Abstract
Introduction: Tepotinib is a targeted agent for patients with advanced non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutation (METex14). Whereas durvalumab is an immune-checkpoint inhibitor (ICI), which has been administered to those with unresectable stage III NSCLC. The efficacy and safety of sequential treatment in patients with METex14 are unclear. Reports have suggested that the administration of tyrosine kinase inhibitors after ICIs could potentially increase the incidence of drug-induced lung injury. Case Presentation: A 76-year-old female patient was diagnosed NSCLC harbouring METex14 with clinical stage IIIA (cT2aN2M0). Chemoradiotherapy and consolidation therapy with durvalumab were initiated to achieve a cure. Durvalumab was discontinued due to interstitial lung disease (ILD). After systemic disease progression was observed, tepotinib was initiated 7 weeks after the last dose of durvalumab. She developed ILD due to the sequential treatment of tepotinib after durvalumab. Conclusion: It is unclear whether tepotinib is safe in patients with METex14 after durvalumab administration. Considering the residual period of ICIs in the body, caution should be exercised when initiating molecular-targeted drugs after ICI administration in patients with NSCLC with METex14.
Introduction
The detection of actionable driver mutations and the administration of targeted therapy could prolong the overall survival of patients with non-small cell lung cancer (NSCLC) [1]. MET exon 14 skipping (METex14) occur in 3–4% of patients with NSCLC while MET amplifications occur in 1–6% of patients [2].
Two pivotal clinical trials, the VISION study and the GEOMETRY mono-1 trial, have demonstrated the benefits of progression-free survival in patients with METex14. The primary endpoints of the 2 studies were objective response rates of 46% and 72% [3, 4]. Based on these trials, the US Food and Drug Administration has approved the drug for patients with metastatic NSCLC with METex14 [5].
The PACIFIC trial, a global phase III study, demonstrated the superiority of durvalumab over placebo in patients with unresectable stage III NSCLC after platinum-based concurrent chemoradiotherapy (CRT) [6]. This trial demonstrated prolonged overall survival and progression-free survival with durvalumab after chemoradiotherapy [7]. Durvalumab has been established as the standard of care in this setting. In that trial, the total population of patients with driver mutations, epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase translocations was limited. Therefore, the safety of tyrosine kinase inhibitor (TKI) following durvalumab treatment remains unclear. Moreover, the appropriate timing for TKI initiation after durvalumab administration remains unclear. Here, we present the case of a patient with METex14-positive NSCLC who developed interstitial lung disease (ILD) after sequential treatment with tepotinib and durvalumab.
Case Report
A 76-year-old female with no history of smoking was referred for an abnormal shadow on a chest radiograph. Contrast-enhanced computed tomography (CT) revealed an abnormal shadow (36 × 34 mm) in the lower lobe of the left lung and swelling of multiple lymph nodes in the mediastinal and hilar lymphadenopathies (Fig. 1). Transbronchial biopsy was performed on the primary lesion of the left lung for pathological diagnosis, which revealed an adenocarcinoma. Additional examinations, including 18F-fluorodeoxyglucose positron emission tomography/CT and magnetic resonance imaging of the brain were performed, and the patient was diagnosed with clinical stage IIIA (cT2aN2M0).
Chest CT showing a solitary lesion in the lower lobe of the left lung (yellow arrow) (a–c) and swelling of multiple hilar and mediastinal lymph nodes (yellow arrow) (c, d).
Chest CT showing a solitary lesion in the lower lobe of the left lung (yellow arrow) (a–c) and swelling of multiple hilar and mediastinal lymph nodes (yellow arrow) (c, d).
We performed next-generation sequencing analysis of the biopsy specimens using the Oncomine Dx Target Test multiple companion diagnostic test system and detected METex14. At this stage, chemoradiotherapy was initiated to achieve a cure.
In March 2022, the patient began chemoradiotherapy (60 Gy plus concurrent low-dose carboplatin [30 mg/m2 per day, 5 days/week for 20 days]). The patient achieves partial response after the completion of chemoradiotherapy; thus, consolidation therapy with durvalumab was initiated in May 2022.
Although tumour shrinkage was maintained after 5 cycles, ILD (grade 2) developed after 17 cycles. The Krebs von den Lungen-6 (KL-6) value was 365 U/mL, which was within the reference range of <500 U/mL. Durvalumab administration was discontinued, and systemic steroid therapy was initiated.
Owing to systemic steroid therapy, her ILD improved, and durvalumab was resumed after the steroid dose was reduced to below 10 mg prednisone daily. In February 2023, after a total of 19 cycles of durvalumab, systemic disease progression was observed, with primary lesions and lymph node, liver, and brain metastases. No symptoms of brain metastasis were observed. Although tepotinib treatment was considered, an increase in adverse events was expected owing to the short period since the last dose of durvalumab. Thus, stereotactic radiotherapy was performed for the brain metastasis (30 Gy/5 in fractions). Tepotinib was initiated in April 2023; 7 weeks after the last dose of durvalumab.
In May 2023, 1 month after tepotinib administration, chest radiography showed patchy infiltrative shadows in both lungs. Chest CT demonstrated consolidation in the upper lobe of the right lung and in the upper and lower lobes of the left lung, despite the patient being asymptomatic (Fig. 2). The KL-6 value was 617 U/mL. We suspected drug-induced lung disease caused by tepotinib and performed a transbronchial lung biopsy of the right upper lobe, which revealed pathological findings of an organising pneumonia pattern (Fig. 3). Corticosteroids were not administered at the time of ILD onset. Based on these findings, we diagnosed Grade 2 drug-induced ILD due to tepotinib. Systemic steroid therapy was initiated at 50 mg/day (prednisone 1 mg/kg). After steroid therapy, the drug-induced pneumonia improved immediately, and ILD was controlled.
The chest CT showed consolidation at the upper lobe in the right lung and the upper and lower lobe in the left lung (yellow arrow) (a–d).
The chest CT showed consolidation at the upper lobe in the right lung and the upper and lower lobe in the left lung (yellow arrow) (a–d).
Histopathological image of peripheral lung specimen by transbronchial lung biopsy. The haematoxylin and eosin staining (a) and the elastic-Masson staining (b) demonstrated the organising pneumonitis. Collagen fibres and fibroblasts indicating organising pneumonia patterns were observed in the alveolar space (yellow arrow).
Histopathological image of peripheral lung specimen by transbronchial lung biopsy. The haematoxylin and eosin staining (a) and the elastic-Masson staining (b) demonstrated the organising pneumonitis. Collagen fibres and fibroblasts indicating organising pneumonia patterns were observed in the alveolar space (yellow arrow).
Discussion
To the best of our knowledge, this is the first report of a patient with METex14 mutation-positive NSCLC who developed ILD after sequential administration of tepotinib and durvalumab. In the present case, ILD was pathologically diagnosed as being caused by tepotinib and improved with steroid treatment. However, whether durvalumab administration affects the onset of ILD is unclear. Moreover, the appropriate timing for TKI initiation after durvalumab administration remains unclear. In our case, as ILD did not occur after re-administration of durvalumab and ILD developed shortly after tepotinib administration, the causative agent was considered to be tepotinib.
In terms of ILD, some characteristics of tepotinib and durvalumab should be considered. Tepotinib is a targeted agent for patients with NSCLC with METex14 and demonstrated efficacy and safety in the VISION study [3], a phase 2 global study. The incidence of ILD caused by MET inhibitors was 3.8% [3] (Japanese subset: 11.8% [8]) in the VISION study of tepotinib and 6.2% [4] (Japanese subset: 15.4% [9]) in the GEOMETRY Mono-1 study of capmatinib. The incidence of ILD caused by MET inhibitors is considered equivalent in global data but appears to be higher in the Japanese subset. Therefore, the possibility of tepotinib-induced ILD should be considered. This trend was also observed in clinical trials involving osimertinib. The incidence rates of ILD and pneumonitis in the FLAURA trial in advanced recurrent stage IV NSCLC were 2% [10] in the global data and 12.3% in the Japanese subset [11]. It is unclear whether the mechanisms underlying ILD are due to TKIs, not only EGFR TKIs but also MET TKIs. Osimertinib and tepotinib are drugs with different mechanisms of action on tumours, although in both cases ILD is more likely to occur in the Japanese population. Contrarily, 1 patient with lung adenocarcinoma was successfully treated with tepotinib after capmatinib-induced ILD [12]. Therefore, it is important to consider the relationship between durvalumab and TKI. However, it remains unclear whether TKIs are safe or effective after durvalumab treatment.
In the PACIFIC trial [6, 7], there were a limited number of patients with driver mutations, EGFR, and anaplastic lymphoma kinase translocation. The number of individuals with METex14 remains unknown. However, some reports have suggested that the incidence of ILD may increase with sequential administration of immuno-checkpoint inhibitor (ICI) and TKI, ranging from 25% to 50% [13, 14].
These results provide evidence for patients with EGFR-positive lung cancer, but not for those with MET-positive lung cancer; however, ICI is considered to have the potential to impact the occurrence of ILDs in TKI. Additionally, there are reports of the possibility that ICI may remain in the body for an extended period and continue to exert its effects. One study reported the binding of nivolumab to memory T cells 20 weeks after administration [15]. It is believed that durvalumab which is equivalent to nivolumab, also remains in the body, and we speculate that this period was influenced by the drug.
In this case, the period from the final administration of durvalumab to the start of tepotinib was approximately 7 weeks, which may be related to the onset of ILD. Therefore, we propose that the timing of TKI initiation after durvalumab treatment should be carefully considered.
Conclusion
It is unclear whether tepotinib is safe in patients with METex14 after durvalumab administration. Considering the residual period of ICIs in the body, caution should be exercised when initiating molecular-targeted drugs after ICI administration.
Acknowledgments
We thank the patient, her family, and the investigators for their support and participation in this study.
Statement of Ethics
This case report was approved by the Ethics Committee of the institutional review boards of Teine Keijinkai Hospital (Permit No. 3-024313-00). Written informed consent was obtained from the patient for publication of this case report and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000543251).
Conflict of Interest Statement
Keiki Yokoo received personal fees from MSD K.K., AstraZeneca, Takeda Pharmaceutical Co. Ltd, Chugai Pharmaceutical Co. Ltd, Eli Lilly Japan K.K., Boehringer-Ingelheim, Bristol-Myers Squibb, NIPPON KAYAKU, and Merck Serono. In addition, payment or honoraria was received for lectures and presentations. Gen Yamada received personal fees from AstraZeneca, Chugai Pharmaceutical Co. Ltd, and Boehringer-Ingelheim. In addition, payment or honoraria was received for lectures and presentations. All other authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Ryota Tatsuhige and Keiki Yokoo drafted and revised the manuscript. Ryota Tatsuhige, Keiki Yokoo, Taku Hatakeyama, Takayuki Nagao, Satoshi Ota, and Gen Yamada were involved in the diagnosis and treatment of the patient and have approved the manuscript. Hirofumi Chiba reviewed the manuscript. All authors have approved the final version and agreed to be accountable for all aspects of the work.
Data Availability Statement
All data generated or analysed during this study are included in this article and its online supplementary material files. Further enquiries can be directed to the corresponding author.