Efficacy of osimertinib in a patient with leptomeningeal metastasis and EGFR uncommon S768I mutation

Abstract

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is more effective for the treatment of naïve advanced non-small cell lung cancer (NSCLC) patients with a common EGFR mutation (exon19 deletion or exon21 L858R point mutation) than first-generation EGFR-TKIs such as gefitinib and erlotinib, based on the results of the FLAURA study [ [1] Soria J.C. Ohe Y. Vansteenkiste J. Reungwetwattana T. Chewaskulyong B. Lee K.H. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 2018; 378: 113-125 Crossref PubMed Scopus (1719) Google Scholar ]. Additionally, osimertinib has a better central nervous system (CNS) efficacy in patients with untreated EGFR-mutated NSCLC, compared with first-generation EGFR-TKIs [ [2] Magnuson W.J. Lester-Coll N.H. Wu A.J. Yang T.J. Lockney N.A. Gerber N.K. et al. Management of brain metastases in tyrosine kinase inhibitor-naive epidermal growth factor receptor-mutant non-small-cell lung Cancer: a retrospective multi-institutional analysis. J. Clin. Oncol. 2017; 35: 1070-1077 Crossref PubMed Scopus (213) Google Scholar ]. However, data on the efficacy of osimertinib in patients with uncommon EGFR mutations is limited, since the FLAURA study did not include patients with uncommon EGFR mutations. On the other hand, a combined analysis of the LUX-Lung clinical trials program, which evaluated the efficacy of afatinib (a second-generation EGFR-TKI), showed that 71.1 % of the patients achieved an objective response, and the progression-free survival (PFS) for the afatinib group was 10.7 months in advanced NSCLC patients with uncommon EGFR mutations [ [3] Yang J.C. Sequist L.V. Geater S.L. Tsai C.M. Mok T.S. Schuler M. et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015; 16: 830-838 Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar ]. Recently, Cho et al. reported the efficacy of osimertinib in patients with NSCLC harboring uncommon EGFR mutations in a phase II study [ [4] Cho J.H. Lim S.H. An H.J. Kim K.H. Park K.U. Kang E.J. et al. Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09). J. Clin. Oncol. 2019; (JCO1900931) Google Scholar ]. The objective response rate of osimertinib was 50 % and the median PFS was 8.2 months. This trial included five evaluable patients for CNS response to osimertinib, and two EGFR uncommon G719X patients (40 %) achieved intracranial responses. However, the sample number of the trial was quite small, and cases with uncontrolled symptomatic brain metastases, such as leptomeningeal metastasis, were not included. It remains unclear whether osimertinib is superior to other EGFR-TKIs, especially afatinib, in patients with uncommon EGFR mutations and leptomeningeal metastasis.