A 43-year-old female never-smoker presented with prolonged paroxysmal cough and was diagnosed with stage IVa (T2bN2M1b) lung adenocarcinoma in Jun 2017. She underwent an endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and immunohistochemistry showed that the nucleoli had obvious heterotypic cells arranged like adenoid and CK (+), TTF-1 (+), NapsinA (+), P63 (+). Enhanced computed tomography (CT) revealed an upper left lung lesion (3.6x2.9 cm) with mediastinal lymph node metastasis (2.1x1.0 cm) and hepatic S4 segment metastasis (1.0x0.9 cm). She received two courses of docetaxel combined with cisplatin chemotherapy as the first-line treatment, and CT revealed no change in the lesion (Figure 1). To explore potential targeted treatment, next-generation sequencing (NGS) analysis was performed on the patient's peripheral blood using a 21 gene panel. The patient was found to carry the classical EML4-ALK fusion. Therefore, crizotinib was commenced at 250 mg bid on September 5th 2017. A follow-up CT conducted on January 17th, 2018 revealed a 61% regression in her primary lung lesion (1.4x1.2 cm), indicating that the patient had achieved partial response (PR). In May 2018, eight months after the onset of crizotinib treatment, the patient was discovered to have tumor progression (PD) due to brain metastases (1.9x1.6 cm) by head MRI and acquired resistance to crizotinib was suspected.
A second blood-based NGS showed the presence of the p.G1202R ALK mutation was observed. The patient was started on brigatinib (180 mg daily with a seven-day lead-in at 90 mg) on May 18th, 2018. Brigatinib is a next-generation oral ALK inhibitor used in the second-line after progression on crizotinib. However, a CT scan conducted after 53 days of brigatinib treatment revealed a new mediastinal lymph node (1.6x1.2 cm), and the appearance of new pericardial metastases. A third NGS testing was therefore performed, and a new type of NTRK arrangement (LIPI-NTRK1, Figure 2) was identified in addition to the two previous alternations. The patient's shortness of breath significantly increased due to the hydrothorax on the left side of the chest. After a pleural puncture, the symptoms were slightly relieved. Given her physical conditions, the patient refused to switch to another regimen, including NTRK inhibitors. She was able to benefit from ALK TKI therapy for 8 months and died on September 24th, 2018, with overall survival of 16 months from the time of diagnosis.