck Biopharma Co. Ltd ., Proper Use Guide of TEPMETKO Tablets 250 mg, https://www.hcpmrkjp.com/wp‐content/uploads/product/tpl_pug.pdf.
- 14. Kato T., Ogura T., Sato M., et al., “Safety and Effectiveness of Tepotinib in Patients With Unresectable, Advanced Orrecurrent Non‐Small Cell Lung Cancer With MET ex 14 Skipping Alterations: Post‐Marketing Surveillance in Japan,” Japanese Journal of Clinical Oncology 55, no. 10 (2025): 1152–1161, 10.1093/jjco/hyaf099. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. National Cancer Institute , Cancer Therapy Evaluation Program (Common Terminology Criteria for Adverse Events (CTCAE) v5.0, 2017), https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. [Google Scholar]
- 16. The Japanese Respiratory Society , The JRS Guidelines for the Management of Drug‐Induced Lung Disease, 2nd ed. (Medical Review Co. Ltd., 2018) [in Japanese]. [Google Scholar]
- 17. Baba T., Kusumoto M., Kato T., et al., “Clinical and Imaging Features of Interstitial Lung Disease in Cancer Patients Treated With Trastuzumab Deruxtecan,” International Journal of Clinical Oncology 28, no. 12 (2023): 1585–1596, 10.1007/s10147-023-02414-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Merck Biopharma Co. Ltd ., Package Insert for TEPMETKO Tablets 250 mg, https://hcp.merckgroup.com/content/dam/web/healthcare/medinfo/documents/tepmetko/tepmetko_insert_202005_JP.pdf.
- 19. Alomar M., Tawfiq A. M., Hassan N., and Palaian S., “Post Marketing Surveillance of Suspected Adverse Drug Reactions Through Spontaneous Reporting: Current Status, Challenges and the Future,” Therapeutic Advances in Drug Safety 11 (2020): 2042098620938595, 10.1177/2042098620938595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Le X., Sakai H., Felip E., et al., “Tepotinib Efficacy and Safety in Patients With MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups From the VISION Study With Relevance for Clinical Practice,” Clinical Cancer Research 28, no. 6 (2022): 1117–1126, 10.1158/1078-0432.CCR-21-2733. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Kudoh S., Kato H., Nishiwaki Y., et al., “Interstitial Lung Disease in Japanese Patients With Lung Cancer: A Cohort and Nested Case–Control Study,” American Journal of Respiratory and Critical Care Medicine 177, no. 12 (2008): 1348–1357, 10.1164/rccm.200710-1501OC. [DOI] [PubMed] [Google Scholar]
- 22. Gemma A., Kudoh S., Ando M., et al., “Final Safety and Efficacy of Erlotinib in the Phase 4 POLARSTAR Surveillance Study of 10,708 Japanese Patients With Non‐Small‐Cell Lung Cancer,” Cancer Science 105, no. 12 (2014): 1584–1590, 10.1111/cas.12550. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Ohe Y., Imamura F., Nogami N., et al., “Osimertinib Versus Standard‐Of‐Care EGFR‐TKI as First‐Line Treatment for EGFRm Advanced NSCLC: FLAURA Japanese Subset,” Japanese Journal of Clinical Oncology 49, no. 1 (2019): 29–36, 10.1093/jjco/hyy179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Sato Y., Sumikawa H., Shibaki R., et al., “Drug‐Related Pneumonitis Induced by Osimertinib as First‐Line Treatment for Epidermal Growth Factor Receptor Mutation‐Positive Non‐Small Cell Lung Cancer: A Real‐World Setting,” Chest 162, no. 5 (2022): 1188–1198, 10.1016/j.chest.2022.05.035. [DOI] [PubMed] [Google Scholar]
- 25. Dong J., Li L., Deng T., Song H., Zhang S., and Zhong M., “Interstitial Lung Disease Associated With ALK Inhibitors and Risk Factors: An Updated Comparative Pharmacovigilance Analysis,” Frontiers in Pharmacology 15 (2024): 1361443, 10.3389/fphar.2024.1361443. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Gemma A., Kusumoto M., Kurihara Y., et al., “Interstitial Lung Disease Onset and Its Risk Factors in Japanese Patients With ALK‐Positive NSCLC After Treatment With Crizotinib,” Journal of Thoracic Oncology 14, no. 4 (2019): 672–682, 10.1016/j.jtho.2018.11.022. [DOI] [PubMed] [Google Scholar]
- 27. Le X. and Heymach J. V., “New Verse for a Familiar Song: Small Molecule Inhibitors for MET Exon 14 Skipping Non‐Small Cell Lung Cancer,” Oncologist 25, no. 10 (2020): 822–825, 10.1634/theoncologist.2020-0760. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Mazieres J., Vioix H., Pfeiffer B. M., et al., “MET Exon 14 Skipping in NSCLC: A Systematic Literature Review of Epidemiology, Clinical Characteristics, and Outcomes,” Clinical Lung Cancer 24, no. 6 (2023): 483–497, 10.1016/j.cllc.2023.06.008. [DOI] [PubMed] [Google Scholar]
- 29. Wolf J., Seto T., Han J. Y., et al., “Capmatinib in MET Exon 14‐Mutated or MET‐Amplified Non‐Small‐Cell Lung Cancer,” New England Journal of Medicine 383, no. 10 (2020): 944–957, 10.1056/NEJMoa2002787. [DOI] [PubMed] [Google Scholar]
- 30. Yu Y., Zhou J., Li X., et al., “Gumarontinib in Patients With Non‐Small‐Cell Lung Cancer Harbouring MET Exon 14 Skipping Mutations: A Multicentre, Single‐Arm, Open‐Label, Phase 1b/2 Trial,” EClinicalMedicine 59 (2023): 101952, 10.1016/j.eclinm.2023.101952. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Oshima Y., Tanimoto T., Yuji K., and Tojo A., “EGFR‐TKI‐Associated Interstitial Pneumonitis in Nivolumab‐Treated Patients With Non‐Small Cell Lung Cancer,” JAMA Oncology 4, no. 8 (2018): 1112–1115, 10.1001/jamaoncol.2017.4526. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Gemma A., Kusumoto M., Sakai F., et al., “Real‐World Evaluation of Factors for Interstitial Lung Disease Incidence and Radiologic Characteristics in Patients With EGFR T790M‐Positive NSCLC Treated With Osimertinib in Japan,” Journal of Thoracic Oncology 15, no. 12 (2020): 1893–1906, 10.1016/j.jtho.2020.08.025. [DOI] [PubMed] [Google Scholar]
- 33. Saito Y., Sasaki S., Oikado K., et al., “Radiographic Features and Poor Prognostic Factors of Interstitial Lung Disease With Nivolumab for Non‐Small Cell Lung Cancer,” Cancer Science 112, no. 4 (2021): 1495–1505, 10.1111/cas.14710. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Tatsuhige R., Yokoo K., Hatakeyama T., et al., “Interstitial Lung Disease due to Tepotinib After Durvalumab in a Patient With Lung Adenocarcinoma Harbouring MET Exon 14 Skipping Mutation: A Case Report,” Case Rep Oncol 18, no. 1 (2025): 144–150, 10.1159/000543251. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Transition of ILD incidence in post‐marketing period in Japan.
Data Availability Statement
Any requests for data by qualified scientific and medical researchers for legitimate research purposes will be subject to Merck's Data Sharing Policy. All requests should be submitted in writing to Merck's data sharing portal (https://www.merckgroup.com/en/research/our‐approach‐to‐research‐and‐development/healthcare/clinical‐trials/commitment‐responsible‐data‐sharing.html). When Merck has a co‐research, co‐development, or co‐marketing or co‐promotion agreement, or when the product has been out‐licensed, the responsibility for disclosure might be dependent on the agreement between parties. Under these circumstances, Merck will endeavor to gain agreement to share data in response to requests.