A 70-year-old female patient without other relevant medical history was started on pemetrexed and carboplatin for mesothelioma after vitamin B12 and folic acid supplementation. The patient developed a rash on the anterior chest wall 7 days after the first cycle which persisted despite treatment with loratadine. Four days after the second cycle (14 days after the onset of the rash), the patient was admitted with widespread maculopapular eruptions treated with betamethasone valerate 0.1% cream along with cetirizine 10 mg twice daily. The patient’s additional symptoms were fever, pancytopenia, including neutropenia, seizures and confusion, pulmonary embolism, and nausea. Over the next few days, the rash continued to coalesce and spread. Forty days after the initial onset, 80% of the total body’s surface area (TBSA) was affected with beginning denudation (). Histology showed widespread epidermal necrosis with multiple dyskeratotic keratinocytes. A TEN-like reaction was diagnosed. Treatment with prednisone 50 mg daily to be weaned off by 10 mg every 7 days was initiated along with supportive measures. The patient could be discharged to the community in a stable condition 50 days after the initial rash. Chemotherapy was discontinued and palliative care was initiated due to the sADRs including the diagnosis of a TEN-like reaction.
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.