The identification of EGFR mutations and the subsequent development of EGFR TKIs have revolutionized the treatment paradigms for NSCLC patients. However, primary resistance to EGFR TKIs exists in a subset of EGFR-mutant patients and acquired resistance inevitably develops with a median progression-free survival (PFS) less than a year1. The rising genetic sequencing has contributed to the detection of potential resistant mechanisms. Herein, we reported that different resistant mechanisms including ROS1 fusion, EGFR T790M, BRAF fusion were detected by multiple genetic examinations during the treatment process of an EGFR mutated NSCLC patient, highlighting the importance of dynamic genetic monitoring to tailor precision therapies.
Case presentation
A 39-year-old Chinese male never-smoker referred to a local hospital for an enlarged lymph node in the right neck in July, 2018. Biopsy of the lymph node led to the diagnosis of metastatic adenocarcinoma of lung origin (T4N3M1b stage IVB). PET-CT revealed a pulmonary mass in the left upper lobe, multiple metastatic lesions in lungs, lymph nodes and skeletons. Blood-based targeted next generation sequencing (NGS) covering 13 oncogenic drivers identified EGFR E746_A750del, an EGFR exon 19 deletion (EGFR 19del). Thereafter, the patient was administered with icotinib as a single agent 125mg daily as first-line treatment on August 13th, 2018. However, the patient presented with an enlarged nodule in the left arm during the treatment. CT after one month demonstrated obvious shrinkage in the lung mass but increased lymph nodes in bilateral axilla (Fig.1). Aspiration biopsy of the arm lesion and subsequent amplification refractory mutation system–polymerase chain reaction for EGFR/ALK/ROS1 mutations confirmed metastatic lung adenocarcinoma with ROS1 fusion and EGFR 19del. Based on the tumor genotyping, the patient received orally crizotinib 250mg and icotinib 125mg daily since October 19th, 2018. CT after one month of combination therapy showed remarkable shrinkage in lymph nodes and stability in the pulmonary mass, contributing to partial response (Fig.1). All treatment-related adverse events such as grade I rash were tolerable. Considering that magnetic resonance imaging after four months (February 28, 2019) showed an apparent increase in cerebral lesions (Fig.1), the patient underwent whole brain palliative radiotherapy from March 5 to March 19, 2019. EGFR analysis on blood sample identified the emergence of EGFR T790M with EGFR 19del during radiotherapy. Thus, the patient was transferred to osimertinib 80mg plus crizotinib 250mg daily on March 13, 2019. However, CT after one month of osimertinib plus crizotinib demonstrated worsening pleural effusion and increased lesions in both lungs. NGS covering 520 genes on blood detected the occurrence of TRIM24-BRAF fusion (Fig. 2), EGFR E746_A750del and TP53 mutation, without EGFR T790M (Burning Rock Biotech). The patient was treated with chemotherapy of paclitaxel combined with nedaplatin for 2 cycles. Then the patient refused further treatment and passed away two days after leaving the hospital on August 15, 2019.