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Osimertinib-Induced Interstitial Lung Disease Presenting as Eosinophilic Pneumonia

2017; Elsevier BV; Volume: 12; Issue: 8 Linguagem: Inglês

10.1016/j.jtho.2017.03.022

1556-1380

Hiroaki Tachi, Toshihiro Shiozawa, Chio Sakai, Mariko Kasuga, Kensuke Nakazawa, Yuko Morishima, Hiroaki Satoh, Nobuyuki Hizawa, Shingo Sakashita, Ikuo Sekine,

Eosinophilic Disorders and Syndromes

Interstitial lung disease (ILD) is one of the most serious side effects induced by EGFR tyrosine kinase inhibitors (TKIs). We report a case of ILD showing predominant eosinophilic infiltration that developed during osimertinib treatment. Stage IIB lung adenocarcinoma harboring an EGFR L858R mutation was diagnosed in a 77-year-old woman with no smoking history. Five years after left upper lobectomy, small nodules appeared on the bilateral lung fields in a regular chest radiographic examination. The patient was treated for postoperative recurrence with gefitinib, carboplatin plus pemetrexed followed by pemetrexed maintenance therapy, and erlotinib. During erlotinib treatment, multiple lung nodules and liver metastases appeared. Ultrasound-guided percutaneous liver biopsy resulted in a pathological diagnosis of metastatic lung adenocarcinoma. A genetic analysis disclosed an EGFR T790M mutation. Thus, fourth-line treatment with osimertinib was initiated at a daily dose of 80 mg. Fourteen days after initiation of osimertinib, fever and hypoxemia developed. The computed tomography revealed thickening of the interlobular septa in the right lung and bilateral pleural effusion in addition to the pulmonary nodules and liver tumor, which decreased in size (Fig. 1). The bronchoalveolar lavage fluid had an elevated cell count with predominance of eosinophils (35.5%), and transbronchial lung biopsy showed slight eosinophilic infiltration into the alveolar septal wall (Fig. 2). There was no evidence of infection or cardiac failure. On the basis of the clinical findings, we diagnosed osimertinib-induced pulmonary toxicity manifesting as eosinophilic pneumonia. The patient was followed with cessation of osimertinib treatment because her general condition was relatively stable. After osimertinib withdrawal, the chest radiograph shadows attenuated gradually and the clinical symptoms improved.Figure 2Representative photographs from bronchoalveolar lavage fluid (A), and transbronchial lung biopsy (B). (A) Total cell count increased with eosinophil predominance. (B) A slight infiltration of eosinophils was observed in the alveolar septal wall.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Osimertinib-induced ILD has been reported with an incidence of 0.95% to 2.37%.1Jänne P.A. Yang J.C. Kim D.W. et al.AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med. 2015; 372: 1689-1699Crossref PubMed Scopus (1640) Google Scholar, 2Goss G. Tsai C.M. Shepherd F.A. et al.Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study.Lancet Oncol. 2016; 17: 1643-1652Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar Although the risk of ILD should be considered during treatment with osimertinib as well as with other EGFR TKIs, the characteristics of osimertinib-induced ILD remain unclear. This patient did not have any risk factors for gefitinib-induced ILD, including interstitial pneumonia, smoking history, and poor performance status, and ILD did not develop during previous gefitinib and erlotinib treatment. Thus, the mechanisms of and risk factors for ILD caused by osimertinib may differ from those caused by other EGFR TKIs. Diffuse alveolar damage is a commonly observed radiological pattern in the ILD induced by EGFR TKIs.3Endo M. Johkoh T. Kimura K. Yamamoto N. Imaging of gefitinib-related interstitial lung disease: multi-institutional analysis by the West Japan Thoracic Oncology Group.Lung Cancer. 2006; 52: 135-140Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar However, this patient presented with radiological findings different from those described in previous reports. In particular, the observed interlobular septal thickening and bilateral pleural effusion were consistent with acute eosinophilic pneumonia.4Daimon T. Johkoh T. Sumikawa H. et al.Acute eosinophilic pneumonia: thin-section CT findings in 29 patients.Eur J Radiol. 2008; 65: 462-467Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Drug-induced eosinophilic pneumonia has been reported as an adverse event with other drugs such as amiodarone and methotrexate,5Allen J.N. Drug-induced eosinophilic lung disease.Clin Chest Med. 2004; 25: 77-88Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar but a literature search did not retrieve any reported cases associated with EGFR TKIs, including osimertinib. To the best of our knowledge, this is the first report of an osimertinib-induced ILD presenting as eosinophilic pneumonia. Physicians should be alert to atypical radiological findings during osimertinib treatment, which is possibly an early sign of ILD induced by this drug. This unique histological feature and the lack of previously reported risk factors suggest the necessity of clinical studies of osimertinib-induced ILD.