ASCO GI 2026 | HERIZON-GEA-01: zanidatamab ± tislelizumab & chemotherapy for HER2+ GEA

So zanidatamab is a bi-specific or bi-protic agent for two epitopes or different binding sites of HER2. So this is close to that of trastuzumab and pertuzumab combination, but this is a bi-specific and bi-protic agent and more efficiently induced binding, especially at the trastuzumab shape, and induced clustering of receptor, more down-regulation, and more activation of complement-dependent site toxicity. And it already showed very nice single-agent activity, as well as the combination activity with chemo and immunotherapy. And this ARIZONA trial is a global phase 3 trial. We, Japan, also enroll many patients. And as a result, it clearly improved the PFS with chemo, zanidatamab , and tucotuzumab combination compared with current previous standard of care TOGA regimen. And also it showed a benefit or positive outcome even with a double rate with chemo zanidatamab compared with chemo strap alone. And overall survival was also met with a triplet combination with a significant difference of median survival by seven months, which was unachievable with any other previous agent. And doublet arm also showed five-month difference. But still, this is not statistically significant at this internal analysis, so we need additional analysis to conclude. The response rate was not so largely different between two or three arms, but the duration of response is clearly different with longer with triplet combination with zanidatamab and T3A combination. And doublet also showed a longer duration of response compared with control arm. Regarding safety profile, we observed the higher incidence of diarrhea with a doublet or triplet, and this is expected based on previous study because zanidatamab targets not only for HER2, but also heterodimer between HER2 and EGFR, and this EGFR signaling inhibition lead to diarrhea, based on my understanding. But usually this happens at a very early time period, and the prophylactic use of anti-diarrheal medication like alophenide is clearly helpful, and usually interruption of chemotherapy like capecitabine is also enough to reduce this kind of diarrhea. So while the safety profile is consistent with the previous report, although the GI toxic striker diarrhea is more commonly observed. But considering the benefit and risk ratio, clearly the magnitude of survival benefit is more compared with the toxicity increase. So overall, I think this could be one of the new standard of care, especially for patients who are fit for intensive treatment. And another interesting aspect is a biomarker analysis. All those exploratory, it should benefit regardless of PD-L1 status. So this is different from Keynote 811, which shows a benefit only in patients with PD-L1-positive or CPS1 or greater. Again, the analysis is exploratory, but maybe zolnidatamab induced more immunological reaction-like or complement-dependent site toxicity, which may change the tumor microenvironment to enhance activity of checkpoint blockade. Surely, we need a more robust data from DAVLET to consider component contribution of T-SULA, but overall, this study is very outstanding trial to show the very remarkable advance, and this should be the first time for us to see their median survival of more than two years in gastric cancer field.

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