A 63-year-old male (an ex-smoker that quit 20 years ago, with smoking history of 15 pack-years) was referred to our outpatient clinic with NSCLC diagnosis to assess treatment options. The tumour was located in the right lung and spread to the mediastinal and supraclavicular lymph nodes. The lesion was detected in the chest CT (April, 2015) performed due to recurring mild exertional dyspnoea, decrease in exercise tolerance and dry paroxysmal cough. On histopathological examination of mediastinal lymph nodes biopsy obtained at mediastinoscopy and the right supraclavicular lymph nodes from fine-needle biopsy metastatic lung adenocarcinoma (TTF1+, Napsin A+) was diagnosed (June, 2015). The patient denied any weight loss. His medical history included mild prostatic hyperplasia, past lithotripsy due to urolithiasis, and in his youth hepatitis A. He is a farm worker.\nThe results of laboratory testing were within normal limits. The chest CT revealed suspicious additional changes in the lung parenchyma as well as bone lesions suggestive of metastases. In PET scan distant metastases were ruled out, however, due to significant regional spread of tumour (stage IIIB) the patient was not eligible for radical radiotherapy. In parallel to the staging procedures, the status of EGFR activating mutations was assessed and the exon 19 deletion was detected. The patient was therefore started on afatinib 40 mg QD.\nAfter 4 weeks of treatment the patient presentedwith a facial rash (grade 1). After 12 weeks of treatment diarrhoea ensued, however, the patient remained professionally active. Diet modification and loperamide as needed were advised. In the chest CT performed after 12 weeks of treatment there was a partial tumour response. With no laboratory abnormalities, the patient continued therapy for 12 months. The rash with no need of treatment persisted.\nIn August 2016 the patient experienced a pathological vertebral fracture with no evidence of lung cancer progression on chest imaging and no evidence of disease progression in the brain MRI. However, a few days later there appeared progressive paraparesis. The spine MRI revealed metastases in vertebral bodies of Th1, Th7 and Th8 with protrusion into the epidural space and spinal cord compression. The patient underwent neurosurgery (posterior decompression and C4-Th11 stabilisation), rehabilitation (physiotherapy and kinesitherapy) and palliative radiotherapy (30 Gy in 10 fractions) for affected area. The treatment with afatinib was continued.\nIn December 2016 (15th month of afatinib treatment) the chest CT revealed progression of the disease in the lungs. Genetic examination of circulating free DNA (cfDNA) was performed and EGFR T790M mutation was found. In December 2016 the treatment with osimertinib 80 mg QD was initiated. The severity of the neurological deficits was slowly improving and the patient recovered the ability to move his legs. Follow-up chest CT, performed after 2 months of treatment, revealed partial regression. In the following examination further regression was observed, with the sum of measurable dimensions of the lesions reduced in size by 38%. Currently, the patient is still experiencing a clinical benefit after 8 months of osimertinib treatment.
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.