<p>Three Novel <em>EGFR</em> Mutations (750_758del, I759S, T751_I759delinsS) in One Patient with Metastatic Non-Small Cell Lung Cancer Responding to Osimertinib: A Case Report</p>

Abstract

Generations of epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR -TKIs) can significantly improve the outcome of EGFR -positive NSCLC patients. However, acquired TKIs-resistant mutations are inevitable. Except the common EGFR alterations, more and more rare mutations are revealed by next-generation sequencing (NGS), the clinical significance of which are still unclear. Here, we report an advanced lung adenocarcinoma patient who harbored two novel EGFR exon 19 deletions (750_758del and I759S) at the beginning and exhibited a short response to icotinib for 7.0 months. Then, secondary resistance EGFR T751_I759delinsS occurred. Chemotherapy combined with bevacizumab and erlotinib was administered in turn but failed. Standard-dose osimertinib (80 mg daily) obtained durable clinical remission for 16 months, and high-dose osimertinib (160 mg daily) further prolonged the survival of 9 months after leptomeningeal metastases (LM) occurring. This study presented the first case of intractable terminal NSCLC in a patient with EGFR 750_758del, I759S and T751_I759delinsS mutations, who responded positively to osimertinib and achieved a prolonged OS of 52 months, providing a potential therapeutic option for the patients harboring these particular EGFR mutations.

Afatinib and osimertinib in lung adenocarcinoma harbored EGFR T751_I759delinsS mutation: A case report

“…The lower detection rate (16.7%) of EGFR exon 20 p.T790M may have resulted in shorter PFS in a previously reported study 9 . A case report showed a patient had PFS 7.0 months to icotinib and had resistant mutation T751_I759delinsS after icotinib treatment 10 . The patient had no response to three combinations with chemotherapy, bevacizumab and erlotinib but had a good response to osimertinib for 16 months.…”

Osimertinib-Centered Therapy Against Uncommon Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer- A Mini Review

“…Furthermore, 10 mM osimertinib induced an EGFR phosphorylation inhibition in the YU-1099 cell line, and the inhibitory concentration for YU-1092 was between 30 and 100 nM. Notably the concentrations that inhibited phosphorylation were used to suppress the proliferation of both cell lines ( 20 ). An in-vivo study in the LC-F-29 EGFR G719A;S768I patient-derived xenograft (PDX) model found a significant shrinkage in tumor size ((>100) 45%, p<0.001 at day 14, versus the control group) ( 19 ).…”

“…A few studies also showed the efficacy of osimertinib in NSCLC patients with uncommon mutations other than G719X, L861Q, and S768I. A study performed in Nanjing, China presented the first case of patients with novel and rare mutations 750_758del, I759S, and T751_I759delinsS, and durable clinical remission was achieved with the standard dose of osimertinib therapy ( 20 ). Notably, the patient had intractable terminal NSCLC but experienced a prolonged 52-week overall survival with Osimertinib ( 20 ).…”

“…A study performed in Nanjing, China presented the first case of patients with novel and rare mutations 750_758del, I759S, and T751_I759delinsS, and durable clinical remission was achieved with the standard dose of osimertinib therapy ( 20 ). Notably, the patient had intractable terminal NSCLC but experienced a prolonged 52-week overall survival with Osimertinib ( 20 ). Another report involved two patients with p.I740_K745dupIPVAIK that showed a positive response to osimertinib therapy.…”

Leptomeningeal Metastases from Solid Tumors: Recent Advances in Diagnosis and Molecular Approaches

“…A CNS recurrence following firstand second-generation TKIs occurs in 40% of patients due to the limited ability to cross the BBB and the development of resistant mechanisms. In this regard, the third-generation TKI osimertinib has shown a higher penetration through the BBB (CSF level 7.51 and 25.2 nmol/L when administered at 160 mg/day and 300 mg bid, respectively) and now is considered the first-line therapy in LM from EGFR-mutated NSCLC based on the results of several studies [115][116][117][118][119][120][121][122][123], regardless of T790 mutation status [121] (Table 4). The studies reported an intracranial response rate of 20-62%, a median PFS of 7.2-17.2 months, a median OS of 11-18 months and a rapid neurological improvement in the majority of patients [118], as well as a clearance of CSF from neoplastic cells in 28% [117].…”