A 52-year-old female patient, a never smoker, was initially diagnosed with advanced-stage lung adenocarcinoma (cT1bN3M0, stage IIIB). Wild-type epidermal growth factor receptor (EGFR mutation), anaplastic lymphoma kinase (ALK) rearrangement, ROS 1 rearrangement, BRAF V600E mutation, and MET exon 14 skipping mutation were detected via accompanying diagnostic tests. Based on the assessment using transbronchial lung biopsy (TBB) samples, the programmed death-ligand 1 expression was <1%. She received concurrent chemoradiation (60 Gy/30 Fr with cisplatin plus S-1), and four systemic treatments including immune check point inhibitor (carboplatin plus paclitaxel plus bevacizumab plus atezolizumab, docetaxel plus ramucirumab, pemetrexed, and nanoparticle albumin-bound paclitaxel) for each relapse at recurrence. However, rapid disease recurrence was observed with the progression of left lower lobe primary tumor, miliary lung metastasis, bilateral malignant pleural effusion, and appearance of carcinomatous lymphangitis on computed tomography (CT) scan (Figure 1). The serum carcinoembryonic antigen (CEA) level increased to 14,333.9 ng/mL. The patient's medical condition was affected as she presented with hypoxia, which required oxygen therapy via nasal cannula at a flow of 4 L per min, cancer pain, and cachexia, which needed opioid treatment. Her Eastern Cooperative Oncology Group PS score was assessed 3. TBB was again conducted for cancer genomic analysis using FoundationOne CDx  as next-generation sequencing and HER2 exon 20 insertion mutation (M774-775ins) and HER2 amplification was detected. Immunohistochemical staining of TBB specimens, which was performed by a pathologist, revealed HER2 positivity (Figure 2).
T-DXd was not approved for the treatment for NSCLC harboring HER2 mutation at that time in Japan. However, the patient's condition was serious, and T-DXd had a promising therapeutic effect against NSCLC harboring HER2 insertion mutation. Therefore, treatment with T-DXd, which was covered using the patient's own expense, was considered. After our cautious explanation about the risks and benefits of the drug was to the patient and her family, their informed consent was obtained. Treatment was started after the use of T-DXd was approved by Ethics Committee Review Board of Nippon Medical School Hospital (approval no. B-2020-297). Although participants received 6.4mg/kg in DISTNY Lung 01 trial, we conducted dose modification to 5.4 mg/kg of T-DXd for avoiding severe adverse event, considering her poor PS. CT scan performed 11 days after the administration of T-DXd presented that the size of the primary tumor decreased. Moreover, lung metastasis and pleural effusion improved (Figure 1). After 13 days the initiation of T-DXd, the need for oxygen administration was eliminated and the patient's PS improved from 3 to 1. After 23 days, she was discharged without O2 administration, and T-DXd treatment was continued in the outpatient department. The serum CEA level significantly decreased to 873 ng/mL with the treatment. The patient experienced adverse events (AEs) such as grade 2 neutropenia and grade 2 nausea, which were correlated with T-DXd treatment. After adjusting for treatment schedule, the patient tolerated the AEs. The durable response of T-DXd was observed between 6 months follow-up terms from initiation of T-DXd and her response was evaluated partial response using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The treatment is still ongoing, and severe AEs including interstitial lung disease (ILD) have not been observed.