Zanidatamab Regimens vs Trastuzumab in HER2 Positive GEA

Key Takeaways

• Both zanidatamab-based regimens were associated with longer progression-free survival than trastuzumab plus chemotherapy.
• Zanidatamab plus tislelizumab plus chemotherapy was associated with longer interim overall survival, whereas zanidatamab plus chemotherapy did not show a statistically significant interim difference.
• Grade 3 or higher adverse events were common across all groups, and diarrhea was the most frequently reported severe event.

The open-label phase 3 HERIZON-GEA-01 trial compared first-line zanidatamab plus tislelizumab plus chemotherapy, zanidatamab plus chemotherapy, and trastuzumab plus chemotherapy in HER2-positive gastroesophageal cancer. Both zanidatamab-containing regimens reached a median progression-free survival of 12.4 months, compared with 8.1 months for trastuzumab plus chemotherapy, in previously untreated, centrally confirmed HER2-positive advanced gastroesophageal adenocarcinoma. In the interim analysis, both zanidatamab-based strategies showed longer progression-free survival than the trastuzumab control.

Investigators randomized 914 patients with previously untreated, centrally confirmed HER2-positive advanced gastroesophageal adenocarcinoma in a 1:1:1 ratio across the three regimens. One group received zanidatamab, a dual HER2-targeted bispecific antibody, plus tislelizumab, an anti-programmed death 1 agent, with chemotherapy. The other groups received zanidatamab plus chemotherapy or trastuzumab plus chemotherapy. The primary end points were progression-free survival and overall survival, and median follow-up was 25.9 months.

Progression-free survival hazard ratios versus trastuzumab plus chemotherapy were 0.63 and 0.65 for the two zanidatamab-containing regimens, with P<0.001 for both comparisons. For interim overall survival, zanidatamab plus tislelizumab plus chemotherapy yielded a median of 26.4 months versus 19.2 months with trastuzumab plus chemotherapy. The hazard ratio for death in that comparison was 0.72, with a 95% confidence interval of 0.57 to 0.90 and P = 0.004. Zanidatamab plus chemotherapy showed a median overall survival of 24.4 months, with a hazard ratio of 0.80, 95% CI 0.64 to 1.01, and P = 0.06.

Grade 3 or higher adverse events occurred in 83.3%, 73.8%, and 74.5% of patients in the zanidatamab-tislelizumab-chemotherapy, zanidatamab-chemotherapy, and trastuzumab-chemotherapy groups, respectively. The highest rate occurred in the zanidatamab-tislelizumab-chemotherapy arm, while the other two groups were similar. Diarrhea was the most common grade 3 or higher adverse event, occurring in 24.8%, 20.0%, and 12.9% of patients, respectively.

The authors concluded that zanidatamab plus chemotherapy, with and without tislelizumab, led to longer progression-free survival than trastuzumab plus chemotherapy. Further analyses are planned to assess zanidatamab plus chemotherapy.