FDA Grants Priority Review to Zanidatamab-Based Regimens in First-Line HER2+ GEA

The FDA has accepted and granted priority review to the supplemental biologics license application (sBLA) seeking the approval of zanidatamab-hrii (Ziihera) in combination with chemotherapy with/without tislelizumab (Tevimbra) for the treatment of adult patients with HER2-positive unresectable locally advanced or metastatic gastric cancer, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma (GEA) in the front-line setting.¹

A target action date of August 25, 2026, has been set by the FDA for the application under the Prescription Drug User Fee Act.

The sBLA was supported by data from the phase 3 HERIZON-GEA-01 trial (NCT05152147), which was the first phase 3 study in metastatic GEA to demonstrate a median progression-free survival (PFS) greater than 1 year and a median overall survival (OS) greater than 2 years.^1,2

Findings from this pivotal study were presented at the 2026 Gastrointestinal Cancers Symposium and showed that patients who received zanidatamab plus tislelizumab and chemotherapy (n = 302) achieved a median PFS of 12.4 months (95% CI, 9.8-18.5) vs 8.1 months (95% CI, 7.0-8.9) in the trastuzumab (Herceptin)–plus-chemotherapy arm (n = 308; HR, 0.63; 95% CI, 0.51-0.78; P < .0001).² Zanidatamab plus chemotherapy alone (n = 304) also elicited a median PFS of 12.4 months (95% CI, 9.8-14.5; HR, 0.65; 95% CI, 0.52-0.81; 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). Regarding OS, zanidatamab plus tislelizumab and chemotherapy demonstrated a clinically meaningful and statistically significant improvement in OS, and zanidatamab plus chemotherapy demonstrated a clinically meaningful effect with a strong trend toward statistical significance for OS compared with the control arm at the time of this first analysis; an additional OS interim analysis for this arm is expected in mid-2026.³

“The HERIZON-GEA-01 trial results are practice changing, supporting the potential of zanidatamab as the HER2-targeted agent of choice in HER2[-positive] first-line locally advanced or metastatic GEA," 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 “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.”

What was the design of HERIZON-GEA-01?

The global trial enrolled patients 18 years of age or older with unresectable, locally advanced or metastatic GEA with HER2-positive disease and an ECOG performance status of 0 or 1.² No prior exposure to treatment for locally advanced/metastatic disease or HER2-targeted treatments and immunotherapy was permitted.

Eligible patients (n = 914) were stratified according to geographic region, HER2 status, and ECOG performance status, and then randomly assigned 1:1:1 to 1 of 3 treatment arms:

• Arm A: trastuzumab and physician’s choice of either capecitabine plus oxaliplatin (CAPOX) or 5-fluorouracil (5-FU) plus cisplatin
• Arm B: intravenous (IV) zanidatamab at 1800 mg (if weighing < 70 kg) or 2400 mg (if weighing ≥ 70 kg) every 3 weeks plus physician’s choice of CAPOX or 5-FU (n = 304)
• Arm C: zanidatamab plus IV tislelizumab at 200 mg every 3 weeks plus physician’s choice of CAPOX or 5-FU

Treatment continued until death, disease progression, or unacceptable toxicity. Of note, chemotherapy could be discontinued after 6 cycles, and prophylaxis to prevent infusion-related reactions and diarrhea was mandatory in arms B and C.

PFS by blinded independent central review and OS served as the study’s dual primary end points. Key secondary end points included confirmed objective response rate (ORR) and safety.

The median ages in the zanidatamab/tislelizumab, zanidatamab/chemotherapy, and trastuzumab arms were 63 (range, 22-81), 62.5 (range, 25-87), and 64 (range, 21-84) years, respectively. Most patients in all 3 arms were male (80.8%; 80.3%; 77.3%), had an ECOG performance status of 1 (59.6%; 55.9%; 61.0%), had metastatic disease (94%; 97%; 97.1%), had HER2 immunohistochemistry (IHC) 3+ status (83.1%; 82.6%; 82.8%), had a PD-L1 tumor area positivity score of 1% or greater (61.9%; 58.6%; 61%), and had received CAPOX as their chemotherapy backbone (90.4%; 90.8%; 91.6%).

What additional efficacy and safety data were reported from HERIZON-GEA-01?

The median follow-up was 25.9 months (range, 7.9-45.5) in the zanidatamab/tislelizumab arm, 26 months (range, 7.6-46) in the zanidatamab/chemotherapy arm, and 25.8 months (range, 7.5-45.6) in the trastuzumab arm. Of note, efficacy benefits were observed regardless of PD-L1 status.

The 9-, 18-, and 24-month PFS rates with zanidatamab plus tislelizumab were 59.7% (95% CI, 53.6%-65.4%), 43.9% (95% CI, 37.4%-50.1%), and 38.2% (95% CI, 31.4%-45.0%), respectively. The corresponding rates in the trastuzumab arm were 43.7% (95% CI, 37.5%-49.7%), 20.9% (95% CI, 15.3%-27.2%), and 15.6% (95% CI, 10.1%-22.1%). The 24- and 30-month OS rates with zanidatamab plus tislelizumab were 54.3% (95% CI, 47.6%-60.5%) and 43.8% (95% CI, 36.5%-50.9%), respectively. The corresponding rates in the trastuzumab arm were 38.8% (95% CI, 32.2%-45.4%) and 30.0% (95% CI, 23.4%-36.8%).

In patients with measurable disease, the confirmed ORRs were 70.7% (95% CI, 65%-76%) with zanidatamab plus tislelizumab and chemotherapy (n = 195); 69.6% (95% CI, 63.9%-75%) with zanidatamab plus chemotherapy (n = 186); and 65.7% (95% CI, 59.9%-71.2%) with tislelizumab plus chemotherapy (n = 198). The median DORs for these respective regimens were 20.7 months (95% CI, 12.6-37.7), 14.3 months (95% CI, 11.5-21.9), and 8.3 months (95% CI, 6.7-9.8).

No new safety signals were identified for either zanidatamab or tislelizumab, and the safety profiles of the zanidatamab–based regimens were deemed generally manageable by investigators. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.7%, 98.7%, and 98.3% of patients in the zanidatamab/tislelizumab, zanidatamab/chemotherapy, and trastuzumab arms, respectively. Any-grade treatment-related AEs (TRAEs) were reported in 98.3%, 97.0%, and 96.4% of patients; 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%).

What additional FDA indications has zanidatamab received?

As of November 2024, zanidatamab is FDA approved for adult patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer based on data from the phase 2b HERIZON-BTC-01 study (NCT04466891).⁴

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 in November 2020.⁵ The agent has also received orphan drug designations from both the FDA and the European Medicines Agency across multiple gastrointestinal tumor types.¹

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://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-fda-acceptance-and-priority-0
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://investor.jazzpharma.com/news-releases/news-release-details/positive-herizon-gea-01-phase-3-results-support-ziiherar
4. 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://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-ziiherar
5. 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://ir.zymeworks.com/news-releases/news-release-details/zymeworks-receives-fda-breakthrough-therapy-designation-her2/