A 49-year-old female patient who had never smoked was initially diagnosed with advanced-stage lung adenocarcinoma (cT4N2M1, stage IV) on December 29, 2020. She complained of irritating dry cough symptoms followed by chest tightness. Computed tomography (CT) revealed a right lower lobe mass in the dorsal segment, multiple enlarged lymph nodes in the right hilar and mediastinum, and multiple lung metastases. Lymphatic dissemination in the right lower lobe of the lung could not be excluded (Fig. 1a). The Eastern Cooperative Oncology Group (ECOG) performance status score was 1. Initial tumor biopsy of the primary mass showed two HER2 exon 21 insertion mutations, T8962A and L869R, with an allelic fraction of 40.00% (Fig. 1b). Hematoxylin and eosin staining of the original aspirated tissue revealed malignant cells forming ductal structures in the lung biopsy specimen (Fig. 1c). Based on the assessment of lung biopsy samples, programmed death-ligand 1(PD-L1) expression was approximately 3% (Fig. 1d). Simultaneously, the patient underwent immunohistochemical (IHC) detection for HER2 expression, which was negative (Fig. 1e).
However, HER2 exon mutations are characterized by a poor response to the currently approved tyrosine kinase inhibitors(TKIs) and immune checkpoint inhibitors(ICIs). Therefore, the patient was first treated with six cycles of bevacizumab(400 mg, day 1) plus systemic chemotherapy with pemetrexed (800 mg, day 1) and carboplatin(400 mg, day 1), and her tumor burden was progressed from March 2021 to June 2021(Fig. 2).
After the failure of first-line combination treatment with bevacizumab plus carboplatin and pemetrexed in July 2021 due to progressive disease (PD)(Fig. 3a), the patient received a combination of bevacizumab (400 mg, day 1) plus abraxane (400 mg, day 1) and nedaplatin(100 mg, day 1) for three cycles as a second-line treatment, and a CT assessment revealed prominent regression of primary lung tumors in the right lower lobe and lung-to-lung metastases from July to September 2021(Fig. 3b,c). She stopped chemotherapy owing to poor performance status without maintenance therapy in October 2021.
Upon progression of the right lower lobar mass, multiple lung nodules and metastatic lymphadenopathies were observed after six months without subsequent treatment in April 2022. Thereafter, the patient received a combination of gemcitabine (1.4 g on day 1 and 8) plus anlotinib (8 mg, twice a day, day1-14) plus carrelizumab (200 mg, day 1) for 2 cycles, and reexamination indicated that multiple metastatic lung lesions became larger and more(Fig. 4a), and a new brain metastatic lesion was observed in June 2022(Fig. 4b).
Herein, the patient received radiotherapy for the metastatic brain lesion (3000cGy/300cGy/10f) and two cycles of bevacizumab(600 mg, day 1) plus abraxane (400 mg, day 1) and cisplatin (30 mg, once a day, day1-4). At the end of radiotherapy, the patient's irritating dry cough symptoms were significantly aggravated, and pulmonary nodules and metastatic lymphadenopathy were observed in August 2022(Fig. 5a).
Thereafter, the patient underwent next-generation sequencing(NGS) of circulating tumor DNA to identify potential treatment opportunities. The sequencing results showed that the patient had two HER2 21 insertion mutations, T8962A and L869R, with allelic fractions of 1.28% and1.37% (Fig. 4c). Although the National Comprehensive Cancer Network (NCCN) guidelines for NSCLC recommend antibody-coupled agents (ADCs) trastuzumab deruxtecan(T-DXd) for patients with HER2 mutant NSCLC in 2022, the patients did not choose it because of the price. After repeated discussions and considering the patient's economic factors, the patient received furmonertinib(80 mg, once a day). Prominent regression of primary lung tumors in the right lower lobe and lung-to-lung metastases was observed after one month of treatment in September 2022 (Fig. 5b). Her irritating dry cough was completely relieved, and prominent regression of brain metastases was observed after one month of treatment (Fig. 5c). Multiple lung metastases were observed slightly larger in January 2023 in serial CT scans (Fig. 6a). Thereafter, the patient received high-dose furmonertinib(160mg, once a day), prominent regression of lung-to-lung metastases was observed after one month of treatment in February 2023(Fig. 6b). The patient is still receiving treatment, without disease progression, 8 months after starting treatment with furmonertinib in August 2022, and her brain metastases remained stable(Fig. 6c). Moreover, there were no treatment-related side effects that could not be tolerated. The tumor markers of the patients are shown in the table below (Table.1). As can be seen from the table, the tumor markers of the patient were significantly reduced after the application of furmonertinib compared to the previous months.