Zanidatamab Triplet May Be a “Game Changer” for Frontline Management of HER2+ GEA

As the first phase 3 study in more than 15 years to show benefit with a regimen other than standard trastuzumab (Herceptin) plus chemotherapy with/without pembrolizumab (Keytruda) as a first-line treatment in HER2-positive gastroesophageal adenocarcinoma (GEA), HERIZON-GEA-01 (NCT05152147) data support expanded access to zanidatamab-hrii (Ziihera)–based combinations for patients regardless of PD-L1 expression, according to experts.

Results from an interim analysis of HERIZON-GEA-01 presented at the American Society of Clinical Oncology (ASCO) 2026 Gastrointestinal (GI) Cancers Symposium showed statistically significant overall survival (OS) and progression-free survival (PFS) benefits with zanidatamab plus tislelizumab (Tevimbra) and chemotherapy compared with trastuzumab (Herceptin) and chemotherapy.¹ Of note, PFS and OS benefits were generally consistent with both zanidatamab-based regimens across key prespecified subgroups, including geographic region and PD-L1 tumor area positivity (TAP) score.

For an expert perspective on the significance of these data and their implications for clinical practice, OncLive spoke with Raji Shameem, MD, a medical oncologist and hematologist at Orlando Health Cancer Institute in Florida, and Manish A. Shah, MD, director of the Gastrointestinal Oncology Program at Weill Cornell Medicine, as well as chief of the Solid Tumor Service and codirector of the Center for Advanced Digestive Care at NewYork-Presbyterian in New York, New York.

“As a next-generation HER2-targeting drug that binds to both [HER2 domains], zanidatamab has shown it is likely better than trastuzumab,” Shah explained. “Notably, the duration of response when tislelizumab is added [to zanidatamab and chemotherapy] is remarkably high. If the toxicity is managed appropriately, patients will benefit.”

“I definitely feel that this will be a game changer for our patients with metastatic HER2-positive upper GI cancer,” Shameem agreed. “It was [arguably one of] the most important presentations at ASCO GI.”

OncLive: What is unique about the mechanism of zanidatamab, and how does this support its use in combination with PD-1 inhibitors?

Shameem: Zanidatamab is a bispecific, biparatropic, anti-HER2 agent. It binds to 2 different epitopes of HER2—extracellular domains 2 and 4—causing a conformational change and HER2 internalization. [Findings from] preclinical studies also showed that it can enhance immune-mediated cytotoxicity by activating complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. It is a novel, first-in-class agent. It already has approval for previously treated HER2-positive biliary tract cancer, and it is a drug I have utilized in my clinic for those patients.

Shah: The data suggest that [zanidatamab] is also a stronger, more potent activator of an immune signal against the antibody HER2 complex. Regarding its [use in] combination with immunotherapy, we know from earlier studies that if a tumor overexpresses PD-L1, adding pembrolizumab to chemotherapy and trastuzumab provides a survival advantage.

What was notable about the trial design?

Shameem: HORIZON-GEA-01 [was designed to evaluate] the combination of zanidatamab plus another immunotherapy drug, tislelizumab. Tislelizumab also has [FDA] approval for upper GI cancer in combination with chemotherapy. There were 3 arms [in HERIZON-GEA]: one arm consisted of tislelizumab, zanidatamab, and chemotherapy; another arm consisted of zanidatamab plus chemotherapy; and the control arm was trastuzumab plus chemotherapy.

Many individuals asked why there was not an arm with pembrolizumab plus trastuzumab plus chemotherapy. Although that is a relevant question, at the time the trial was conducted, there were global regulatory limitations, and not all patients were able to receive pembrolizumab. Interestingly, this trial included patients who expressed PD-L1 as well as those who did not.

What were the key efficacy results from HERIZON-GEA? How do these results compare with historical benchmarks from KEYNOTE-811?

Shameem: Our current treatment paradigm is based on [data from the phase 3] KEYNOTE-811 [NCT03615326], which [evaluated] the combination of chemotherapy, trastuzumab, and pembrolizumab. This is our go-to regimen for HER2-positive metastatic upper GI cancers. Per the FDA, pembrolizumab in combination with chemotherapy and trastuzumab is indicated for patients expressing PD-L1 with a combined positive score [CPS] of 1 or greater. Historically, that trial showed a [median] PFS of [10.9] months and a [median] OS of [20 months].^2,3 The HERIZON-GEA-01 trial sought to improve outcomes for these HER2-positive patients.

Shah: The first end point was PFS of the triplet [n = 302] vs trastuzumab and chemotherapy [n = 308], and the results were quite significant.¹ The median PFS improved from 8.1 months [95% CI, 7.0-8.9] with trastuzumab and chemotherapy to 12.4 months [95% CI, 9.8-18.5] with the triplet. The HR was 0.63 [95% CI, 0.51-0.78; P < .0001], representing a 37% reduction in the risk of progression for those receiving the triplet. At the 2-year landmark, the PFS rate for the standard of care was 15.6% [95% CI, 10.1%-22.1%]. In contrast, with the zanidatamab triplet, the 2-year PFS rate was 38.2% [95% CI, 31.4%-45.0%], which is more than double the standard rate. We also looked at PFS for zanidatamab and chemotherapy vs trastuzumab and chemotherapy and saw similar benefits, [but the data suggest] that tislelizumab provides a modest benefit.

Regarding OS, the triplet showed significant improvement; the median OS was 26.4 months [95% CI, 21.5-30.3] compared with 19.2 months [95% CI, 16.8-21.8] for trastuzumab and chemotherapy [HR 0.72; 95% CI, 0.57-0.90; P = .0043]. At 2 years, 54.3% [95% CI, 47.6%-60.5%] of patients were still alive with the triplet vs 38.8% [95% CI, 32.2%-45.4%] in the control arm. There were also improvements in response rates with the addition of zanidatamab and immunotherapy. These data look quite compelling, and we’re hopeful that we’ll have approval to use it soon.

What primary safety concerns were associated with zanidatamab, and how were these managed during the trial?

Shameem: [If we administer zanidatamab], we must counsel patients about diarrhea. Diarrhea tends to occur early on but generally improves over time. In this trial, antidiarrheal prophylaxis was mandated, requiring patients to take loperamide at 4 mg twice daily during the first week of cycle 1. There were reported cases of diarrhea, but the majority were low grade, and the median time to resolution was approximately 3 weeks. We acknowledge that toxicity can occur, but there were no new safety signals compared [with] our historical baseline for these agents.

Unlike the standard triplet regimen comprising trastuzumab, chemotherapy, and pembrolizumab, which is only indicated for patients with PD-L1–positive tumors, the HERIZON-GEA trial showed benefit with the zanidatamab triplet in all-comers. What could these results mean for patients with PD-L1–negative disease, in terms of expanding access to effective therapy?

Shah: In the comparison of the zanidatamab triplet vs trastuzumab and chemotherapy, we saw that patients with PD-L1 TAP less than 1 still experienced a benefit. We still need to examine the data comparing zanidatamab plus tislelizumab and chemotherapy vs zanidatamab and chemotherapy alone to isolate the benefit of tislelizumab in high vs low PD-L1 populations. Current guidance for other immunotherapies is to limit use to scores of 1 or higher, partly because some patients with PD-L1 less than 1 had no survival benefit or even worse outcomes with pembrolizumab. However, with zanidatamab, which is a better activator of the immune system, it is possible that the PD-L1 score matters less and that adding tislelizumab is effective regardless. It will be helpful to see the rest of those data before making firm decisions.

Based on these results, do you agree that zanidatamab-based regimens have the potential to replace trastuzumab in the first-line setting? In which patient populations do you think it could be used without immunotherapy in this setting?

Shah: I believe zanidatamab is a better way to target HER2 than trastuzumab [based on] the data so far. The triplet is very active and compelling. There aren’t absolute contraindications, necessarily. We just need to be aware that the diarrhea can be an issue and to select patients accordingly. For instance, if a patient has a job that would be compromised by significant diarrhea, that is a consideration, as you do not see the same degree of diarrhea with trastuzumab. Apart from that, most HER2-positive patients should be eligible.

Zanidatamab currently holds accelerated FDA approval in previously treated HER2-positive biliary tract cancer. What further efficacy data are expected to read out from this study, and how might they further support the transition of zanidatamab into the first line?

Shah: It is terrific that we already have approval in biliary tract cancer, and many GI oncologists already have experience with zanidatamab. The study included 30% of patients from North America and Europe, which is a sizable [proportion]. Hopefully, the FDA will grant approval to the triplet combination in gastric cancer. [Because] this study did not compare the triplet with trastuzumab, pembrolizumab, and chemotherapy, we will likely have 2 options for PD-L1–positive tumors. There are other HER2-targeted agents like fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] that are approved in the second-line setting, and tucatinib is another FDA-approved HER2-targeted TKI.

From a drug development standpoint, we do not yet know the efficacy of T-DXd following zanidatamab; we need data on that. My expectation is that zanidatamab will likely replace trastuzumab in the first-line setting and that tislelizumab will be approved for use in combination. There were no real unexpected adverse effects from tislelizumab. It is a good combination, and the investigators should be complimented for completing this important study.

References

1. Elimova E, Rha SY, Shitara K, et al; on behalf of the HERIZON-GEA-01 study group. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): primary analysis from HERIZON-GEA-01. J Clin Oncol. 2026;44(suppl 2):LBA285. doi:10.1200/JCO.2026.44.2_suppl.LBA285
2. FDA approves pembrolizumab for HER2-positive gastric or gastroesophageal junction adenocarcinoma expressing PD-L1 (CPS ≥ 1). FDA. March 19, 2025. Accessed February 10, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-her2-positive-gastric-or-gastroesophageal-junction-adenocarcinoma
3. Janjigian YY, Kawazoe A, Bai Y, et al. Final overall survival for the phase III, KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2+ advanced, unresectable or metastatic G/GEJ adenocarcinoma. Ann Oncol. 2024;35(suppl 2):S877-S878. doi:10.1016/j.annonc.2024.08.1466