A 45-year-old male, asymptomatic, heavy smoker (10 cigarettes a day) had an incidental finding of a lung occupying lesion from a computed tomography (CT) scan performed for health examination in March 2018. The chest CT revealed a mass which was 23 mm in maximum diameter in his superior lobe of right lung and enlargement of lymph nodules of the mediastinum and right hilar. He underwent right upper lobectomy with systematic nodal dissection. Acinar adenocarcinoma and papillary adenocarcinoma were confirmed by the pathological examination, and the right paratracheal and subcarinal lymph nodules were invaded by tumor (pT1bN2M0, stage IIA). Next-generation sequencing (NGS) test for a large panel showed a deletion of exon 19 of EGFR gene and EML4-ALK rearrangement and the mutation abundance was 1.97% and 13.79%. Subsequently, EGFR exon 19 confirmed by immunohistochemistry (IHC) and ALK rearrangement verified by fluorescence in situ hybridization (FISH). The patient Eastern Cooperation Oncology Group performance score (ECOG-PS) was 1 at one month after surgery, and he initially received adjuvant chemotherapy regimen with pemetrexed and nedaplatin (Day 1: 500 mg/m² + Day 1–2: 80 mg/m², 21 days/ cycle) in May 2018. After 6 cycles of chemotherapy, icotinib, a first generation of EGFR-TKI, (125 mg thrice daily) was selected as maintenance regimen. In December 2018, there was no inducement for the patient and he suffered headache, dizziness, nausea, projectile vomited and developed forced right lateral decubitus position. He had a positive Babinski sign and couldn’t complete both hands alternating movement test and finger-nose test. Brain magnetic resonance imaging (MRI) revealed cerebellar metastasis (CM) and leptomeningeal carcinomatosis (LMC) (Fig. 1). The patient began treatment with ALK-TKI alectinib (600 mg twice daily) combined with icotinib (125 mg thrice daily). In the same time, mannitol was used to decrease intracranial pressure. Three days after treatment, the patient was able to walk, and headache, dizziness, nausea as well as vomit was relieved. Brain MRI scanning demonstrated a marked regression of LMC after 2 months. However, the therapy was ceased after 3 months because the patient suffered from dizziness, and brain MRI revealed leptomeningeal progression compared with before. Considering that alectinib was beneficial for brain metastasis, he then switched to take alectinib (600 mg twice daily) combined with Osimertinib (160 mg once daily). A month later, this therapy was terminated after further CM progression showed in brain MRI and three new lesions in cerebellum was confirmed. A pulmonary nodule, meanwhile, was revealed by chest CT scanning which was in left upper lobe. We tried to analyze circulating tumor cells and cell-free tumor DNA in cerebrospinal fluid (CSF), but no valuable information found. Subsequently, he began treated both brigatinib (180 mg once daily with 7-day lead-in period at 90 mg) and bevacizumab (Day 1:10 mg/kg, 21 days/ cycle) from June 2019. After one cycle of this therapy, brain MRI scanning and chest CT scanning revealed a decrease of brain metastasis and pulmonary metastasis. Nevertheless, brigatinib was discontinued after 6 months due to nausea, vomiting and loss of appetite. The patient was subsequently switched to lorlatinib (25 mg once daily) combined with bevacizumab (7.5 mg/kg D1, 21 days/ cycle), and lorlatinib followed was gradually incremented to 75 mg daily. Mild tachycardia and hallucinations were apparent temporarily and recovered without any management. Brain MRI scan and chest CT scan were performed bimonthly that showed stable disease in the next 8 months of this treatment, and the patient remains on this therapy util reporting this case.
A 48-year-old male non-smoker suddenly appear to be having an epileptic seizure and fell down in April 2018. Brian MRI revealed brain nodules and metastases cannot be rule out. FDG-PET scan was performed next, revealing the presence of a lesion in the lower right lung and multiple brain lesions. The pathological examination of CT guided percutaneous lung puncture biopsy revealed an adenocarcinoma, and we made a diagnosis of right lower lobe adenocarcinoma at stage IV. The patient had a good performance status and he was initially received first-line chemotherapy regimen of PP (pemetrexed 500 mg/m2 D1 + nedaplatin mg/ m2 D1, 21 days a cycle) in May 2018 every three weeks up to 4 cycles. The patient had a stable disease (SD) and was performed NGS detection which identified L858Q mutation (0.30%) in exon 21 concomitant with ALK-SH3RF3 fusion gene (0.33%) in the tumor cell. Then, based on the molecular finding, he started to take first-generation ALK-TKI crozitinib (250 mg twice daily), and disease stability was achieved for 8 months (Fig. 2). At progression, he received EGFR-TKI gefitinib (250 mg once daily), but the drug was stopped for skin toxicity after 1 month. In April 2019, whole-brain radiation (WBRT) was given for 20 times. In June 2019, the patient started taking brigatinib (180 mg once daily with 7-day lead-in period at 90 mg) combined with icotinib (250 mg thrice daily). 5 months later, CT scans evidenced a partial response in the brain lesions. However, the progressive disease (PD) was confirmed by brain MRI in May 2020, with a progression-free survival (PFS) of 11 months. The therapy regimen was switched to alectinib (600 mg twice daily) combined with icotinib (250 mg thrice daily). Unfortunately, the therapy response was assessed as PD with the efficacy evolution showed an enlarged tumor size after 2 months of this therapy. his cancer progressed again and he began taking ceritinib (750 mg Daily) combine with icotinib for about 1 month and then experienced PD. Next, the patient was treated with loratinib (100 mg daily) and the clinical response was not available util reporting this case.
In March 2015, a 61-year-old female non-smoker who was asymptomatic was found a lung mass in the right lower lobe with malignant pleural effusion in physical examination. Percutaneous pulmonary biopsy was diagnosed of right lower lobe adenocarcinoma at stage IV, and the tumor tissue was too small to perform the gene test. The patient worried about the side effect of chemotherapy. In April 2015, she started to take gefitinib (250 mg once a day) and had a partial response after 3 months (mutation status was unknown) (Fig. 3). In August 2016, she began receiving temozolomide combined with gefitinib because of the discovery of brain lesions by MRI. In November 2016, pleural effusion was suddenly increased and considered the progression disease. Then, plasma-based NGS was performed and the EGFR mutation (T790M, exon20) was found. He was treated with AZD9291 since November 2016 and the disease stability was achieved for 11 months. In October 2017, CT-scan revealed the progression of pulmonary nodules as well as pleural effusion, and the patient was treated with CT-guided seed implantation and AZD9291 treatment was continued simultaneously. Then, a new lung biopsy specimen was obtained and NGS was performed, which showed the concomitant of EGFR exon 19 deletion and EML4-ALK rearrangement and the mutation abundance was 16.69% and 22.29%, respectively. For this reason, the treatment regimen was switched to crozitinib (250 mg twice daily) combined with AZD9291 (80 mg daily) in January 2018. After 7 months of this therapy, the drug was discontinued for the presence of chest distress and breath obstruction. Followed CT scan revealed the massive right-side pleural effusion and left-sided pneumonia, and disease progression again was confirmed. We conducted re-biopsy and NGS to the patient, and the result of NGS was consist with the previous one. A right thoracic drainage and cis-platinum intrapleural infusion was performed in July 2018. Then, the patient initially received chemotherapy of PP (pemetrexed 500 mg/m2 D1 + nedaplatin mg/ m2 D1, 21 days/cycle) plus bevacizumab (7.5 mg/kg D1, 21 days/cycle) and continued taking AZD9291. However, cardiac insufficient was happened to her on the fourth day of 7th cycle chemotherapy with the left ventricular ejection fraction of 44%. Thus, she ceased to take AZD9291 and continued the pemetrexed (pemetrexed 500 mg/m2 D1, 21 days/cycle) plus bevacizumab (7.5 mg/kg D1, 21 days/cycle) for another 22 cycles and stable disease was achieved. In April 2020, the patient suffered with headache and dizziness with an unsteady step, and LM) couldn’t be rule out but we were not obtained evidence from imaging test. From May 2020 to reporting this case (September 2020), the patient was treated with Osimertinib (160 mg, once a day). After 4 months, CT scan showed a right-side pleural effusion was increased again with elevated levels of carcinoma embryonic antigen (CEA), and the Osimertinib was discontinued.