Multiple oncogenic molecular alterations have been discovered that serve as potential drug targets in non-small cell lung cancer (NSCLC). While the pathogenic and pharmacological features of common targets in NSCLC have been widely investigated, those of uncommon targets are still needed to be clarified. Human epidermal growth factor receptor 2 (HER2, ERBB2)-altered tumors represent a highly heterogeneous group of diseases, which consists of three distinct situations including mutation, amplification and overexpression. Compared with breast and gastric cancer, previous studies have shown modest and variable results of anti-HER2 treatments in lung cancers with HER2 aberrations, thus effective therapies in these patients represent an unmet medical need. By far, encouraging efforts towards novel treatment strategies have been made to improve the clinical outcomes of these patients. In this review, we describe the biological and clinicopathological characteristics of HER2 alterations and systematically sum up recent studies on emerging therapies for this subset of patients.

Background This is the first case report describing a patient with non-small cell lung cancer(NSCLC) harboring two rare human epidermal growth factor receptor 2 (HER2) exon 21 insertion mutations, who responded to furmonertinib treatment. Furmonertinib maybe one effective and economical treatment for NSCLC patients harboring HER2 mutations with minor side effects.Case presentation: We present a case report of a 49-year-old female diagnosed with stage IV lung adenocarcinoma. Firstly, We describe the patient's treatment history, including failed third-line combination treatments of systemic chemotherapy with bevacizumab or carrelizumab or anlotinib, primary lung tumor recurrence, bilateral lung metastases progression, and new brain metastatic lesion detection. Next, we detail the patient's fourth-line treatment with radiotherapy for brain metastases and two cycles of bevacizumab plus Abraxane and cisplatin, however, the disease progressed and relapsed. After that, comprehensive genomic profiling revealed two HER2 exon 21 insertion mutations. Finally, the patient received furmonertinib 80 mg a day and achieved a near-complete response after one month of treatment. The patient is still receiving treatment, without disease progression 8 months after starting treatment with furmonertinib.Conclusion Furmonertinib may be effective for NSCLC patients with HER2 T8962A and L869R mutations and further studies are needed to confirm these results in prospective clinical trials.

Contrary to the success of antihuman epidermal growth factor receptor 2 (HER2) therapy in HER2-amplified breast cancer, the optimal targeted drug therapy for HER2-amplified lung cancer remains to be determined clinically. In this report, a nonsmoker, Chinese, old, male patient was diagnosed with cT2bN3M0 nonsmall cell lung cancer with genetic testing revealing HER2 amplification. Though the patient received successful microwave ablation, the results of reexamination after two cycles of afatinib monotherapy showed disease progression. Then the treatment regimen was switched to pan-HER inhibitor pyrotinib 400 mg daily, with which the patient remained with stable disease for 9 months. After computed tomography showed tumor enlargement in October 2021, anlotinib was added to the present treatment. This case suggests that pyrotinib may provide a novel effective treatment option for HER2-amplified lung cancer.