A combination of systemic therapy and radiation therapy is the standard treatment for advanced GEA and BTC, when surgery is not an option. Systemic therapy (which is administered through an intravenous (IV) line and circulates throughout the body) includes chemotherapy, targeted therapy, and immunotherapy.1,2
The goal for treatment is to reduce cancer burden and to prevent the further spread of the disease.1 In advanced cases, goals include managing symptoms, improving quality of life, and prolonging life from weeks to months.4
For advanced GEA, chemotherapy with oxaliplatin is preferred over cisplatin in systemic therapy, while targeted treatment for HER2-positive GEAs involves addition of trastuzumab or an FDA-approved biosimilar first-line chemotherapy.5,6 A recent study has shown that in patients with advanced GEA, those treated with anti-HER2 therapy fare better than those who did not receive targeted therapy.7
Currently, first-line treatments for unresectable and metastatic BTC include chemotherapy with PD-1 directed immunotherapy, such as durvalumab or pembrolizumab; HER2 directed treatment is included in subsequent therapy regimens in the event of disease progression.6
Anti-HER2 treatments include three drug classes. The first are antibodies, such as trastuzumab, pertuzumab, and zanidatamab that bind to the HER2 protein and affect its functioning. Tyrosine kinase inhibitors (TKIs), such as lapatinib block addition of a phosphate group to a protein called tyrosine kinase, which is responsible for signaling pathways that regulate cell growth and cell death. Finally, antibody drug conjugates (ADCs), such as trastuzumab deruxtecan, consist of an antibody bound to a cytotoxic molecule via a linker molecule. The antibody binds to the HER2 protein on the cancer cell and the cytotoxic molecule causes damage to the cancer cell.8 Sometimes, dual agent treatment, such as combining a HER2 targeting agent with chemotherapy or with immunotherapy leads to a better pathological response and is used to treat advanced GEA and BTC.9
Currently, trastuzumab and trastuzumab deruxtecan are FDA-approved for patients with HER2-positive GEA and zanidatamab is the only FDA-approved HER2-targeted treatment for previously treated, unresectable or metastatic HER2+ (IHC 3+) BTC.3,8 Trastuzumab deruxtecan is FDA-approved for certain patients with HER2-positive locally advanced or metastatic GEA (IHC 3+ or IHC 2+/ISH+) who have recieved a prior trastuzumab-based regimen and HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.10
Some examples of HER2-targeted therapies in the pipeline include the antibody margetuximab, TKIs neratinib and afatinib, and ADC disitamab vedotin (DV, RC48-ADC).7
