Ask AI
Back Back
HER2pos GEA and BTC
Personalized Care of Patients With HER2-Positive Advanced BTC and GEA

Released: April 22, 2026

Richard Kim
Richard Kim, MD
Activity Information

Activity

Continue to Activity
Key Takeaways
  • HER2 is an important actionable biomarker in advanced BTC and GEA. When HER2 overexpression or amplification is detected, HER2-directed therapies should be strongly considered where indicated, with careful consideration of patients’ preferences and treatment goals.
  • T-DXd is specifically approved for patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regimen and agnostically for patients with HER2-positive advanced solid tumors after prior systemic therapy and without satisfactory alternative treatment options.
  • Currently, zanidatamab is approved by the FDA for the treatment of patients with previously treated, unresectable or metastatic HER2-positive BTC. Of note, data from the phase III HERIZON-GEA-01 trial demonstrated statistically significant improvements in progression-free survival with zanidatamab plus chemotherapy with or without tislelizumab vs trastuzumab plus chemotherapy.

Overview of Advanced GEA and BTC and Treatment Landscape for HER2-Positive Disease
Gastroesophageal adenocarcinoma (GEA) arises from the distal esophagus, gastroesophageal junction, and proximal stomach. Biliary tract cancers (BTCs) consist of a heterogeneous collection of malignancies also known as cholangiocarcinoma (CCA). BTCs are classified by their primary location into intrahepatic CCA, extrahepatic CCA, and gallbladder carcinoma. Patients with either unresectable advanced or metastatic GEA or BTC have poor prognosis. Although chemotherapy remains a mainstay in the management of patients with advanced GEA or BTC, the treatment landscape in these diseases has evolved with the advent of immune-directed therapies and molecularly directed therapies.

At the initial diagnosis of advanced GEA, treatment guidelines currently recommend biomarker testing for HER2 overexpression/amplification, PD-L1 expression, microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) status, high tumor mutation burden (TMB-H), CLDN18.2 protein expression, BRAF V600E mutation, NTRK fusions, and RET fusions. For patients with advanced BTCs, testing for the presence of HER2 overexpression and/or amplification, NTRK fusions, MSI-H/dMMR, TMB-H, FGFR2 fusions/rearrangements, IDH1 mutations, RET fusions, BRAF V600E mutation, KRAS G12C mutation, and NRG1 fusions are recommended.

In GEA and BTC, HER2 is an important and actionable biomarker, and it is implicated as a key driver of tumorigenesis. Among patients with GEA, the incidence of HER2 overexpression or amplification is approximately 20%, whereas in BTC, it has been reported in approximately 5% to 20% of CCAs and approximately 15% to 30% of gallbladder cancer cases. HER2 overexpression and/or amplification can be detected by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or next-generation sequencing. However, it is important to note that analysis of tumor tissue by IHC with or without FISH is the most commonly used and most effective technique. At the time of disease progression on HER2-directed therapy, a repeat biopsy (if feasible) is recommended to reassess for HER2 overexpression/amplification status before making next-line treatment decisions.

To be eligible for an approved HER2-directed therapy in GEA, HER2 positivity is defined as IHC 3+ or IHC 2+/ISH+ disease. FDA-approved regimens for patients with HER2-positive advanced GEA are chemotherapy plus trastuzumab with or without pembrolizumab, and trastuzumab deruxtecan (T-DXd). Of note, to be eligible for the FDA-approved HER2-directed therapies in BTC, HER2 positivity is defined as IHC 3+. The FDA-approved regimens for patients with HER2-positive advanced BTC are T-DXd and zanidatamab. Whereas T-DXd is specifically indicated in the pretreated advanced HER2-positive GEA setting after a prior trastuzumab-based regimen, its FDA approval in BTC is agnostic, with approval for patients with unresectable or metastatic HER2-positive solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options. Specifically, zanidatamab is approved for the treatment of patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC. When indicated for advanced GEA or BTC, zanidatamab and T-DXd are approved in the previously treated, unresectable or metastatic HER2-positive setting.

Importance of Patient and Caregiver Empowerment
Before making a treatment decision, it is critical that the healthcare team discusses the biomarker test results and the efficacy and safety of the potential treatment options with the patient and caregiver. The importance of this approach cannot be overstated. To assess the experiences of patients and/or the caregivers of patients with GEA and/or BTC during their treatment course, Decera Clinical Education partnered with Smart Patients to conduct a survey. In total, 55 individuals responded to the survey; 70% of these were patients and 30% were caregivers. None of the respondents had BTC or were taking care of patients with BTC, and approximately 90% represented GEA and the remaining represented gastric or esophageal cancers. Among the respondents, 40% indicated a lack of knowledge about the HER2 expression status of their disease or their care receiver’s disease. Of interest, among the respondents who were tested for HER2, only 12% stated that their healthcare team clearly explained the implications of HER2 testing whereas 20% stated that their healthcare team failed to clearly explain to them what HER2 testing meant. These responses are interesting because patients need to be made aware of the type of disease that they have. From the results of this survey, it appears that there is an opportunity for improvement in care by more consistently discussing biomarker testing with patients and their caregivers and clearly communicating the implications of the test results with them.

Also, in this survey, 47% indicated that they felt involved by their healthcare team in their treatment decision-making process, which included a clear discussion of the benefits and risks of their treatment options. By contrast, 36% of the respondents did not feel involved in the treatment decision-making process and felt that their healthcare team did not clearly discuss treatment options with them. Among 45 respondents, 36% expressed satisfaction with the treatment decision-making process and felt that the treatment plan was tailored specifically to their preferences and treatment goals. However, 27% did not feel like the treatment plan was tailored to their preferences and treatment goals.

When the respondents were asked about their expectations regarding treatment-related adverse events, 64% stated that they were well prepared for the anticipated treatment-related adverse events based on communications with their healthcare team whereas 23% were not. Although this is encouraging, it is clear that there is room for improvement regarding clearly discussing vital information with our patients and their caregivers before and during treatment. Overall, only one half of the respondents positively rated the quality of communication they received with their healthcare team during the course of treatment.

At this juncture, it is very important to emphasize that clear communication between the healthcare team and the patient/caregiver helps to improve awareness of the disease and treatment expectations, instill confidence in the treatment approach, and improve emotional and mental well-being of the patient and caregiver during the course of treatment. The incorporation of appropriate patient and caregiver empowerment strategies have a high potential to reduce panic during treatment, reduce frustrations during the course of the disease, and encourage adaptive caregiving while enhancing a sense of achievable treatment wins. Healthcare professionals should clearly discuss the benefits vs risks of all potential treatment options with the patients and their caregivers. This should include a discussion of patients’ preferences and treatment goals before making treatment decisions. Unfortunately, this survey revealed that for more than one half of the respondents (55%), the possibility of enrolling on a clinical trial was not discussed with them. It is very important to note that optimal strategies to engage patients and their caregivers in their care need to be incorporated into the treatment decision-making process, and this should include a discussion of possible clinical trial enrollment.

Future Directions and Overall Conclusions
Looking forward, there are many ongoing clinical trials for patients with advanced HER2-positive GEA or BTC, and the treatment landscape continues to expand. As of April 2026, zanidatamab is only specifically approved for the treatment of patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC. In the advanced GEA setting, data from the ongoing randomized phase III HERIZON-GEA-01 trial investigating zanidatamab-based combination therapies for patients with newly diagnosed advanced HER2-positive GEA were recently presented at the American Society of Clinical Oncology GI Cancers Symposium 2026 (NCT05152147). Progression-free survival, a primary endpoint of the trial, was significantly improved with zanidatamab and chemotherapy with or without tislelizumab, an immune checkpoint inhibitor (ICI), vs trastuzumab plus chemotherapy. Regarding overall survival, the coprimary endpoint, there was a significant improvement with zanidatamab plus chemotherapy and tislelizumab vs trastuzumab plus chemotherapy. The study is still active although it is no longer enrolling patients. I am excited about these data and awaiting more data after extended follow-up. Zanidatamab has received Orphan Drug designation from the FDA for GEA and from the European Medicines Agency for the treatment of gastric cancer.

Additional key ongoing phase III clinical trials for patients with HER2-positive advanced GEA include the DESTINY-Gastric05 trial of T-DXd plus chemotherapy with or without pembrolizumab vs trastuzumab plus chemotherapy with or without pembrolizumab for patients with previously untreated HER2-positive advanced GEA (NCT06731478). In addition, the ARTEMIDE-Gastric01 trial is investigating rilvegostomig, a bispecific antibody, plus chemotherapy in combination with T-DXd or trastuzumab vs trastuzumab plus chemotherapy and pembrolizumab for the first-line treatment of HER2-positive gastric cancer (NCT06764875). A key ongoing phase III trial in BTC is the HERIZON-BTC-302 trial of standard-of-care chemotherapy alone or in combination with an ICI vs zanidatamab plus standard-of-care chemotherapy with or without an ICI as first-line therapy for patients with HER2-positive advanced BTC (NCT06282575). The DESTINY-BTC01 trial is also investigating T-DXd with or without rilvegostomig vs standard-of-care gemcitabine plus cisplatin and durvalumab as first-line therapy for patients with HER2-positive advanced BTC (NCT06467357).

It is well-known that the treatment of patients with advanced GEA or BTC harboring an identified targetable alteration should be directed at that alteration as soon as it is detected because targeted therapies are associated with improved efficacy and tolerability compared with cytotoxic chemotherapy alone. Overall, the future for our patients with HER2-positive advanced BTC or GEA is exciting and promising, and there are several ongoing trials investigating HER2-targeted therapies in earlier lines of treatment.

Your Thoughts
What are your biggest challenges regarding the care of people with HER2-positive BTC and/or GEA? Answer the polling question and join the conversation in the discussion box below.

You may go online for more coverage of HER2-positive advanced GEA and BTC.

Continue to Activity

Poll

1.

Which HER2-targeted therapies are you currently using or are you planning to use in your practice for patients with HER2-positive advanced GEA and BTC?

Submit