In a never-smoking 52-year-old female, the lung cancer was detected during the diagnostic work-up for exertional dyspnea. In chest CT (April 2014) a tumour in the lower left lobe with accompanying left-sided hydrothorax were reported. Lung adenocarcinoma was diagnosed on histological examination of sections obtained through core needle biopsy, and EGFR activating mutation (deletion in exon 19) was confirmed. In May 2014 gefitinib 250mg QD was initiated, which led to the partial disease response. In June 2015, after around 13 months of treatment, progression in the left lung ensued. In subsequent video-thoracoscopy the metastatic nodules in parietal pleura were biopsied and T790M resistance mutation was confirmed.\nIn July 2015 the patient was enrolled into an expansion cohort of phase I trial assessing the clinical activity of rociletinib, a 3rd generation EGFR inhibitor. After 6 months of treatment, the patient reported conjunctivitis, prolongation of QTc in ECG (QTcB up to 482 ms) and hyperglycaemia, deemed as related to rociletinib. After 12 months of treatment in July 2016 multiple brain metastases were diagnosed. The experimental therapy was continued as the patient was benefiting from disease control in the lungs. In September 2016 the vision impairment ensued that required ophtalmological consultation. The surgical treatment was recommended because of the predicted high dynamics of this type of cataract. Due to increasing toxicity of rociletinib and central nervous system progression the patient was ultimately taken off the trial.\nIn view of osimertinib availability in extended access program, blood sample was taken to determine the resistance mutation to 1st and 2nd generation TKIs. In examination of plasma cell-free DNA T790M mutation was detected. In September 2016 the treatment with osimertinib 80 mg QD was started.\nSince December 2016 the patient was receiving low molecular weight heparin in therapeutic doses, i.e. Clexane 100mg QD, because of the deep vein thrombosis recurrence requiring hospitalization. In the head and chest CT, performed 10 weeks after osimertinib initiation, almost complete remission of CNS metastases and further control of chest lesions were reported. The patient has completed 8 months treatment now and is not reporting any treatment related side effects.\nGiven the high clinical efficacy and beneficial toxicity profile of osimertinib, this drug is currently being investigated in the first line of treatment of advanced NSCLC with activating EGFR mutations. The available clinical data suggests high effectiveness of the agent in this setting. Median progression free survival and objective response rates in previously untreated NSCLC patients with activating EGFR mutations in expanded cohort from phase I trial AURA were 19.3 months and 77%, respectively []. During American Society of Clinical Oncology Annual Meeting 2017 (ASCO 2017) reports on mechanisms of resistance to osimertinib were presented. Among the most common molecular changes after progression on osimertinib (also detectable in liquid biopsy) was MET amplification, present in 30% of the cases []. In three of these patients partial response was attained after administration of MET inhibitor in conjunction with EGFR TKI, which suggests new treatment option for patients with MET amplification as a resistance mechanism. Another group of molecular determinants of resistance to osimertinib includes mutations within EGFR, e.g. C797S, and, in other genes, e.g. PIK3CA E545K, BRAF V600E, or KRAS G12S as well as amplification of HER2 and FGFR1 []. In patients with HER2 amplification as a resistance mechanism to EGFR TKIs, the combination of trastuzumab and paclitaxel resulted in partial responses in 41% of the patients []. Moreover, in patients with oligo-progression on osimertinib, ablative therapy of up to five metastatic lesions (surgery or stereotactic radiotherapy) was safe and allowed for continuation of TKI treatment []. The results of the phase III FLAURA trial, assessing efficacy of osimertinib in comparison to 1st generation EGFR TKIs (gefitinib or erlotinib) in first line of treatment of NSCLC patients with activating EGFR mutations, are soon to be announced.\nIn summary, osimertinib provides a novel, highly efficacious treatment for NSCLC patients progressing on EGFR TKIs with T790M mutation confirmed as the resistance mechanism. The drug is also effective in patients with brain metastasis who exhausted possibilities of local ablative therapies. The presence of T790M can be determined in tissue or liquid biopsy obtained after progression on EGFR TKIs. Osimertinib has a favourable toxicity profile, with mild rash and diarrhoea being the most common.
In October 2017, a 51-year-old man, suffering from loose blisters, large-area skin peelings (nearly involving the entire body), mucosal erosion and fever, visited The First Affiliated Hospital with Nanjing Medical University. He had been diagnosed with stage IV EGFR-mutation-positive advanced NSCLC with pleural metastasis in 2016 and received treatments at a thoracic hospital regularly. After chemotherapy (pemetrexed plus cisplatin for six cycles) was completed, icotinib continued to be used till August 2017 when the drug resistance was revealed. Once EGFR T790M mutation was diagnosed, he started taking AZD-9291 with a dose of 80 mg/day to delay the disease progression. Twenty-one days later, he presented with several oral blisters and scattered erythematous maculopapular rashes, which rapidly developed into mucosal erosion and general epidermal detachment involving his entire body with exfoliation on his back skin (). When admitted into our department, he was unable to get up owing to severe pain, extreme feebleness, fever, and lower limb edema.