Erlotinib/osimertinib

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Development of resistance in advanced lung adenocarcinoma: case report A 52-year-old woman acquired resistance to osimertinib and further developed resistance to erlotinib while being treated for lung adenocarcinoma [routes not stated]. The woman presented with advanced lung adenocarcinoma and widespread metastases to the pleura, abdominal lymph nodes, adrenal glands, liver, bone and brain. On anamnesis, it was noted that at the time of diagnosis, she exhibited molecular profiling EGFR exon 19 deletion (delE746_T751insV) in single-gene assays. Subsequently, she started receiving osimertinib 80 mg/day. A rapid clinical and radiographic improvement was seen; however, she developed side-effects, manifesting as low-grade rash, paronychia and thrombocytopenia. All these side-effects were tolerable. At 10 months, a systemic disease control was maintained. Although; asymptomatic, new brain metastases was detected. One month later, a systemic disease progression was observed in the lungs, pleura and abdomen. The woman’s osimertinib dose was therefore increased to 160 mg/day. At this time, a liquid biopsy sample showed EGFR delE746_T751insV/C797S, which indicated an acquired mechanism of resistance to osimertinib. Consequently, her treatment was switched to second-line, dose-escalated, singleagent erlotinib 1500 mg/week. Although she developed lowgrade diarrhoea, rash and dry skin due to erlotinib. Whereas, her respiratory symptoms were found to be improved and partial response in the chest, abdomen and brain was noted. Her disease remained under control for 4 months with this therapy. However, at 5 months after initiation of erlotinib, she exhibited CNS progression. At 5.5 months after therapy initiation, an intrathoracic disease progression was noted. Her liquid biopsy sample showed an EGFR delE746_T751insV with T790M and C797S, which suggested an acquired resistance to erlotinib as well [durations of treatments to reactions onsets not stated]. She was thus shifted to hospice care as her clinical condition deteriorated rapidly and further palliative cancerdirected therapies were deferred. She died at 18 months into the course of chemotherapy [immediate cause of death not stated]. Author comment: "[F]rontline osimertinib can lead to acquired, on-target resistance through development of EGFR C797S". "Given that evolution of EGFR T790M is well established as the most common mechanism of acquired resistance when gefitinib or erlotinib is given". "Administration of osimertinib . . .commenced with expected and tolerable toxicities (low-grade rash, paronychia, and thrombocytopenia)". "Erlotinib was well tolerated (low-grade diarrhoea, rash, and dry skin)". Rangachari D, et al. EGFR-Mutated Lung Cancers Resistant to Osimertinib through EGFR C797S Respond to First-Generation Reversible EGFR Inhibitors but Eventually Acquire EGFR T790M/C797S in Preclinical Models and Clinical Samples. Journal of Thoracic Oncology 14: 1995-2002, No. 11, Nov 2019. 803436658 Available from: URL: http://doi.org/10.1016/j.jtho.2019.07.016 - USA

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