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Experts Discuss Contemporary HER2-Directed Treatment in Advanced Gastroesophageal Biliary Tract Cancers

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Released: July 16, 2026

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HER2-directed treatment strategies in gastroesophageal adenocarcinoma (GEA) and biliary tract cancer (BTC) continue to evolve, with the FDA recently approving first-line zanidatamab-based treatment strategies for advanced GEA based on data from the phase III HERIZON-GEA-01 trial. In this commentary, expert faculty discuss key questions surrounding HER2-targeted therapy in these GI cancers.

Michel Ducreux
Michel Ducreux, MD, PhD
Geoffrey Ku
Geoffrey Ku, MD
HER2 in GEA and BTC

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In this commentary, Michel Ducreux, MD, PhD, and Geoffrey Ku, MD, address key questions regarding HER2-directed treatment strategies in gastroesophageal adenocarcinoma (GEA) and biliary tract cancer (BTC), including recent data, treatment selection, and sequencing considerations.

Can you describe the recent zanidatamab approval in GEA?

Geoffrey Ku, MD:
The FDA recently approved 2 zanidatamab-containing first-line regimens for adults with unresectable locally advanced or metastatic HER2-positive GEA. Zanidatamab plus fluoropyrimidine- and platinum-containing chemotherapy was approved for patients with HER2 immunohistochemistry (IHC) 3+ disease, and zanidatamab plus tislelizumab and fluoropyrimidine- and platinum-containing chemotherapy was approved for patients with HER2 IHC 3+ or IHC 2+/ISH+ disease.

These approvals were based on the randomized phase III HERIZON-GEA-01 study. Both zanidatamab-containing regimens significantly improved progression-free survival (PFS) compared with trastuzumab plus chemotherapy, with median PFS extending from 8.1 months with trastuzumab plus chemotherapy to 12.4 months with both zanidatamab plus tislelizumab and chemotherapy (HR: 0.63; P <.001) and zanidatamab plus chemotherapy (HR: 0.65; P <.001). The addition of tislelizumab also significantly improved overall survival (OS), with a median OS of 26.4 vs 19.2 months (HR: 0.72; P =.004). Although zanidatamab plus chemotherapy showed a numerical OS improvement at the interim analysis, with a median OS of 24.4 months, the difference did not reach statistical significance (HR: 0.80; P = .06). Diarrhea is an important toxicity with zanidatamab and requires proactive management, although treatment discontinuation due to diarrhea was uncommon in HERIZON-GEA-01. Overall, these approvals expand first-line treatment options for advanced HER2-positive GEA.

How does one decide between the HERIZON‑GEA‑01 and KEYNOTE‑811 regimens for first-line treatment of advanced GEA?

Michel Ducreux, MD, PhD:
At this time, there is no head-to-head comparison of the HERIZON-GEA-01 and KEYNOTE-811 regimens, so we cannot definitively say that one is superior. KEYNOTE-811 established pembrolizumab plus trastuzumab and chemotherapy for first-line treatment of HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma with PD-L1 combined positive score ≥1, whereas HERIZON-GEA-01 demonstrated a significant PFS improvement with zanidatamab plus chemotherapy, with or without tislelizumab; the zanidatamab plus tislelizumab combination also significantly improved OS.

For an eligible patient, zanidatamab plus chemotherapy and tislelizumab is personally very appealing because it combines dual HER2 targeting with PD-1 inhibition and has demonstrated both PFS and OS benefits. In practice, the choice should be individualized based on HER2 and PD-L1 status, the approved indication, toxicity profile, comorbidities, treatment availability, and patient preference.

Geoffrey Ku, MD:
One challenge in interpreting the HERIZON-GEA-01 data is that the control arm was trastuzumab plus chemotherapy without immunotherapy. In that context, the comparison of zanidatamab plus chemotherapy vs trastuzumab plus chemotherapy in HERIZON-GEA-01 largely reflects the benefit of zanidatamab vs trastuzumab as the HER2-directed therapy. Zanidatamab plus chemotherapy significantly improved PFS and showed a numerical improvement in OS, while zanidatamab plus tislelizumab and chemotherapy significantly improved both PFS and OS compared with trastuzumab plus chemotherapy.

Although the zanidatamab plus chemotherapy and zanidatamab plus tislelizumab arms in HERIZON-GEA-01 were not powered for a direct comparison, the results suggest that adding immunotherapy may provide additional benefit, consistent with the treatment approach used in KEYNOTE-811.

In practice, I favor trastuzumab-based therapy for patients with baseline diarrhea or those at high risk for diarrhea, such as those with inflammatory bowel disease or a high-output ileostomy. I would also consider trastuzumab for patients with borderline performance status in whom treatment-related diarrhea could compromise their ability to continue therapy. For otherwise fit patients with normal bowel function, zanidatamab-based therapy has become a very reasonable first-line option.

Should all patients receiving zanidatamab and chemotherapy in the HERIZON-GEA-01 setting also receive tislelizumab?

Geoffrey Ku, MD:
One important point from HERIZON-GEA-01 is that approximately one third of patients had PD-L1–negative tumors, and in the prespecified subgroup analysis, PFS and OS outcomes favored the triplet vs trastuzumab plus chemotherapy in both PD-L1–negative and PD-L1–positive subgroups. Therefore, for a patient who is eligible for immune checkpoint inhibition, I would generally consider the triplet regimen.

The efficacy results derived from zanidatamab, tislelizumab, and chemotherapy compared with zanidatamab and chemotherapy appear directionally similar to those seen with pembrolizumab added to trastuzumab and chemotherapy in KEYNOTE-811, with improvements in survival. Of importance, however, HERIZON-GEA-01 was not designed or powered to directly compare zanidatamab plus chemotherapy with zanidatamab plus tislelizumab and chemotherapy, so any incremental benefit attributable to tislelizumab cannot be determined precisely.

From a practical standpoint, the FDA-approved indication for zanidatamab plus tislelizumab and chemotherapy is not restricted by PD-L1 status. Thus, PD-L1 negativity alone would not preclude use of the triplet in an otherwise appropriate patient.

What is the optimal approach to sequencing T‑DXd and zanidatamab in BTC?

Michel Ducreux, MD, PhD:
The optimal sequencing of zanidatamab and trastuzumab deruxtecan (T-DXd) in HER2-positive BTC is not yet established, and there are no prospective data defining the preferred order. Zanidatamab is FDA approved for the treatment of patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC. T-DXd is FDA approved for the treatment of patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

A practical consideration is whether HER2 expression or ERBB2 amplification is retained after zanidatamab therapy. If HER2 remains strongly expressed, I would be comfortable using zanidatamab first and reserving T-DXd for subsequent therapy. Zanidatamab may also be somewhat easier to tolerate for some patients, which can make it attractive earlier in the treatment course.

On the other hand, there is an argument for using T-DXd earlier, while a patient still has adequate performance status to tolerate its toxicity profile. If HER2 expression or ERBB2 amplification is lost after HER2-directed therapy, that could also influence the value of subsequent HER2-targeted treatment. Ultimately, this remains an area of uncertainty, and sequencing should be individualized based on HER2 status, prior therapy, toxicity considerations, and the patient’s overall clinical condition.

Your Thoughts
How are you currently incorporating zanidatamab-based regimens into treatment selection and sequencing for patients with HER2-positive GEA or BTC, and what clinical factors most influence your decisions?

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What factors will most influence your choice in recommending first-line therapy for advanced HER2-positive GEA cancers (ie, zanidatamab-based therapy vs pembrolizumab/trastuzumab-based therapy)?

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