Successful Treatment with Osimertinib and Chemotherapy in a Non–Small Cell Lung Cancer Patient with EGFR Mutation and Meningeal Carcinomatosis

A 60-year-old patient with lung adenocarcinoma with EGFR exon 19 deletion was treated with both first- and second-generation EGFR tyrosine kinase inhibitor (TKIs) for 3 years and finally acquired resistance. A rebiopsy sample from his lung disease showed the T790M resistance mutation. Osimertinib was effective for 8 months, at which time his lung disease progressed again (Fig. 1A). Then, he received cytotoxic chemotherapy with pemetrexed, carboplatin, and bevacizumab, and rapid improvement in his lung disease was observed (Fig. 1B); however, meningeal carcinomatosis developed for the first time immediately after he stopped taking osimertinib. Molecular analysis of the tumor cells detected in the patient's cerebrospinal fluid (CSF) revealed the presence of EGFR exon 19 deletion but not T790M mutation. Although meningeal carcinomatosis developed for the first time during the chemotherapy, the extracranial disease that had become resistant to osimertinib was well controlled with cytotoxic chemotherapy alone. Also, the fact that meningeal carcinomatosis emerged immediately after the patient had stopped taking osimertinib and the fact that tumor cells in his CSF were positive for activating EGFR mutation suggested that chemotherapy was not effective but osimertinib might still be effective against meningeal carcinomatosis. Therefore, we decided to continue chemotherapy for extracranial disease and once again began administering osimertinib for meningeal carcinomatosis. Within several days after the patient had begun taking osimertinib again, his neurological symptoms disappeared rapidly and the number of tumor cells in his CSF was dramatically reduced. So far, his extracranial disease has maintained shrinkage for at least 10 months without deterioration of his neurological symptoms. Preclinical studies have shown that osimertinib is quite brain penetrable and is more effective against brain metastases and meningeal carcinomatosis in EGFR mutation–positive NSCLC than first- or second-generation EGFR TKIs are.1Nanjo S. Ebi H. Arai S. et al.High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells.Oncotarget. 2016; 7: 3847-3856Crossref PubMed Scopus (56) Google Scholar, 2Ballard P. Yates J.W. Yang Z. et al.Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity.Clin Cancer Res. 2016; 22: 5130-5140Crossref PubMed Scopus (470) Google Scholar Clinically, osimertinib demonstrated remarkable efficacy against central nervous system (CNS) metastases in the pooled analysis of the 2 phase II studies of osimertinib for T790M-positive NSCLC.3Goss G. Tsai C.M. Shepherd F.A. et al.CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials.Ann Oncol. 2018; 29: 687-693Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Although the T790M status of the CNS metastases was not assessed in the pooled analysis, considering that T790M is less common in the CNS disease, a substantial number of the patients should have had T790M-negative CNS metastases and osimeritinib should therefore have been active against sensitizing EGFR mutation in the CNS disease.4Hata A. Katakami N. Yoshioka H. et al.Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: comparison between T790M mutation-positive and mutation-negative populations.Cancer. 2013; 119: 4325-4332Crossref PubMed Scopus (157) Google Scholar This combination cannot be recommended for routine use because both safety and efficacy data are lacking, and switching to chemotherapy is the standard once resistance to osimertinib has developed; however, the efficacy of the cytotoxic chemotherapy for meningeal carcinomatosis is quite limited. Our case suggests that considering the favorable efficacy of osimertinib against CNS metastases in EGFR mutation–positive NSCLC with or without T790M mutation, combination of osimertinib and chemotherapy should be one of the treatment options in patients such as ours, for whom there is a reasonable rationale for such treatment.