The FDA has approved zanidatamab-hrii (Ziihera) in combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab-jsgr (Tevimbra) as first-line treatment for adult patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH] positive), unresectable locally advanced or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma, as detected by an FDA-approved test; and zanidatamab in combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for adult patients with HER2-positive (IHC 3+) unresectable locally advanced or metastatic gastric, GEJ, or esophageal adenocarcinoma, as detected by an FDA-approved test.1
The FDA also approved 2 companion diagnostics, the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the VENTANA HER2 Dual ISH DNA Probe Cocktail, for identifying patients with HER2-positive (IHC3+ or IHC2+/ISH+) gastric, GEJ, and esophageal adenocarcinoma who are eligible for treatment with zanidatamab.
The approvals were based on findings from the phase 3 HERIZON-GEA-01 trial (NCT05152147). In the trial’s primary analysis, zanidatamab plus tislelizumab and chemotherapy elicited a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with trastuzumab (Herceptin) plus chemotherapy.1,2 The median PFS in the intention-to-treat (ITT) population was 12.4 months (95% CI, 9.8-18.5) with zanidatamab plus tislelizumab and chemotherapy (n = 302) vs 8.1 months (95% CI, 7.0-8.9) with trastuzumab plus chemotherapy (n = 308; HR, 0.63; 95% CI, 0.51-0.78; P < .0001). The median OS was 26.4 months (95% CI, 21.5-30.3) vs 19.2 months (95% CI, 16.8-21.8), respectively (HR, 0.72; 95% CI, 0.57-0.90; P = .0043).
The regimen was previously granted priority review in April 2026 under the Real-Time Oncology Review program.3
Zanidatamab Is FDA Approved As a New Frontline Standard in HER2+ Gastric Cancer
- The FDA has approved zanidatamab plus chemotherapy, with or without tislelizumab, for the management of first-line HER2-positive unresectable locally advanced or metastatic gastric cancer, based on data from the HERIZON-GEA-01 trial.
- The zanidatamab/tislelizumab/chemotherapy triplet reduced the risk of disease progression or death by 37% (HR, 0.63) and improved median OS by more than 7 months (26.4 vs 19.2 months; HR, 0.72) compared with trastuzumab plus chemotherapy.
- PD-L1 subgroup analyses presented at the 2026 ASCO Annual Meeting confirmed that PFS and OS benefits were consistent regardless of PD-L1 status by TAP score or CPS.
How was the HERIZON-GEA-01 trial designed?
HERIZON-GEA-01 is a global, randomized, open-label, multicenter phase 3 trial that enrolled previously untreated patients with locally advanced, unresectable, recurrent, or metastatic HER2-positive gastroesophageal adenocarcinoma (GEA), defined as IHC 3+ or IHC 2+/ISH+ disease.2 Patients were randomly assigned 1:1:1 to receive trastuzumab plus chemotherapy, zanidatamab plus chemotherapy (n = 304), or zanidatamab plus tislelizumab and chemotherapy. The chemotherapy backbone consisted of investigator’s choice of capecitabine plus oxaliplatin, or fluorouracil plus cisplatin.
The study’s dual primary end points were PFS by blinded independent central review (BICR) and OS; key secondary end points included objective response rate (ORR) and duration of response (DOR).
What are notable additional efficacy data from HERIZON-GEA-01?
Additional efficacy data showed that at a median follow-up of 25.9 months (range, 7.5-46.0), the triplet regimen of zanidatamab plus tislelizumab and chemotherapy continued to demonstrate durable PFS and OS benefit over trastuzumab plus chemotherapy, with 18-month PFS rates of 43.9% (95% CI, 37.4%-50.1%) in the triplet arm, 38.0% (95% CI, 31.5%-44.4%) in the zanidatamab/chemotherapy doublet arm, and 20.9% (95% CI, 15.3%-27.2%) in the control arm. Both zanidatamab-containing regimens elicited prolonged DORs relative to trastuzumab plus chemotherapy, with the median DOR reaching 20.7 months (95% CI, 12.6-37.7) in the triplet arm, 14.3 months (95% CI, 11.5-21.9) in the zanidatamab doublet arm, and 8.3 months (95% CI, 6.7-9.8) in the control arm.
Data from a preplanned PD-L1 subgroup analysis, which used both the prespecified PD-L1 tumor area positivity (TAP) score and the exploratory combined positive score (CPS) with a cutoff of 1, were shared during the 2026 ASCO Annual Meeting.4 These data showed that the PFS and OS benefits with the zanidatamab triplet were consistent regardless of PD-L1 expression, including among patients with TAP less than 1% (PFS HR, 0.47; OS HR, 0.49) and a CPS less than 1 (PFS HR, 0.48; OS HR, 0.43).
What is the safety profile of these zanidatamab-based regimens?
The safety profiles of the zanidatamab-based regimens were considered manageable, with no new safety signals identified across either investigational arm.2 Diarrhea was the most common adverse effect (AE) observed with zanidatamab-containing regimens but was generally manageable with prophylaxis, allowing most patients to continue treatment; grade 3 or higher diarrhea occurred in 24.8% of patients in the triplet arm, 20.0% of those in the zanidatamab doublet arm, and 12.9% of those in the control arm. As expected given the addition of an immune checkpoint inhibitor, the triplet regimen was also associated with immune-mediated AEs reflective of tislelizumab exposure, alongside higher rates of treatment discontinuation and interruption relative to the zanidatamab doublet and control arms.
References
- FDA approves zanidatamab-hrii and tislelizumab-jsgr for HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma. FDA. August 25, 2026. Accessed August 25, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanidatamab-hrii-and-tislelizumab-jsgr-her2-positive-gastric-gastroesophageal-junction
- Shitara K, Elimova E, Liu T, et al; HERIZON-GEA-01 Investigators. Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. N Engl J Med. 2026;394(20):2002-2014. doi:10.1056/NEJMoa2517729
- Jazz Pharmaceuticals announces FDA acceptance and priority review of supplemental biologics license application for Ziihera (zanidatamab-hrii) combinations in first-line HER2+ locally advanced or metastatic GEA. News release. Jazz Pharmaceuticals. April 27, 2026. Accessed August 26, 2026. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-fda-acceptance-and-priority-0
- Rha SY, Shitara K, Lin S, et al. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (mGEA): PD-L1 subgroup analysis from HERIZON-GEA-01. J Clin Oncol. 2026;44(suppl 16):4010. doi:10.1200/JCO.2026.44.16_suppl.4010
