In December 2019, a 59-year-old male (non-smoker) was admitted to our center due to cough for two weeks. The contrast-enhanced thoracic computed tomography (CT) revealed a primary lesion (lesion 1, 92x58 mm) in the right upper lobe of the lung and multiple metastases with a maximum size of 37x24 mm (lesion 2) in the left lower lobe of the lung, and distant spread to mediastinal lymph nodes was suspected ( Figures 1A, B ). Pathological investigations were performed on the lymph node specimens obtained by EBUS-TBNA, and the findings were, as follows: lung adenocarcinoma ( Figure 2A ) with TTF-1(+) ( Figure 2B ), NapsinA(+) ( Figure 2C ), CK7(+) ( Figure 2D ), D2-40(-), CD56(-), Wilms tumor(-), Caplonin(-), CDX-2(-), SATB2(-), Ki67(60% +), EGFR exon19 deletion and PD-L1 TPS 15%. Finally, the diagnosis of lung adenocarcinoma (T4N3M1a, stage IVA) with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 1 was made based on the clinical findings. Then, 125 mg of icotinib was orally administered, three times daily.
In March 2020, the thoracic CT revealed that the primary tumor and metastases decreased in size ( Figures 1C, D ): lesion 1 (42x39 mm) and lesion 2 (20x15 mm). Partial remission was also considered. However, in June 2020, the two lesions mentioned above enlarged (lesion 1, 100x80 mm; lesion 2, 65x62 mm), and a new lesion (lesion 3, 15x9 mm) was found in the right lower lobe ( Figures 1E, F ). Furthermore, multiple metastases were found in the left cerebellum and right frontal lobe by brain magnetic resonance imaging (MRI,  Figure 1G ). Therefore, the clinical response was evaluated as a progressive disease. The treatment was changed to pemetrexed (940 mg/day) and carboplatin (600 mg/day). The plasma next-generation sequencing (NGS) test revealed an EGFR T790M mutation, and that the EGFR exon 19 deletion did not disappear. Then, 80 mg of osimertinib was orally administered, once daily.
In July 2020, lesion 1 (69x41 mm,  Figures 1H, I ), lesion 2 (30x18 mm), and lesion 3 (10x6 mm) all decreased in size. Furthermore, an improvement was revealed by the brain MRI. The response was considered as partial remission. However, in August 2020, lesion 3 increased in size (25x14 mm,  Figure 1J ), and the pathological evidence of lung biopsies obtained by CT-guided procedures confirmed the squamous cell carcinoma ( Figure 2E ) with P40(+) ( Figure 2F ), CK5/6(+) ( Figure 2G ), CK7(-), NapsinA(-), TTF-1(-), CgA(-), CD56(-), Syn(-), Ki67(30% +), EGFR exon19 deletion, T790M mutant, MET amplification (high-throughput sequencing), and PD-L1 TPS 20%.
After the multi-disciplinary team (MDT) discussion, pembrolizumab (200 mg/day), paclitaxel liposome (250 mg/day) and carboplatin (600 mg/day) were incorporated into the present treatment with osimertinib. After two cycles of chemotherapy, in October 2020, a stable condition was suggested by the thoracic CT (lesion 1, 70x42 mm; lesion 2, 32x21 mm; lesion 3, 10x5 mm) and brain MRI (no obvious changes). Subsequently, the patient refused further chemotherapy, and only pembrolizumab was given for the third cycle of therapy. After one week, due to suspicion of cardiac injury, the use of pembrolizumab was interrupted, and osimertinib and crizotinib (250 mg, three times daily) were administered after the MDT meeting. The thoracic CT findings revealed that the patient's condition improved again: lesion 1 (65x40 mm), lesion 2 (26x17 mm), and lesion 3 (disappeared). However, transient strabismus and unconsciousness suddenly occurred, and a lesion in the brain developed, as revealed by the MRI, which was treated with low-dose radiotherapy at 24 Gy in eight fractions.
In January 2021, the thoracic CT findings (lesion 1, 73x54 mm; lesion 2, 33x26 mm) revealed that the patient's condition developed. This situation was further confirmed in May 2021 by CT imaging, and the ECOG-PS score was evaluated as 2. The treatment was switched to pembrolizumab (200 mg/day) and anlotinib (8 mg, three times daily, every three weeks, with one week intervals). In June 2021, the disease developed with enlarged lesions (lesion 1, 57x78 mm; lesion 2, 60x84 mm). Progressive status was considered, and the ECOG-PS score was evaluated as 3. Then, treatment with everolimus was initiated (5 mg, three times daily). Finally, the patient died in August 2021.