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Jump to Key Points The FDA has approved zanidatamab (Ziihera, Jazz Pharmaceuticals) with or without tislelizumab (Tevimbra, BeOne Medicines) in combination with chemotherapy for first-line HER2-positive, unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma.
The agency also approved two diagnostic tests to identify patients eligible for the treatment regimens, which both require fluoropyrimidine and platinum chemotherapy, specifically. These tests include the Pathway anti-HER-2/neu (4B5) rabbit monoclonal primary antibody, and the Ventana HER2 dual in situ hybridization (ISH) DNA probe cocktail, both from Roche Diagnostics.
Zanidatamab is a bispecific HER2 antibody previously approved for previously treated, unresectable or metastatic HER2-positive biliary tract cancer. Tislelizumab is a PD-1 checkpoint inhibitor that carries previous indications for unresectable or metastatic esophageal squamous cell carcinoma and PD-L1-positive, HER2-negative gastric or gastroesophageal junction adenocarcinoma.
In the approval trial, HERIZON-GEA-01, median overall survival (OS) was 26.4 months with zanidatamab plus tislelizumab and chemotherapy.
- FDA approved zanidatamab ± tislelizumab + chemo for 1L HER2+ unresectable/metastatic GEA.
- Eligible tumors: IHC 3+ or IHC 2+/ISH+; requires fluoropyrimidine + platinum backbone.
- HERIZON-GEA-01: OS 26.4 mo with zanidatamab+tislelizumab vs 19.2 mo trastuzumab.
- PFS improved: 12.4 mo with combo vs 8.1 mo with trastuzumab; benefit regardless PD-L1.
- Zanidatamab warnings: diarrhea, embryo-fetal toxicity, LV dysfunction, infusion reactions.
Jazz called the combination a new standard of care for the disease, in a press release.
The current standard includes the older HER2 blocker trastuzumab with chemotherapy, plus the PD-1 inhibitor pembrolizumab in PD-L1 positive patients.
HERIZON-GEA included 914 HER2-positive patients (immunohistochemistry [IHC] 3+ or IHC 2+/ISH+) in more than 30 countries. They were randomized evenly to either zanidatamab, zanidatamab plus tislelizumab, or — as a control group — trastuzumab, all on a background of either capecitabine and oxaliplatin or fluorouracil and platinum chemotherapy.
Median progression-free survival (PFS) was 12.4 months with zanidatamab and tislelizumab vs 8.1 months with trastuzumab. The median OS of 26.4 months with the combination topped 19.2 months in the trastuzumab group. The benefit with the combination held regardless of PD-L1 expression and at HER2 IHC expressions of both 2+ and 3+.
Zanidatamab alone with chemotherapy also showed a median PFS improvement over the control group, but it was limited primarily to patients with IHC 3+ tumors. In those patients, median PFS was 14.2 months with zanidatamab vs 7.6 months with trastuzumab. There was no statistically significant OS benefit at the time of the analysis.
Zanidatamab carries a black box warning of diarrhea and embryo-fetal toxicity, as well as warnings and precautions for left ventricular dysfunction and infusion-related reactions.
Tislelizumab labeling includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.
For patients less than 70 kg, zanidatamab is dosed at 1800 mg every 3 weeks or 1200 mg every 2 weeks. For patients 70 kg or heavier, the dose is 2400 mg every 3 weeks or 1600 mg every 2 weeks.
Tislelizumab is dosed at 150 mg every 2 weeks, 200 mg every 3 weeks, 300 mg every 4 weeks, or 400 mg every 6 weeks until disease progression or unacceptable toxicity.
M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net
