Potential treatment strategy for the rare osimertinib resistant mutation EGFR L718Q

Abstract

Epidermal growth factor receptor (EGFR) L718Q is a rare resistant mutation which independently leads to third-generation tyrosine kinase inhibitor (TKI) resistance. Although a few studies have examined its resistance mechanisms, no effective treatment strategy has yet been proposed for patients with this mutation. Here, we report an effective treatment strategy for the rare EGFR L718Q mutation for the first time. A 44-year-old Chinese male patient initially presented with the sensitizing EGFR L858R mutation, and the progression-free survival (PFS) time after initial icotinib treatment was 9 months. When the progression of the disease (PD) and the EGFR T790M mutation were identified, he did not respond to the osimertinib treatment. Through comprehensive next-generation sequencing (NGS) of the surgical specimen, the rare EGFR L718Q mutation was eventually identified as having a frequency of 68.84%, together with an EGFR amplification with a copy number of 11.54. The previous treatment response was retrospectively explained, and the patient faced the challenge of not being able to benefit from any targeted therapy. Following chemotherapy with a personalized regimen which effectively modified the proportion of sensitive and resistant cells, significant response to osimertinib re-challenge was observed, and another PFS of 4.7 months was achieved. Unfortunately, four EGFR mutations, EGFR L858, T790M, L718Q, and C797S, were simultaneously detected in his late stage, and led to further progression of disease.

Keywords: Non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR) L718Q; osimertinib resistance; treatment strategy; tyrosine kinase inhibitors (TKIs) re-challenge.

Figure 1

Computed tomography (CT) imaging of the course of disease. (A) The patient initially presented with a mass measuring 10 mm in diameter in the left upper lobe (LUL). Imaging features associated with malignancy were present, including ill-defined margin, corona radiata sign, and convergence of the blood vessels. Metastatic lesions were also present. (B) Significant shrinkage of the LUL mass and the disappearance of some metastatic lesions were observed after 4 weeks of icotinib treatment. According to the response evaluation criteria in solid tumors (RECIST), the patient achieved partial response (PR). (C) After 9 months of icotinib treatment, CT confirmed the progression of disease (PD), evinced by the enlargement of the LUL mass, and the emergence of metastatic tumors. At the same time, the EGFR T790M mutation was detected in the NGS-based ctDNA testing. (D) After 4 weeks of osimertinib treatment, CT showed further enlargement of metastatic nodules and a large volume of pleural effusion. EGFR L718Q mutation and EGFR amplification were identified in the subsequent comprehensive NGS evaluation of the surgical specimen.

Figure 2

The case history and a summary of the tumor clonal evolution. The patient initially presented with the EGFR L858R mutation identified from his fine needle aspiration sample, and achieved a PFS of 9 months after the icotinib treatment. At the time of disease progression, the first-generation TKI resistant mutation, EGFR T790M, was identified, and the treatment with osimertinib was initiated. However, he was resistant to the third-generation TKI. Five months later, the rare EGFR L718Q and EGFR amplification were confirmed through comprehensive NGS in his surgical specimen which could retrospectively explain his osimertinib resistance and help to inform using an effective chemotherapy regimen, which would re-model the composition of the tumor. After 4 courses of the chemotherapy with cisplatin/gemcitabine, the patient was responsive to the osimertinib re-challenge, achieving a PFS of 5 months, because the sensitive cell subpopulation with the EGFR T790M mutation was dominant. He suffered from the disease progression in his late stage due to the four EGFR mutations, EGFR L858R, T790M, L718Q, and C797S. The overall survival (OS) of this stage IV lung adenocarcinoma (C-T4N2M1a) was 30 months.