The treatment paradigm for HER2-positive advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma has been reshaped by the integration of immune checkpoint inhibitors into trastuzumab-based chemotherapy. The phase III KEYNOTE-811 trial established the benefit of adding pembrolizumab to trastuzumab and chemotherapy, whereas the HERIZON-GEA-01 trial, presented at 2026 ASCO GI Cancers Symposium, explored a distinct strategy – enhancing HER2 blockade itself through substitution with the bispecific antibody zanidatamab, with or without PD-1 inhibition. Below, Editorial Board member Dr Ken Kato (National Cancer Center Hospital, Tokyo, Japan) reveals why these trials are establishing new standards of care and have the potential to redefine first-line treatment strategies.
In HERIZON-GEA-01, replacing trastuzumab with zanidatamab plus chemotherapy resulted in a marked improvement in progression-free survival (PFS). Median PFS was 12.4 months with zanidatamab plus chemotherapy compared with 8.1 months in the trastuzumab-based control arm, corresponding to a hazard ratio (HR) of approximately 0.65. The addition of tislelizumab to zanidatamab and chemotherapy yielded a similar median PFS of 12.4 months with a slightly lower HR of ~0.63, suggesting that the majority of early disease-control benefit was driven by intensified HER2 targeting rather than by immunotherapy alone.
Overall survival (OS) data further differentiated the treatment strategies. In the triplet arm of zanidatamab plus tislelizumab and chemotherapy, median OS reached 26.4 months, compared with 19.2 months in the control arm (HR ~0.72), achieving statistical significance at the interim analysis. In contrast, zanidatamab plus chemotherapy without immunotherapy demonstrated a median OS of 24.4 months with an HR of ~0.80, narrowly missing statistical significance at the time of reporting. These results suggest that while enhanced HER2 blockade provides substantial survival benefit, the addition of PD-1 inhibition may be required to fully translate this benefit into a statistically robust OS advantage.
These outcomes compare favorably with those of KEYNOTE-811, in which the addition of pembrolizumab to trastuzumab and chemotherapy improved median PFS from approximately 7.3 to 10.9 months (HR ~0.72) and median OS from 15.7 to 20.1 months (HR ~0.79) in patients with PD-L1 CPS ≥1. While direct cross-trial comparisons are inherently limited, the numerically longer median PFS and OS observed in HERIZON-GEA-01—particularly in the zanidatamab-based triplet arm—raise the hypothesis that optimizing HER2 blockade may deliver deeper and more durable disease control than simply adding immunotherapy to a first-generation anti-HER2 backbone.
Safety profiles also warrant careful consideration. In HERIZON-GEA-01, diarrhea was the most characteristic adverse event associated with zanidatamab, occurring in approximately 60–65% of patients at any grade and grade ≥3 diarrhea in around 5–7%. These events were generally manageable with supportive care and dose modifications, but represent a clinically relevant toxicity distinct from that seen with trastuzumab. In contrast, KEYNOTE-811 reported lower rates of diarrhea (any grade ~35–40%, grade ≥3 <5%), with immune-related adverse events reflecting the addition of pembrolizumab. Thus, treatment selection may ultimately require balancing incremental efficacy against differing toxicity profiles.
Looking ahead, longer follow-up of OS in HERIZON-GEA-01 will be particularly informative, not only to confirm the durability of benefit but also to assess how the OS hazard ratio evolves over time. Whether the observed OS advantage with zanidatamab-based regimens is maintained, attenuated or further strengthened with extended follow-up – particularly in the setting of subsequent lines of therapy and potential crossover – will be critical for defining the true magnitude of clinical benefit. Late separation of survival curves or stabilization of the HR would further support the concept that upgrading HER2 targeting confers sustained survival advantage.
In summary, KEYNOTE-811 established the current standard by demonstrating that adding pembrolizumab to trastuzumab and chemotherapy improves PFS and OS, particularly in PD-L1–positive disease. HERIZON-GEA-01, presented at ASCO-GI 2026, extends this paradigm by showing that substituting trastuzumab with zanidatamab yields substantial gains in PFS and numerically superior OS, with further OS improvement when combined with PD-1 inhibition. Together, these trials suggest an evolution from ‘adding immunotherapy to trastuzumab’ toward ‘upgrading HER2 targeting and selectively integrating immunotherapy’, a shift that may redefine first-line treatment strategies for HER2-positive gastric and GEJ adenocarcinoma as longer-term survival data mature.
Disclosure: Ken Kato has no financial or non-financial conflicts of interest to declare in relation to this article.
This content has been developed independently by Touch Medical Media for touchONCOLOGY. It is not affiliated with the 2026 ASCO GI Cancers Symposium. Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Cite: ASCO GI26 highlights: HERIZON-GEA-01 and KEYNOTE-811. touchONCOLOGY. January 22nd, 2026
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