Successful Treatment with Erlotinib after Gefitinib-Induced Severe Interstitial Lung Disease
Authors: Masayuki Takeda, Isamu Okamoto, Chihiro Makimura, Masahiro Fukuoka, Kazuhiko Nakagawa
Journal: Journal of Thoracic Oncology (2010)

A 62-year-old woman with an 18-pack-year history of smoking was found to have a solitary spiculated lesion in the right upper lung lobe and multiple pulmonary nodules on a computed tomography (CT) scan of the chest. A transcutaneous CT-guided needle biopsy specimen of the lung revealed adenocarcinoma. She received four cycles of chemotherapy with docetaxel and cisplatin, after which CT revealed marked tumor shrinkage. During follow-up for 3 months, progressive disease was diagnosed on the basis of the presence of an enhancement of cortical sulci on a CT scan of the brain. Mutation analysis of the lung cancer specimen showed the presence of an exon-19 deletion in the epidermal growth factor receptor (EGFR) gene, and gefitinib was administered orally at a dose of 250 mg once daily (Figure 1A). After 24 days of gefitinib, the patient manifested acutely deteriorating dyspnea with fever and cough. A chest CT scan revealed extensive bilateral ground-glass opacities throughout both lungs (Figure 1B). The results of sputum culture of bacteria or fungi and general blood tests, including those for fungal antigen and cytomegalovirus antigen, were negative. The patient had no prior interstitial lung disease (ILD) or preexisting collagen-vascular disease. Therefore, we concluded that the clinical course and imaging results were consistent with gefitinib-induced ILD. Gefitinib therapy was discontinued, and the treatment with high-dose methylprednisolone was initiated. Given that her symptoms and radiologic findings of gefitinib-induced ILD improved, the patient was discharged 14 days after discontinuation of gefitinib. As a result of progression of brain metastasis soon after discontinuation of gefitinib, whole-brain radiation therapy was delivered. Three months after discontinuation of gefitinib, the patient again experienced neurologic progression because of the brain metastasis, and the development of symptomatic brain metastasis was considered to be a contraindication for treatment with cytotoxic agents. After receiving full informed consent for the risk of recurrent ILD and high mortality rate after the onset of ILD, we administered erlotinib at a dose of 150 mg/d (Figure 1C). Nine weeks after the initiation of erlotinib treatment, a chest CT scan revealed no evidence of ILD and a reduction in the size of multiple pulmonary metastatic nodules (Figure 1D). After 11 weeks of erlotinib treatment, she developed meningeal carcinomatosis with progressive neurologic symptoms and discontinued erlotinib treatment. ILD has not been identified during the course of treatment with erlotinib. Gefitinib-induced ILD is the most problematic toxicity, with an incidence reported to be approximately 4% in Japan and with about one third of the cases being fatal.1Ando M Okamoto I Yamamoto N et al.Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib.J Clin Oncol. 2006; 24: 2549-2556Crossref PubMed Scopus (320) Google Scholar The predictive risk factors for ILD development include male sex, smoking, and the existence of pulmonary fibrosis. The discovery of somatic mutations in the tyrosine kinase domain of EGFR and of the association of such mutations with a high response rate to EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib has had a profound impact on the treatment of advanced non-small cell lung cancer. Gefitinib-induced severe ILD has been reported only rarely in EGFR mutation-positive patients, although the prevalence of EGFR mutations is estimated to be low in patients with risk factors for ILD.2Tamura K Okamoto I Kashii T et al.Multicentre prospective phase II trial of gefitinib for advanced non-small cell lung cancer with epidermal growth factor receptor mutations: results of the West Japan Thoracic Oncology Group trial (WJTOG0403).Br J Cancer. 2008; 98: 907-914Crossref PubMed Scopus (195) Google Scholar The mechanism of gefitinib-induced ILD has not been fully elucidated. The previous findings suggest that inhibition of EGFR-mediated signaling by gefitinib impairs the repair of and thereby exacerbates lung injury.3Hardie WD Prows DR Leikauf GD et al.Attenuation of acute lung injury in transgenic mice expressing human transforming growth factor-alpha.Am J Physiol. 1999; 277: L1045-L1050PubMed Google Scholar, 4Hardie WD Prows DR Piljan-Gentle A et al.Dose-related protection from nickel-induced lung injury in transgenic mice expressing human transforming growth factor-alpha.Am J Respir Cell Mol Biol. 2002; 26: 430-437Crossref PubMed Scopus (27) Google Scholar, 5Suzuki H Aoshiba K Yokohori N et al.Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis.Cancer Res. 2003; 63: 5054-5059PubMed Google Scholar In the present case, the patient received oral erlotinib (150 mg) daily, which results in a steady-state plasma trough concentration, that is approximately 3.5 times that for gefitinib (250 mg), and tumor shrinkage was observed with no evidence of ILD. These observations suggest that blockade of the EGFR signaling pathway by EGFR-TKIs is not necessarily associated with the incidence of drug-related ILD. Erlotinib and gefitinib share a 4-anilinoquinazoline base structure but differ in the substituents attached to the quinazoline and anilino rings. Minor differences in the chemical structure of these compounds may, thus, influence lung toxicity. We could successfully manage the patient who had once developed gefitinib-induced ILD with a full dose of erlotinib. The present case demonstrated that erlotinib may be one of the treatment options in such patients when alternative therapeutic options are limited. Because EGFR TKI-induced ILD has a high associated mortality, a careful assessment of clinical symptoms and radiographic findings and informed consent are needed in this setting.