Kohei Shitara, Elena Elimova, Sun Young Rha, Lin Shen, T. Liu, J. Tabernero, K.-W. Lee, M. Schenker
9 min
Standard first-line treatment for HER2-positive advanced gastroesophageal adenocarcinoma typically involves platinum-based chemotherapy combined with the monoclonal antibody trastuzumab. However, clinical outcomes remain limited. This phase 3, open-label, randomized trial (HERIZON-GEA-01) evaluated whether zanidatamab—a bispecific antibody that binds to two distinct domains of the HER2 receptor—could offer superior efficacy when added to chemotherapy, compared to the current standard of trastuzumab plus chemotherapy. Researchers also tested whether adding the PD-1 inhibitor tislelizumab to the zanidatamab regimen provided further benefit. The trial enrolled 914 patients across 33 countries, comparing three arms: zanidatamab-tislelizumab-chemotherapy, zanidatamab-chemotherapy, and the control arm of trastuzumab-chemotherapy.
At a median follow-up of 25.9 months, both zanidatamab-based regimens showed significantly longer progression-free survival (median 12.4 months for both) compared to the trastuzumab-chemotherapy control (median 8.1 months). When examining overall survival, the triple-therapy regimen (zanidatamab-tislelizumab-chemotherapy) was superior to the control (median 26.4 months vs. 19.2 months). In the interim analysis, the zanidatamab-chemotherapy group (without tislelizumab) demonstrated a median overall survival of 24.4 months, but this did not meet the prespecified threshold for statistical significance (P=0.06).
The safety profile was consistent with the known toxicities of the agents involved. Diarrhea was the most common high-grade adverse event, appearing more frequently in the zanidatamab-containing groups (up to 24.8% for grade 3+) than in the trastuzumab group (12.9%). Prophylactic measures for infusion reactions and diarrhea were implemented, which helped manage the clinical burden. While these findings position zanidatamab as a potent new option, clinicians should monitor for higher rates of gastrointestinal events. These results suggest that zanidatamab may eventually displace trastuzumab as a cornerstone of first-line therapy for this specific patient population.
BACKGROUND Zanidatamab, a dual human epidermal growth factor receptor 2 (HER2)–targeted bispecific antibody, plus chemotherapy both with and without tislelizumab (anti–programmed death 1), showed encouraging efficacy and safety as first-line therapy in phase 2 studies involving patients with HER2-positive gastroesophageal adenocarcinoma. METHODS In an open-label, phase 3 trial, we randomly assigned, in a 1:1:1 ratio, patients with previously untreated, centrally confirmed HER2-positive advanced gastroesophageal adenocarcinoma to receive zanidatamab and tislelizumab plus chemotherapy, zanidatamab plus chemotherapy, or trastuzumab plus chemotherapy. The two primary end points were progression-free survival and overall survival. RESULTS At a median follow-up of 25.9 months, progression-free survival was longer with zanidatamab–tislelizumab–chemotherapy (median among 302 patients, 12.4 months) and zanidatamab–chemotherapy (median among 304 patients, 12.4 months) than with trastuzumab–chemotherapy (median among 308 patients, 8.1 months) (hazard ratio for progression or death with zanidatamab–tislelizumab–chemotherapy, 0.63 [95% confidence interval {CI}, 0.51 to 0.78]; hazard ratio with zanidatamab–chemotherapy, 0.65 [95% CI, 0.52 to 0.81]; P<0.001 for both comparisons). Overall survival was longer with zanidatamab–tislelizumab–chemotherapy than with trastuzumab–chemotherapy (median, 26.4 vs. 19.2 months; hazard ratio for death, 0.72; 95% CI, 0.57 to 0.90; P=0.004). At this interim analysis, overall survival did not differ significantly between zanidatamab–chemotherapy (median, 24.4 months) and trastuzumab–chemotherapy (hazard ratio, 0.80; 95% CI, 0.64 to 1.01; P=0.06). The incidence of grade 3 or higher adverse events was 83.3% with zanidatamab–tislelizumab–chemotherapy, 73.8% with zanidatamab–chemotherapy, and 74.5% with trastuzumab–chemotherapy; diarrhea was the most common such event, in 24.8%, 20.0%, and 12.9% of patients, respectively. CONCLUSIONS Zanidatamab plus chemotherapy, both with and without tislelizumab, led to longer progression-free survival than trastuzumab plus chemotherapy among patients with HER2-positive advanced gastroesophageal adenocarcinoma. At this interim analysis, overall survival was longer with zanidatamab–tislelizumab–chemotherapy than with trastuzumab–chemotherapy; further analyses are planned to assess zanidatamab–chemotherapy. Diarrhea was a common adverse event. (Funded by Jazz Pharmaceuticals and others; HERIZON-GEA-01 ClinicalTrials.gov number, NCT05152147.)
Alex: Before we get to that comparison, why add a separate immunotherapy if the antibody already recruits immune activity?
Sam: The added drug is tislelizumab. It blocks programmed death one, or PD-1, an immune checkpoint. The hypothesis was that combining this blockade with zanidatamab’s immune effects would further strengthen the response against the tumor.
Alex: That gives the study two related questions: whether replacing the HER2 antibody helps, and whether the immunotherapy-containing combination helps. How did they organize the test?
Sam: They randomly assigned 914 patients across an international network of hospitals. Everyone was assigned chemotherapy. One group received trastuzumab, another zanidatamab, and another zanidatamab together with tislelizumab.
Alex: With a targeted treatment, misclassifying the target could muddy the result. How did they establish that patients belonged in this population?
Sam: A central laboratory confirmed HER2 positivity before enrollment. Patients had unresectable or advanced disease and relatively preserved daily functioning. They had not received systemic treatment for advanced disease, or previous HER2-targeted drugs or checkpoint inhibitors.
Alex: And what counted as success? Tumor shrinkage can be useful, but it is not the same as extending life.
Sam: The two primary outcomes were progression-free survival and overall survival. Progression-free survival means time until the cancer worsens or the patient dies. Although treatment was open-label, an independent review team, blinded to treatment assignment, assessed progression from scans.
Alex: That separation matters: patients and clinicians knew the treatment, but the central scan reviewers did not. What did those reviewers find?
Sam: Median progression-free survival was 12.4 months with either zanidatamab regimen, compared with 8.1 months with trastuzumab and chemotherapy. Both comparisons were statistically significant. Alternative analyses using different rules for handling the follow-up data gave consistent results.
Alex: The same median in the two experimental groups could tempt someone to say immunotherapy added nothing. Is that a fair reading?
Sam: No. Equal medians do not establish equal outcomes across the full follow-up period. The stated testing strategy compared each experimental regimen with trastuzumab and chemotherapy. It does not establish the incremental benefit of tislelizumab through a definitive comparison between the experimental groups.
Alex: Then the survival result becomes especially important. Did the combination actually extend life against the comparator?
Sam: Median overall survival was 26.4 months with zanidatamab, tislelizumab, and chemotherapy, compared with 19.2 months with trastuzumab and chemotherapy. That difference met the trial’s prespecified significance criteria. It was observed at the first interim survival analysis.
Alex: What about replacing trastuzumab without adding the immunotherapy? That could matter for patients who cannot receive it.
Sam: Survival was numerically longer with zanidatamab and chemotherapy alone, but that comparison did not meet the prespecified significance criteria. Further survival analyses are planned. For now, the established benefit for that regimen is delayed progression, not a demonstrated extension of life.
Alex: The gains need a toxicity account alongside them. What did patients experience?
Sam: About 83 percent of patients receiving the immunotherapy-containing combination had an adverse event of grade three or higher, meaning severe or worse. That proportion was higher than with trastuzumab and chemotherapy. Serious adverse events and treatment discontinuations were also more frequent.
Alex: Which adverse effect most clearly separated the antibody treatments?
Sam: Severe or worse diarrhea affected about a quarter of patients receiving the immunotherapy-containing combination, compared with about thirteen percent receiving trastuzumab and chemotherapy. Diarrhea was also more frequent with zanidatamab without tislelizumab. It generally began early in treatment.
Alex: Was this observed without preventive treatment, or did it happen despite precautions?
Sam: The zanidatamab groups received mandatory diarrhea prevention during the first treatment cycle, plus medication to prevent infusion reactions. The authors suggest those precautions reduced high-grade diarrhea relative to earlier trials. Adding tislelizumab also introduced immune-mediated adverse events, mostly mild or moderate.
Alex: Now the main limitation: a contemporary regimen can include pembrolizumab. Why was that not the comparator?
Sam: The trial was designed before the relevant pembrolizumab results were reported. Trastuzumab plus chemotherapy reflected standard care at that time. The study therefore cannot tell us whether this new combination is superior to trastuzumab, pembrolizumab, and chemotherapy.
Alex: The authors report survival results consistent across immune-marker subgroups. Could that close the gap indirectly?
Sam: It cannot. The marker was programmed death ligand one, or PD-L1, a protein used to characterize immune-checkpoint signaling. Those subgroup analyses were exploratory and underpowered, with no definitive subgroup conclusions justified. They also cannot substitute for a missing treatment comparison.
Alex: So who should read the full document, and where should they begin?
Sam: Researchers in gastrointestinal oncology, HER2-targeted therapy, or antibody–immunotherapy combinations should read it closely. Start with the Efficacy section, separating progression from survival and the two experimental comparisons. Then read Safety, and the Discussion’s account of the outdated comparator and remaining survival follow-up.
Alex: And for a researcher outside those areas, what is the line to remember?
Sam: This trial found better disease control with both new antibody regimens, and longer survival with the immunotherapy-containing combination. But beating the tested treatment does not establish superiority over today’s immunotherapy-containing alternative.
Alex: Keep that comparison in mind when you read the claim.