Zanidatamab-Based Regimens Redefine First-Line Treatment of HER2-Positive Gastroesophageal Adenocarcinoma

Clinical Summary: 

• Design/Population: The phase 3 HERIZON-GEA-01 trial evaluated first-line zanidatamab plus chemotherapy, with or without tislelizumab, versus trastuzumab plus chemotherapy in patients with HER2-positive gastroesophageal adenocarcinoma.
• Key Outcomes: Zanidatamab-based therapy improved outcomes compared with trastuzumab plus chemotherapy, with the triplet of zanidatamab, tislelizumab, and chemotherapy demonstrating progression-free and overall survival benefit. Clinical benefit with the triplet was observed irrespective of PD-L1 status, although diarrhea was an important treatment-related toxicity requiring proactive management.
• Clinical Relevance: These findings establish zanidatamab-based therapy as a new first-line treatment option for HER2-positive gastroesophageal adenocarcinoma and expand the integration of immunotherapy irrespective of PD-L1 status.

Geoffrey Ku, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses how findings from the phase 3 HERIZON-GEA-01 trial are reshaping first-line treatment of HER2-positive gastroesophageal adenocarcinoma following the approval of zanidatamab plus chemotherapy, with or without tislelizumab.

He reviews the progression-free and overall survival benefits observed with zanidatamab-based therapy compared with trastuzumab plus chemotherapy and explains how the results establish zanidatamab as a new HER2-directed treatment option in the first-line setting.

Dr Ku also discusses the added role of tislelizumab, including the clinical benefit observed irrespective of PD-L1 status, and how these findings may influence selection between the approved zanidatamab-based regimens. Finally, he highlights diarrhea as an important treatment-related toxicity and discusses the role of proactive management in maintaining therapy and maximizing clinical benefit.

Transcript: 

Hi, I'm Geoffrey Ku. I'm a GI medical oncologist at Memorial Sloan Kettering, and my research focuses on esophageal and gastric cancer. 

I think today is a landmark day and we really have practice-changing and groundbreaking data based on the approval of zanidatamab as first-line therapy for HER2-positive gastroesophageal cancer. This is based on the HERIZON-GEA-01 study, which is a global, randomized study that compared zanidatamab-containing regimens to the control arm of trastuzumab and chemotherapy.

The study demonstrated that zanidatamab with chemotherapy, with or without tislelizumab, has really established a new standard of care compared to trastuzumab and chemotherapy in terms of improving progression-free survival, as well as overall survival in the arm containing zanidatamab, tislelizumab, which is an anti-PD-1 antibody, and chemotherapy.

The HERIZON-GEA-01 study had 2 experimental arms: Arm B was zanidatamab and chemotherapy, and arm C was the combination of zanidatamab, tislelizumab, and chemotherapy. Both of these arms were compared independently to the control arm which is trastuzumab and chemotherapy.

Essentially, the study showed that arm C, which was zanidatamab, tislelizumab, and chemotherapy, was superior to trastuzumab and chemotherapy. One of the very pleasant surprises from this study was that all patients who received the combination of zanidatamab, tislelizumab, and chemotherapy seemed to benefit irrespective of PD-L1 status. 

In this study, ⅓ of patients had PD-L1-negative tumors and those patients seemed to derive benefit from the triplet combination of zanidatamab, tislelizumab, and chemotherapy. This is in contrast to the previous front-line regimen of pembrolizumab, trastuzumab, and chemotherapy in which the benefit really seemed to be restricted only to tumors that were PD-L1 positive. 

The FDA approval for zanidatamab and chemotherapy, with or without tislelizumab—so both combinations were approved—is actually irrespective of PD-L1 status. Specifically, when we're considering the triplet combination of zanidatamab, tislelizumab, and chemotherapy it really can be offered irrespective of PD-L1 status because all patients seem to derive benefit. 

I think there's a lot to kind of tease apart in the study because of the three-arm design. The way I think about it is that arm B versus arm A, so zanidatamab and chemotherapy versus trastuzumab and chemotherapy, essentially shows that zanidatamab is the superior anti-HER2 therapy compared to trastuzumab. 

At the same time, when we look at arm C versus arm B, keeping in mind that the study was not designed for a direct comparison of both experimental arms, all oncologists and even patients will be interested in the comparison between both experimental arms. I do think that the addition of tislelizumab conveys an additional incremental benefit to zanidatamab and chemotherapy, just like we saw in KEYNOTE-811, where the addition of pembrolizumab to trastuzumab and chemotherapy conveys additional benefit as well.

I think the very pleasant surprise was that the triplet combination of zanidatamab, tislelizumab, and chemotherapy seems to benefit all patients irrespective of PD-L1 status. So, I think that all of that is upside and good news. The one thing I'm always also very quick to add is that we do have to be mindful of the toxicity of zanidatamab-containing regimens, which really is diarrhea. 

There was a grade 3/4 diarrhea rate of 20% with zanidatamab and chemotherapy and 25% with the addition of tislelizumab to the doublet combination. Now, the good news is that the diarrhea can be managed, patients do have to be on mandatory loperamide prophylaxis for the first week. Beyond that, I think if they have ongoing diarrhea symptoms, they should continue with loperamide. 

Grade 3/4 diarrhea typically developed around day 7 and typically resolved after about 14 to 21 days. Less than 5% of patients had to discontinue zanidatamab because of the diarrhea.So, the diarrhea is absolutely something we have to be mindful of on behalf of our patients, it's something we have to very carefully manage. But I think as long as it's carefully managed, it really results in treatment discontinuation of zanidatamab very, very rarely and does allow patients to experience the benefit of the regimen.

Source: 

Shitara K, Elimova E, Liu T, et al. Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. N Engl J Med. Published online: May 27, 2026. doi: 10.1056/NEJMoa2517729