Enhertu expands treatment scope into HER2 solid tumors

Expanded indications to first-line breast cancer and second-line gastric cancer

Improved key endpoints versus standard therapy

The HER2-targeted antibody-drug conjugate (ADC) ‘Enhertu’ is accelerating its expansion into the solid tumor market by broadening its indications in Korea.

As Enhertu expands its indications to include first-line breast cancer and second-line gastric cancer treatment, there is growing speculation that treatment strategies for HER2-positive solid tumors may shift toward ADCs.

ADC anticancer drug ‘Enhertu’

According to industry sources on the 9th, the Ministry of Food and Drug Safety recently approved the expansion of Enhertu’s (trastuzumab deruxtecan) indications to include first-line therapy for HER2-positive metastatic breast cancer and second-line therapy for HER2-positive metastatic gastric cancer.

This approval allows Enhertu to be used in combination with pertuzumab as first-line therapy for patients with unresectable or metastatic HER2-positive breast cancer, as well as for patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma whose disease has progressed following trastuzumab-based therapy.

Enhertu was previously approved as a second-line treatment for HER2-positive metastatic breast cancer and a third-line treatment for HER2-positive metastatic breast cancer.

Enhertu is a next-generation ADC that combines a monoclonal antibody with the same structure as trastuzumab, which binds to specific target receptors overexpressed on the surface of cancer cells, with a highly potent topoisomerase I inhibitor payload via a tumor-selective cleavage linker.

An ADC is a novel anticancer drug created by linking an antibody that binds to a specific target antigen on the surface of cancer cells to a drug (payload) with cytotoxic activity via a linker. This therapy has the advantage of enhancing treatment efficacy while minimizing side effects by leveraging the antibody’s target selectivity and the drug’s cytotoxic activity to ensure the drug acts selectively on cancer cells.

For over a decade, the THP regimen, which is a combination of taxane chemotherapy, Herceptin (trastuzumab), and Perjeta (pertuzumab), has remained the standard first-line treatment for HER2-positive metastatic breast cancer. However, limitations have been noted, as a significant number of patients experience disease progression within two years, and some are unable to proceed to subsequent treatments.

In the DESTINY-Breast09 study, which served as the basis for this approval, the Enhertu and Perjeta combination reduced the risk of disease progression or death by 44% compared to the existing standard THP regimen. The median progression-free survival (PFS) was 40.7 months, an extension of more than one year compared to 26.9 months in the THP group.

In terms of response rates, the objective response rate (ORR) in the Enhertu combination group was 85.1%, higher than the 78.6% in the THP group, and the complete response (CR) rate was 15.1%, exceeding the 8.5% in the control group.

At the European Society for Medical Oncology Asia Congress (ESMO Asia 2025) held last year, analysis results for the Asian patient population of the trial were also released. An analysis of 346 Asian patients, including those from South Korea, showed that the median PFS in the Enhertu plus Perjeta combination group was 40.7 months, reducing the risk of progression by 45% compared to the THP group’s 24.7 months.

Potential shift in gastric cancer treatment strategies

Enhertu’s expansion is not limited to breast cancer. It is also showing potential to improve survival in HER2-positive gastric cancer, an area with long-standing unmet needs, which is raising expectations for a shift toward ADC-based treatment strategies.

HER2-positive gastric cancer is considered a prime area of unmet medical need. While the 5-year survival rate for early-stage gastric cancer exceeds 90%, it drops sharply in the metastatic stage. According to national cancer registry statistics, the 5-year relative survival rate for patients with metastatic gastric cancer is only around 6–7%.

Nevertheless, the treatment landscape for HER2-positive gastric cancer has remained largely unchanged for a long time since Herceptin plus chemotherapy became the standard first-line treatment in 2010. Although various HER2-targeted therapies have been developed since then, they have failed to demonstrate clinical outcomes in gastric cancer as clear as those seen in breast cancer.

In fact, treatment strategies based on Perjeta, Kadcyla (trastuzumab emtansine), and lapatinib have all failed to achieve significant improvements in survival in gastric cancer clinical trials. As a result, HER2-positive gastric cancer has been considered a tumor type with limited responsiveness to HER2-targeted therapy.

Amid this context, Enhertu demonstrated an improvement in overall survival (OS) in the second-line treatment of HER2-positive metastatic gastric cancer through the DESTINY-Gastric04 study. In the trial, Enhertu reduced the risk of death by 30% compared to the standard combination of Cyramza (ramucirumab) and paclitaxel, and the median OS was 14.7 months, an improvement over the 11.4 months observed in the control group.

Progression-free survival (PFS) was 6.7 months versus 5.6 months, and ORR was 44.3% versus 29.1%, respectively.