Key Ideas

Treatment of metastatic gastroesophageal adenocarcinoma is now almost entirely biomarker-directed, built around four established markers: MMR, HER2, PD-L1, and Claudin 18.2. A new bispecific HER2-directed antibody, zanidatamab, combined with chemotherapy and immunotherapy, has shown the strongest survival data yet reported in HER2-positive disease and is likely to become a new frontline standard. 

A Biomarker-Driven Approach From the Start

Treatment selection for metastatic gastroesophageal adenocarcinoma now proceeds through a structured biomarker sequence. Mismatch repair (MMR) status is assessed first, since MMR-deficient tumors are candidates for immunotherapy. For MMR-proficient tumors, HER2 status comes next. HER2-positive disease is further stratified by PD-L1 status: HER2-positive, PD-L1-positive disease is currently eligible for chemotherapy, trastuzumab, and immunotherapy together, while HER2-positive, PD-L1-negative disease is treated with chemotherapy and trastuzumab. For HER2-negative disease, PD-L1 and Claudin 18.2 status each carry their own treatment implications. Patients without any actionable biomarker remain candidates for chemotherapy alone. Reflex biomarker testing on all available tissue, whether from primary or metastatic sites, has become standard practice to make sure these results are available when treatment decisions need to be made.

The Foundation: Three Key HER2 Trials

Three trials define the current HER2-positive treatment landscape.

The ToGA trial, conducted many  years ago, first established the role of trastuzumab in HER2-positive gastroesophageal adenocarcinoma. This global phase 3 trial randomized patients with HER2 IHC 3+ or IHC 2+/FISH-positive disease to chemotherapy (capecitabine, 5-FU, and/or cisplatin) with or without trastuzumab and found both an overall survival and progression-free survival benefit with addition of trastuzumab, along with a low rate of added toxicity. One durable consideration: trastuzumab has a long half-life, so decline in left ventricular ejection fraction can still be observed six to seven months after a patient stops the drug. In majority of patients trastuzumab induced cardiotoxicity is often reversible after stopping the drug.

HER2 status itself is determined by overexpression and gene amplification: IHC 3+ is considered HER2-positive, IHC 0/1+ is HER2-negative, and IHC 2+ is equivocal and requires in situ hybridization (ISH) testing, with a HER2-to-CEP17 signal ratio of 2.0 or greater confirming HER2 positivity.

More than a decade after ToGA, the KEYNOTE-811 trial evaluated tested adding pembrolizumab to trastuzumab and chemotherapy (CapeOX and cisplatin plus 5FU) in advanced, unresectable, or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Among patients with PD-L1 CPS of 1 or greater, median overall survival was 20.1 months with addition of pembrolizumab , versus 15.7 months without pembrolizumab. Notably, in roughly 15% of enrolled patients who were PD-L1-negative, adding pembrolizumab did not help and appeared detrimental to overall survival. Based on this, and following an initial broader approval, the FDA in 2025 narrowed the pembrolizumab indication to HER2-positive gastric or GEJ adenocarcinoma with PD-L1 CPS greater than 1.

HERIZON-GEA-01: A New Standard on the Horizon

Zanidatamab is a novel bispecific antibody that binds two distinct HER2 epitopes simultaneously (the trastuzumab-binding domain, ECD4, and the pertuzumab-binding domain, ECD2). Following encouraging phase 2 data combining zanidatamab with chemotherapy in the first-line setting, the phase 3 HERIZON-GEA-01 trial enrolled patients with unresectable, locally advanced, recurrent, or metastatic gastroesophageal adenocarcinoma (HER2 IHC 3+, or IHC 2+ with FISH positivity) and randomized them to one of three arms: trastuzumab plus chemotherapy, zanidatamab plus chemotherapy, or zanidatamab plus chemotherapy plus Tislelizumab(the triplet). Dual primary endpoints were progression-free survival and overall survival.

The results favored zanidatamab-based therapy across the board. Median progression-free survival was 12.4 months with both the zanidatamab-chemotherapy doublet and the triplet, compared with 8.1 months with trastuzumab-chemotherapy, and this benefit was held even in PD-L1-negative patients. Median overall survival was 26.4 months with the triplet and 24.4 months with the doublet, compared with 19.2 months with trastuzumab-chemotherapy (whose overall survival data is not mature yet.). Objective response rate approached 70% with both zanidatamab-containing regimens, and median duration of response was notably longer with the triplet (20.7 months) than with trastuzumab-chemotherapy.

This benefit came with added toxicity: more than 72% of patients on the triplet experienced a grade 3 or higher treatment-related adverse event, including infusion reactions, pulmonary toxicity, and left ventricular dysfunction, with diarrhea as the most common adverse event (occurring in roughly 20% of patients receiving zanidatamab in any arm). A mandatory diarrhea prophylaxis protocol (loperamide 4 mg twice daily for the first seven days of cycle 1) meaningfully reduced this from what would otherwise likely have exceeded 50% of patients.

What This Means for Practice

If approved based on these results, the zanidatamab-trastuzumab-chemotherapy triplet is likely to become a new frontline standard for HER2-positive metastatic gastroesophageal adenocarcinoma, though careful patient selection will be needed given the added toxicity. Mature overall survival data for the doublet versus triplet are still awaited. A notable caveat: the HERIZON-GEA-01 trial did not enroll patients in the United States (though it did include some in Canada and parts of Europe), which may factor into the timing or scope of a US approval decision.

One open, genuinely difficult question raised in discussion of this data: since PD-L1 CPS was not a stratification factor in HERIZON-GEA-01 (though it was captured retrospectively). The comparator arm in this trial did not include immunotherapy even though virtually all patients had some degree of PD-L1 positivity. The exact contribution of adding Tislelizumab to the zanidatamab-chemotherapy backbone remains somewhat uncertain, since overall survival, progression-free survival, and objective response rate were fairly similar between the doublet and triplet. The clearest signal favoring the triplet was a longer duration of response. In practice, a patient's overall performance status, comorbidities, and personal preference around toxicity are likely to matter as much as PD-L1 status in deciding whether to add Tislelizumab particularly for older patients with more medical comorbidities.

After First-Line Trastuzumab: HER2 Status Can Change

An important and underappreciated point: after progression on trastuzumab-based first-line therapy, up to 40% (and possibly considerably more, potentially 60% or higher, following newer HER2-directed regimens) of patients lose HER2 expression, driven by tumor heterogeneity, development of resistant clones, and other co-occurring mutations such as MET or ERBB2-related alterations. This makes repeat biopsy at the time of progression valuable to confirm whether HER2-directed therapy remains an appropriate option, since biopsy and tissue confirmation are key to identifying which patients can still benefit.

Several trials address this second-line and beyond setting specifically for patients who have progressed on trastuzumab:

  • The DESTINY-Gastric01 trial, a randomized phase 2 study in an Asian patient population who had progressed through at least two prior lines of therapy, found an overall survival and progression-free survival benefit for trastuzumab deruxtecan over physician's choice of chemotherapy. All patients had confirmed HER2 positivity prior trastuzumab exposure.

  • The DESTINY-Gastric02 trial extended this to a US patient population, requiring biopsy-confirmed HER2 positivity after progression on trastuzumab before randomizing patients to trastuzumab deruxtecan versus physician's choice of chemotherapy, and found an objective response rate of 38%). Based on this body of evidence, the FDA approved trastuzumab deruxtecan in January 2021 for HER2-positive, locally advanced or metastatic gastric or GEJ adenocarcinoma following a prior trastuzumab-based regimen.

  • The DESTINY-Gastric04 trial compared trastuzumab deruxtecan against ramucirumab plus paclitaxel (a standard second-line option) in patients with confirmed HER2 positivity after progression on trastuzumab and found an overall survival advantage for trastuzumab deruxtecan (14.7 versus 11.4 months), along with better objective response rate and duration of response.

Beyond two lines of HER2-directed therapy, treatment options remain an active area of investigation, with several new second-generation antibody-drug conjugates now in clinical trials for this setting.

For Patients

Treatment for advanced stomach and esophageal cancers (gastroesophageal adenocarcinoma) increasingly depends on specific markers found through testing of the tumor tissue, most importantly a protein called HER2, along with mismatch repair status, PD-L1, and a marker called Claudin 18.2. Knowing which of these markers a tumor has helps doctors choose the most effective combination of chemotherapy, targeted therapy, and immunotherapy for each patient.

A new drug called zanidatamab, which attaches to HER2 in a different way than the older drug trastuzumab, has shown the best survival results reported so far for HER2-positive gastroesophageal cancer when combined with chemotherapy and, in some cases, immunotherapy. If approved, this combination is likely to become a new standard first treatment for this type of cancer, though it does come with a real increase in side effects, including a notable risk of diarrhea (which can be reduced significantly with a preventive medication regimen), so it will not necessarily be the right choice for every patient.

For patients whose cancer progresses after initial HER2-targeted treatment, it's important to know that HER2 status can change over time, sometimes disappearing in a large proportion of patients. This means a repeat biopsy at the time of progression can be valuable to determine whether continuing HER2-directed treatment still makes sense, or whether a different approach is now more appropriate.

Anyone with newly diagnosed or progressing gastroesophageal cancer should ask their care team about biomarker testing (including HER2, PD-L1, mismatch repair, and Claudin 18.2), whether repeat biopsy at progression might change the treatment plan, and whether a clinical trial might be appropriate for their specific situation.

Key Takeaways

  • Treatment of metastatic gastroesophageal adenocarcinoma is guided by four key biomarkers: MMR, HER2, PD-L1, and Claudin 18.2, tested on available tumor tissue.

  • The phase 3 HERIZON-GEA-01 trial found that zanidatamab (a bispecific HER2-directed antibody) combined with chemotherapy, with or without Tislelizumab, produced the strongest survival results reported to date in HER2-positive gastroesophageal adenocarcinoma (median overall survival of 24.4 to 26.4 months, versus 19.2 months with trastuzumab-chemotherapy).

  • This benefit came with meaningfully more toxicity, including a diarrhea rate that requires mandatory prophylaxis, supporting careful patient selection, particularly for older or more comorbid patients.

  • Up to 40% or more of patients lose HER2 expression after first-line trastuzumab-based therapy, making repeat biopsy at progression valuable before continuing HER2-directed treatment.

  • Trastuzumab deruxtecan is FDA approved in the second-line setting following trastuzumab-based therapy, based on the DESTINY-Gastric01, -02, and -04 trials, the latter showing an overall survival advantage over ramucirumab plus paclitaxel.

References

  1. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA). Lancet. 2010;376:687-697.

  2. Janjigian YY, Kawazoe A, Yañez P, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma (KEYNOTE-811). Lancet. 2023.

  3. HERIZON-GEA-01: Zanidatamab plus chemotherapy, with or without tislelizumab/pembrolizumab, versus trastuzumab plus chemotherapy in HER2-positive gastroesophageal adenocarcinoma. Presented 2025-2026.

  4. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer (DESTINY-Gastric01). N Engl J Med. 2020;382:2419-2430.

  5. Van Cutsem E, di Bartolomeo M, Smyth E, et al. Trastuzumab deruxtecan in Western patients with HER2-positive advanced gastric or gastroesophageal junction cancer (DESTINY-Gastric02).

  6. Trastuzumab deruxtecan versus ramucirumab plus paclitaxel in HER2-positive gastric/GEJ cancer after trastuzumab-based therapy (DESTINY-Gastric04).