Enhertu (fam-trastuzumab deruxtecan-nxki)

NSCLCs harboring ECD-ERBB2 mutations are associated with a unique clinico-genomic phenotype and improved outcomes with first-line chemoimmunotherapy. These findings have implications for optimizing treatment strategies in this disease.

Currently, no first-line HER2-directed agents are available and, until recently, trastuzumab deruxtecan, a HER2-targeting antibody-drug conjugate, was the only approved HER2-directed treatment option in the previously treated setting. In the current review, we summarize the development of treatment options for HER2-mutant NSCLC, including antibody-drug conjugates and tyrosine kinase inhibitors.

By contrast, sacituzumab govitecan is a TROP-2-targeted ADC conjugated through a hydrolysable CL2A linker to SN-38, the active metabolite of irinotecan. Clinically, trastuzumab deruxtecan has shown substantial efficacy in both HER2-positive and HER2-low breast cancer, whereas sacituzumab govitecan has demonstrated efficacy across triple-negative and hormone receptor-positive/HER2-negative breast cancers. Collectively, these agents highlight how variations in target antigen, linker chemistry, and payload potency impact ADC activity, therapeutic index, and potential strategies for sequential treatment in advanced breast cancer.

A number of BM treatment-effective drugs have shown BM-preventive effects: In NSCLC, the EGFR-inhibitor osimertinib and ALK inhibitors like alectinib, brigatinib and lorlatinib lower the incidence of BM. In HER2-positive breast cancer, tucatinib and trastuzumab deruxtecan have preventive activity in patients without BM at baseline...Preventing BM requires a personalized, multidisciplinary approach, integrating tumor biology, individual risk assessment, and therapeutic advances. Secondary prevention in patients with BM is as vital as tertiary prevention, warranting prospective validation of preclinical concepts.

P2, N=39, Recruiting, Peking Union Medical College | Trial primary completion date: Jul 2026 --> Jul 2028

USP9X inhibition enhances the lysosomal targeting of HER2, thereby potentiating ADC payload release and reducing tumor recurrence after T-DXd treatment. Our results elucidate the functional relevance of HER2 heterogeneity and propose improved therapies for these tumors.

P2, N=1, Active, not recruiting, Brown University | Trial completion date: Jan 2026 --> May 2026

P1/2, N=159, Not yet recruiting, Centro Di Riferimento Oncologico Di Aviano

A retrospective analysis was conducted on 104 patients diagnosed with advanced breast cancer who received trastuzumab deruxtecan treatment at the Affiliated Hospital of Xuzhou Medical University, with the study period spanning from January 2023 to September 2025. Earlier initiation of trastuzumab deruxtecan may maximize survival benefits. These findings help bridge the gap between clinical trial evidence and routine clinical practice.

P2, N=150, Not yet recruiting, Jiangsu HengRui Medicine Co., Ltd.