December 17, 2025
HER2 remains one of the most aggressive and clinically relevant molecular drivers across multiple solid tumors. Each year, more than 2 million patients are diagnosed with breast cancer, over 1.1 million with gastric cancer, and nearly 600,000 with bladder cancer, with HER2 overexpression contributing to disease progression and poor outcomes across these settings.
In 2025, HER2-targeted oncology entered a period of accelerated innovation. The field has expanded beyond traditional monoclonal antibodies into antibody-drug conjugates, bispecific antibodies, tyrosine kinase inhibitors, and immuno-oncology combinations. Across breast, gastric or gastroesophageal junction, and urothelial cancers, late-stage clinical readouts increasingly support a consistent trend: therapies that demonstrated efficacy in later lines are now moving earlier in the treatment pathway, with meaningful gains in progression-free survival and, in several cases, overall survival.
HER2-Targeted Therapies by Tumor Type and Line of Therapy
The table below summarizes HER2-directed regimens shown in the graphic, organized by tumor type, mechanism, and typical line-of-therapy positioning based on pivotal trials and company disclosures.
| Tumor Type | Therapy or Regimen | Mechanism | Typical Line of Therapy |
| Breast cancer | Enhertu | ADC | Neoadjuvant; later-line |
| Breast cancer | Enhertu plus pertuzumab | ADC plus monoclonal antibody | First-line advanced or metastatic |
| Breast cancer | Enhertu to THP sequence | ADC plus monoclonal antibody | Neoadjuvant |
| Breast cancer | Tucatinib plus trastuzumab plus pertuzumab | TKI plus monoclonal antibody | First-line advanced or metastatic |
Abbreviations: ADC equals antibody-drug conjugate; TKI equals tyrosine kinase inhibitor; IO equals immuno-oncology therapy; GEJ equals gastroesophageal junction; UC equals urothelial carcinoma; THP equals trastuzumab, pertuzumab, and docetaxel.
Breast Cancer: Earlier-Line Intensification Takes Hold
In metastatic HER2-positive breast cancer, the shift toward earlier-line intensification is already established. Daiichi Sankyo and AstraZeneca’s Enhertu plus pertuzumab delivered one of the strongest first-line progression-free survival readouts reported to date in DESTINY-Breast09, with a median PFS of 40.7 months versus 26.9 months and a 44 percent reduction in progression risk.
Pfizer’s HER2CLIMB-05 reinforced this direction, demonstrating that adding tucatinib to first-line maintenance therapy with trastuzumab and pertuzumab meaningfully reduced progression risk. Together, these results signal a structural change in first-line HER2-positive breast cancer treatment, with ADC and TKI-based combinations increasingly displacing older sequential strategies.
Gastric and GEJ Cancer: Post-Trastuzumab Landscape Reshaped
Historically, HER2-positive gastric and GEJ cancers have lacked effective options following trastuzumab failure. In 2025, this dynamic began to shift. The HERIZON-GEA-01 trial showed that zanidatamab, with or without tislelizumab, delivered statistically significant improvements in progression-free survival and clinically meaningful overall survival trends compared with trastuzumab plus chemotherapy, positioning it as a potential new first-line standard.
At the same time, the later-line landscape continues to strengthen. Enhertu and Anbenitamab demonstrated compelling activity in previously treated disease, reinforcing the durability of HER2 as a target in gastric and GEJ tumors and supporting a more continuous HER2-directed treatment paradigm.
Urothelial Cancer: ADC and IO Combinations Advance
In urothelial carcinoma, HER2-directed strategies are gaining momentum. Disitamab vedotin plus toripalimab produced strongly positive Phase 3 results in the RC48-C016 trial, improving both progression-free and overall survival regardless of cisplatin eligibility or HER2 expression level. These findings highlight the potential for ADC plus immuno-oncology combinations to redefine first-line treatment strategies in HER2-expressing urothelial cancer.
Strategic Implications
Across solid tumors, HER2-targeted therapies are no longer confined to late-line settings. The convergence of positive first-line data across breast, gastric or GEJ, and urothelial cancers suggests a consolidation of HER2 as one of the most strategically important molecular franchises in oncology. As these regimens move earlier in the disease course, the competitive landscape is increasingly defined by combination strategies, durability of response, and differentiation across mechanisms rather than target validation alone.
Therapy classifications and line-of-therapy positioning were derived from company press releases and pivotal trials including HER2CLIMB-05, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Breast09, HERIZON-GEA-01, DESTINY-Gastric02, DESTINY-Gastric04, KN026-001, K-CWISE, and RC48-C016.
