FDA Grants Priority Review to Zanidatamab Combos in HER2+ Gastroesophageal Adenocarcinoma

The FDA has granted a priority review to a supplemental biologics license application (sBLA) for zanidatamab-hrii (Ziihera) containing regimens for the frontline treatment of patients with HER2-positive unresectable locally advanced or metastatic gastric, gastroesophageal junction (GEJ), or gastroesophageal adenocarcinoma (GEA).¹ 

The sBLA is supported by findings from the phase 3 HERIZON-GEA-01 trial (NCT05152147). Results from the study shared at the 2026 Gastrointestinal Cancers Symposium showed that the median progression-free survival (PFS) was 12.4 months among patients treated with zanidatamab plus tislelizumab and chemotherapy (n = 302) compared with 8.1 months in the trastuzumab plus chemotherapy arm (n = 308; HR, 0.63; 95% CI, 0.51-0.78; P <.0001).² The median PFS was also 12.4 months  (95% CI, 9.8-14.5; HR, 0.65; 95% CI, 0.52-0.81; P <.0001) in a cohort of patients treated with zanidatamab plus chemotherapy alone (n = 304).

The median overall survival (OS) was 26.4 months vs 19.2 months in the zanidatamab plus tislelizumab and chemotherapy arm vs the control arm of trastuzumab plus chemotherapy, respectively. This difference trended toward significance but fell short of the prespecified threshold at the first interim analysis (HR, 0.72; 95% CI, 0.57-0.90; P = .0043). There is an additional OS analysis scheduled for this year.³ 

There were no new safety signals with zanidatamab or tislelizumab compared with prior use of the treatments and investigators considered the zanidatamab–based regimens to have generally manageable safety profiles.

The sBLA is being reviewed under the FDA’s Real-Time Oncology Review program. The FDA has set a Prescription Drug User Fee Act action date of August 25, 2026.¹

"The HERIZON-GEA-01 trial results are practice changing, supporting the potential of zanidatamab as the HER2-targeted agent-of-choice in HER2+ first-line locally advanced or metastatic GEA. Importantly, the results demonstrated adding tislelizumab to zanidatamab plus chemotherapy further enhanced clinical benefit and marked the first immuno-oncology combination to show efficacy across both PD-L1–positive and PD-L1–negative tumors in this clinical setting," Rob Iannone, MD, MSCE, executive vice president, global head of R&D, and chief medical officer of Jazz Pharmaceuticals, stated in a news release.¹ "We look forward to continuing to work closely with the FDA to obtain approval and quickly bring zanidatamab to market for GEA patients in need of new options.”

HERIZON-GEA-01 Design, Patient Data, and Additional Safety Insight

HERIZON-GEA-01 is a global, randomized phase 3 trial evaluating zanidatamab-based regimens compared with trastuzumab plus chemotherapy as first-line treatment for patients with HER2-positive metastatic gastroesophageal adenocarcinoma. The trial has dual primary endpoints of PFS and OS. It is an open-label study in which eligible patients were randomized 1:1:1 to 1 of 3 arms: zanidatamab plus tislelizumab and chemotherapy; zanidatamab plus chemotherapy alone; or trastuzumab plus chemotherapy (control arm).

To qualify for inclusion, patients had to be 18 years or older, have unresectable locally advanced or metastatic GEA, be HER2-positive via immunohistochemistry, have an ECOG performance status of 0 or 1, be treatment naive for locally advanced or metastatic disease, and have received no prior HER2-targeted therapy or immunotherapy in any setting. HER2 positivity was confirmed centrally and defined as IHC 3+ or IHC 2+/ISH+. Patients were enrolled regardless of PD-L1 status.

A total of 914 patients were randomized between December 2021 and February 2025, with demographics and baseline disease characteristics balanced across arms. Median age was approximately 63 years, with the majority of patients having metastatic disease at enrollment. HER2 IHC 3+ disease was present in over 80% of patients across arms, and PD-L1 tumor area positivity scores were distributed across both less than 1% and greater than or equal to 1% categories.

Any-grade treatment-related AEs (TRAEs) occurred in 98.3%, 97.0%, and 96.4% of patients in the zanidatamab/tislelizumab plus chemotherapy, zanidatamab/chemotherapy, and trastuzumab/chemotherapy arms, respectively; of these, 71.8%, 59%, and 59.6% had grade 3 or higher TRAEs. TRAEs led to discontinuation of any component of treatment (42.5%; 34.4%; 29.1%), zanidatamab or trastuzumab (11.9%; 8.5%; 2.3%), and tislelizumab (14.3%; not applicable [N/A]; N/A). The most common TRAEs were diarrhea (82%; 76%; 48%), nausea (51%; 50%; 42%), vomiting (38%; 39%; 28%), decreased appetite (40%; 36%; 28%), and anemia (38%; 35%; 37%).

The FDA previously granted breakthrough therapy designation to zanidatamab in combination with fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab, for the first-line treatment of patients with HER2-positive unresectable locally advanced or metastatic gastric, GEJ, or GEA.⁴

Zanidatamab is approved by the FDA for adult patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer.⁵ 

REFERENCES

1. 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 April 27, 2026. https://tinyurl.com/4cmy69ku

2. Elimova E, Rha SY, Shitara K, et al. 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 4):LBA285. doi:10.1200/JCO.2026.44.2_suppl.LBA285

3. Positive HERIZON-GEA-01 phase 3 results support Ziihera (zanidatamab-hrii) as HER2-targeted agent-of-choice and Ziihera combination regimens as new standard of care in first-line HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma. News release. Jazz Pharmaceuticals, plc. November 17, 2025. Accessed April 27, 2026. https://tinyurl.com/4z8t6fw7

4. Zymeworks receives FDA breakthrough therapy designation for HER2-targeted bispecific antibody zanidatamab in patients with biliary tract cancer. News Release. Zymeworks Inc. November 30, 2020. Accessed April 27, 2026. https://tinyurl.com/yrfcyu4m

5. Jazz Pharmaceuticals announces U.S. FDA approval of Ziihera (zanidatamab-hrii) for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC). News release. Jazz Pharmaceuticals. November 20, 2024. Accessed April 27, 2026. https://tinyurl.com/2x6wnw9v