Advanced non-small cell lung cancer (NSCLC) is often complicated by leptomeningeal metastases (LMs), especially in patients carrying EGFR mutations. EGFR tyrosine kinase inhibitors (TKIs) are the first-line drug for patients with specific gene mutations, such as EGFR exon 19 deletion or exon 21 L858R mutation. However, after long-term TKI use, patients eventually develop drug resistance and acquire new mutations. Acquiring the EGFR T790 M mutation during TKI treatment is a marker for first/second generation TKI resistance. Osimertinib (a third-generation TKI) could overcome this resistance, especially for patients who have already developed NSCLC-LM. Treating NSCLC patients with osimertinib resistance is challenging. Our aim was to investigate whether afatinib is effective in NSCLC-LM patient who showed resistance to osimertinib. Herein, we report two patients with resistance to first- and third-generation TKIs who benefited from second-generation TKI.Case one: A 43-year-old man was diagnosed with stage 3A NSCLC with EGFR exon 19 deletion. He underwent surgery and received 4 rounds of chemotherapy (oxaliplatin combined with liposomal paclitaxel), after which the disease was controlled by icotinib (a first-generation TKI) for 4 years. Then, he showed poor drug response and bone metastasis. A liquid biopsy was carried out, and the EGFR L858R/T790 M compound mutation was found. The patient was given osimertinib (a third-generation TKI). The patient was in a stable condition for 2 years and then he developed bilateral peripheral facial palsy. Brain MRI showed enhancement in the left temporal lobe and meninges, and cerebrospinal fluid (CSF) cytology detected tumour cells in the CSF. NSCLC-LM was diagnosed. His performance status (PS) score was 3-4. Liquid biopsy and next-generation sequencing were performed again. Different gene mutations and copy number alterations were found this time, including EGFR L858R, but without the EGFR T790 M mutation. His disease was controlled with intrathecal methotrexate and oral afatinib (a second generation TKI). The patient has shown clinical remission (PS score: 1-2) until now, which is longer than 10 months.A 50-year-old man was diagnosed with NSCLC in May 2020. He underwent one round of chemotherapy before thoracoscopic partial lobectomy of the right upper lung. Histological study of the lung tissue showed lung adenocarcinoma with the EGFR L858R mutation. Then, the disease was controlled with icotinib. One year later, he was diagnosed with NSCLC-LM. Liquid biopsy and sequencing showed an EGFR L858R/S768I compound mutation. The patient was treated with osimertinib. His condition was stable for 5 months before his central nervous system (CNS) symptoms were exacerbated. Liquid biopsy and sequencing were carried out again, and his gene mutation profile had not changed much. Then, the patient was given afatinib, and his condition has remained stable for 11 months.Afatinib might be suitable for NSCLC-LM patients with EGFR compound mutations who show resistance to icotinib and osimertinib, since it might help overcome first- and third-generation TKI resistance.© 2023 The Authors. Published by Elsevier Ltd.