Human epidermal growth factor receptor 2 (HER2) is one of the most extensively studied and clinically validated targets in the field of antibody-drug conjugates (ADCs). Belonging to the ERBB receptor tyrosine kinase family, HER2 is frequently overexpressed or amplified in a variety of epithelial-origin tumors, including breast cancer, gastric cancer, and non-small cell lung cancer (NSCLC). HER2-positive tumors are often characterized by high aggressiveness and poor prognosis, making HER2 a critical focus for targeted cancer therapies.

Approved HER2-Targeted ADCs

To date, there are 19 ADCs approved worldwide. Among them, four HER2-targeting ADCs have received regulatory approval worldwide:

• ◆ Trastuzumab emtansine (T-DM1, Kadcyla®)

• ◆ Trastuzumab deruxtecan (T-DXd/DS-8201, Enhertu®)

• ◆ Disitamab vedotin (RC48, Aidixi®, approved in China)

• ◆ Trastuzumab rezetecan (Shr-A1811, approved in China)

Among them, Enhertu® has emerged as a benchmark therapy due to its outstanding clinical efficacy and innovative mechanism of action.

1. Trastuzumab emtansine (T-DM1, Kadcyla®)

Trastuzumab emtansine holds a pioneering role in ADC history. It was the first HER2-targeted ADC approved for breast cancer treatment and also the first ADC globally approved for the treatment of solid tumors.

2013 FDA approval (EMILIA trial)

Based on the results of the Phase III EMILIA study, the U.S. Food and Drug Administration (FDA) approved T-DM1 in 2013 for the treatment of patients with HER2-positive metastatic breast cancer (mBC) who had previously received trastuzumab and a taxane but experienced disease progression. [1]

2019 FDA approval (KATHERINE trial)

In 2019, the FDA expanded approval to include adjuvant treatment for patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. This approval was supported by interim results of the KATHERINE trial, published in the New England Journal of Medicine (NEJM). [2]

Long-Term KATHERINE Trial Analysis

In January 2025, the updated prespecified final analysis of the Phase III KATHERINE trial were published in NEJM. The study demonstrated that seven-year invasive disease-free survival (iDFS) was 80.8% with T-DM1 compared to 67.1% with trastuzumab, reflecting a 13.7 percentage point improvement. T-DM1 also led to a significantly lower risk of death than trastuzumab (unstratified hazard ratio, 0.66; 95% CI, 0.51 to 0.87; P = 0.003). The seven-year overall survival (OS) rate reached 89.1% with T-DM1 versus 84.4% with trastuzumab, a difference of 4.7 percentage points. [3]

2. Trastuzumab deruxtecan (T-DXd/DS-8201, Enhertu®)

Trastuzumab deruxtecan (DS-8201), co-developed by Daiichi Sankyo and AstraZeneca, is a third-generation HER2-targeted ADC. Its structure consists of a humanized anti-HER2 monoclonal antibody, a cleavable tetrapeptide linker, and a potent topoisomerase I inhibitor payload (Dxd). This innovative design offers several important advantages. With a high drug-to-antibody ratio (DAR) of up to 8, trastuzumab deruxtecan can deliver a greater amount of cytotoxic payload to tumor cells. Its membrane-permeable payload enables a strong bystander effect, allowing the drug to target not only HER2-expressing cancer cells but also neighboring tumor cells with lower HER2 expression. In addition, the ADC demonstrates high stability in circulation, which helps minimize premature drug release and reduces off-target toxicity, ultimately improving both safety and therapeutic efficacy.

Since its initial FDA approval in December 2019 for third-line treatment of HER2-positive breast cancer, trastuzumab deruxtecan has rapidly expanded its indications. Today, it is approved for:

• ◆ Second-line treatment of HER2-positive advanced breast cancer

• ◆ Second-line treatment of HER2-low advanced breast cancer

• ◆ Third-line treatment of locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

• ◆ Unresectable or metastatic HER2-mutant non-small cell lung cancer (NSCLC)

• ◆ Unresectable or metastatic HER2-positive solid tumors

Figure 1.  ENHERTU® has expanded to six indications, source: reference [4]

With continuous label expansions and exceptional clinical outcomes, it achieved global sales of $3.7 billion in 2024, ranking first among all ADC products.

Latest Findings from DESTINY-Breast09

At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Daiichi Sankyo and AstraZeneca presented updated results from the Phase III DESTINY-Breast09 trial. The study evaluated trastuzumab deruxtecan in combination with pertuzumab versus the current first-line standard of care (taxane + trastuzumab + pertuzumab, THP) in patients with HER2-positive metastatic breast cancer.

Key findings included:

• ◆ Progression-free survival (PFS): Median PFS reached 40.7 months with the DS-8201 combination, compared to 26.9 months in the control group—a nearly 14-month improvement (HR = 0.56, p < 0.00001).

• ◆ Objective response rate (ORR): 85.1% in the DS-8201 arm versus 78.6% with THP.

• ◆ Complete response (CR) rate: 15.1% with DS-8201, almost double that of the control group (8.5%).

• ◆ Durable response: At 24 months, 73.3% of patients in the DS-8201 combination group remained in remission, compared with 54.9% in the THP group.

Overall survival (OS) data are still maturing, but these results highlight the strong potential of DS-8201 in redefining first-line therapy for HER2-positive metastatic breast cancer.

3. Disitamab vedotin (RC48, Aidixi®)

Disitamab vedotin (RC48), developed independently by RemeGen in China, is a novel HER2-targeted antibody-drug conjugate (ADC) that combines a new humanized anti-HER2 antibody with the potent cytotoxic payload monomethyl auristatin E (MMAE). It has been approved by the National Medical Products Administration (NMPA) for the treatment of HER2-overexpressing gastric cancer, urothelial carcinoma, and breast cancer.

Clinical studies have demonstrated encouraging efficacy across multiple tumor types:

• ◆ Gastric cancer (C008 study): For patients with HER2-overexpressing gastric cancer, RC48 achieved an ORR of 24.4%, with a mPFS of 4.1 months and a mOS of 7.9 months. [6]

• ◆ Urothelial carcinoma (C005 study): In patients with HER2-overexpressing urothelial carcinoma, RC48 showed an impressive ORR of 51.2%, mPFS of 6.9 months, and mOS of 13.9 months. [6]

• ◆ Breast cancer (C006 study): Compared with the combination of lapatinib and capecitabine, RC48 delivered significantly greater benefit for patients with HER2-overexpressing breast cancer. The mPFS was 9.86 months vs. 4.9 months, and the mOS was not yet reached vs. 25.9 months in the control group [7].

4. Trastuzumab rezetecan (Shr-A1811)

Trastuzumab rezetecan (SHR-A1811), developed independently by Jiangsu Hengrui Pharmaceuticals, consists of an anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload (SHR169265, also known as rezetecan) with a DAR of 6. The therapy has been approved by the NMPA for the treatment of HER2 (ERBB2) mutant non-small cell lung cancer (NSCLC).

Clinical results from the HORIZON-Lung study demonstrated impressive efficacy in this patient population. Among patients with HER2-mutant NSCLC, SHR-A1811 achieved an objective response rate ORR of 73% and a mPFS of 11.5 months. Notably, in patients with brain metastases, the mPFS was 9.9 months, underscoring the drug’s therapeutic potential in this challenging setting [8].

HER2 ADCs in Clinical Development

Beyond the four HER2-targeted ADCs that have already gained regulatory approval, multiple additional candidates are currently in clinical development. Several HER2 ADCs are in Phase III trials, exploring indications across a wide spectrum of cancers, including breast cancer, gastric cancer, lung cancer, ovarian cancer, endometrial cancer, and urothelial carcinoma.

Table 1. HER2 ADCs in clinical phase III

Conclusion and Outlook

Nearly 40 years after the discovery of the HER2 gene, innovation in linker strategies and payload-release mechanisms continues to improve both efficacy and safety profiles of ADCs. With multiple next-generation HER2 ADCs in development, the field is poised to bring new therapeutic opportunities and renewed hope to patients with HER2-positive and HER2-mutant cancers worldwide.

About Huateng Pharma

PEG linkers play a crucial role in the design of ADCs, ensuring stability, controlled release, and optimal therapeutic performance. For example, ARX-788 utilizes a hydroxylamine-PEG4 linker, SYD985 employs an mc-PEG2-Val-Cit-PABA-Cyc linker, and DP303c incorporates PEG2-Val-Cit-PABC linkers—highlighting the versatility of PEG-based chemistries in modern ADC development. At Huateng Pharma, we supply high-quality PEG derivatives manufactured to GMP standards, supporting both research and commercial-scale needs. We also provide custom synthesis services to meet specific project requirements, including PEG linkers with tailored molecular weights, branching, and functional groups that may not be listed in our online catalog. With our expertise, we deliver flexible and reliable solutions to help our partners accelerate ADC innovation and achieve their unique quality specifications.

References:
[1] Sunil Verma et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N Engl J Med 2012;367:1783-91.
[2] G. von Minckwitz et al.Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019;380:617-28.
[3] Geyer Jr, Charles E., et al. Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. New England Journal of Medicine 392.3 (2025): 249-257.
[4] https://www.daiichisankyo.com/files/investors/library/materials/2024/FY2024_Oncology_Business_Briefing_E.pdf 
[5] https://www.astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-plus-pertuzumab-reduced-the-risk-of-disease-progression-or-death-by-44-percent-vs-THP-as-1st-line-therapy-in-patients-with-HER2-positive-metastatic-breast-cancer-in-DESTINY-Breast09-Phase-III-trial.html
[6] Zhou, X., Wang, L., Mu, L., Zhu, J., Chen, Y., & Liu, Y. (2023). Efficacy and safety analysis of a HER2-targeting antibody-drug conjugate combined with immune checkpoint inhibitors in solid tumors: A real-world study. Aging (Albany NY), 15(24), 15473. https://doi.org/10.18632/aging.205382
[7] https://aacrjournals.org/clincancerres/article/31/12_Supplement/PS8-06/753554/Abstract-PS8-06-A-randomized-open-label-phase-III
[8] Ziming Li, Yan Wang, et al, Trastuzumab rezetecan, a HER2-directed antibody–drug conjugate, in patients with advanced HER2-mutant non- small-cell lung cancer (HORIZON-Lung): phase 2 results from a multicentre, single-arm study, Lancet Oncol. 2025.
[9] Wang, R., Hu, B., Pan, Z. et al. Antibody–Drug Conjugates (ADCs): current and future biopharmaceuticals. J Hematol Oncol 18, 51 (2025). https://doi.org/10.1186/s13045-025-01704-3