Jazz’s Ziihera Wins FDA Approval for First-Line Treatment of HER2-Positive Gastric Cancer

Jazz Pharmaceuticals’ bispecific antibody Ziihera, which is challenging the first-line gastric cancer treatment market, has received approval from the US Food and Drug Administration (FDA). With the approval, Ziihera is expected to become a new HER2-targeted treatment option that could replace Herceptin (trastuzumab), which has been the standard of care for more than 10 years.

Jazz announced on the 26th that Ziihera had received FDA approval for use, in addition to standard chemotherapy, with or without BeiGene’s Tevimbra, in previously untreated patients with HER2-positive, advanced gastroesophageal adenocarcinoma (GEA).

In the phase 3 HERIZON-GEA-01 trial, the combination of Ziihera, Tevimbra and chemotherapy reduced the risk of death by 28% compared with Herceptin plus chemotherapy. Median overall survival (OS) was 26.4 months, 7.2 months longer than in the control group.

When the data were released in January, physicians and analysts said the Ziihera combination regimen could change clinical practice for first-line GEA treatment.

Of particular note, the treatment was effective regardless of PD-L1 expression status. Merck’s previously approved Keytruda could be used only in tumors expressing PD-L1.

In subgroup analyses, the Ziihera, Tevimbra and chemotherapy combination produced longer survival than the control regimen in both PD-L1-positive and PD-L1-negative patients. In patients with PD-L1-negative tumors, defined as a tumor area positivity (TAP) score of less than 1, median OS was 29.7 months—an extension of 13.9 months.

Rob Iannone, Jazz’s head of research and development (R&D), said, "For the first time in this disease, which has a very poor prognosis, median survival exceeded 2 years, and the treatment showed broad activity regardless of PD-L1 status."

Ziihera (zanidatamab) is a bispecific antibody that simultaneously binds to extracellular domains 2 and 4 of the HER2 receptor. Because a single antibody cannot bind to two sites on the same receptor due to their physicochemical positioning, it draws together two different receptors to create "receptor clustering." The company said this mechanism promotes immunogenic cell death, producing synergy with PD-1 inhibition even in PD-L1-negative tumors.

The group that received Ziihera plus chemotherapy without a PD-1 inhibitor had not yet shown a statistically significant improvement in OS at the first interim analysis. However, a preliminary favorable trend, with a 20% reduction in the risk of death, was observed, and progression-free survival (PFS) improved significantly by 35%. The PFS improvement rate in the three-drug combination group that included Tevimbra was 37%. Both Ziihera combination groups recorded a median time to disease progression of 12.4 months, substantially exceeding the 8.1 months in the control group.

Jazz expects to accumulate a sufficient number of events for the second interim OS analysis of the two-drug combination group by the end of September.

HER2-positive GEA is a much larger market than biliary tract cancer, the first indication for which Ziihera was approved. An estimated 20% of GEA, the fifth most common cancer worldwide, is HER2-positive.

Jefferies analysts estimated Ziihera’s peak sales in GEA alone at $1.5 billion (approximately 2.1 trillion won) after the HERIZON-GEA-01 data were released. Jazz has projected peak sales of more than $2 billion across all indications.

Iannone said the company is also considering studies of Ziihera in early-stage gastric cancer, for which no HER2-targeted treatment has been approved. The company is conducting trials in breast cancer patients who have failed prior HER2 treatment and in colorectal cancer, among other indications.