New Protocol: Zanidatamab with Chemotherapy for Metastatic HER2-Positive Gastroesophageal Cancer

In a phase 3 open-label randomized trial of previously untreated HER2-positive advanced gastroesophageal adenocarcinoma, zanidatamab plus chemotherapy both with and without tislelizumab significantly improved progression-free survival compared to trastuzumab plus chemotherapy. Zanidatamab with tislelizumab also showed a significant overall survival benefit. While diarrhea and other gastrointestinal toxicities were more common with zanidatamab regimens, the safety profile was manageable and consistent with known effects.

Study

Open-label, phase 3 randomized trial [HERIZON-GEA-01]

Previously untreated HER2-positive advanced gastroesophageal adenocarcinoma

Zanidatamab+Tislelizumab+Chemotherapy (Zan-Tis-C, n=302) vs Zanidatamab+Chemotherapy (Zan-C, n=304) vs (Tras-C, n=308)

Efficacy

ORR: 70.7% vs 69.6% vs 65.7% (Zan-Tis-C vs. Zan-C vs. Tras-C)

CR: 19.6% vs 17.1% vs 11.0%

mPFS: 12.4 mos vs 12.4 mos vs 8.1 mos (HR 0.63 for Zan-Tis-C vs Tras-C [0.51-0.78]; HR 0.65 for Zan-C vs. Tras-C [0.52-0.81])

PFS at 18 mos: 43.9% vs 38.0% vs 20.9%

Median OS: 26.4 mos vs 24.4 mos vs 19.2 mos (HR 0.72 for Zan-Tis-C vs. Tras-C [0.57-0.90]; HR 0.80 for Zan-C vs. Tras-C [0.64-1.01])

OS at 24 mos: 54.3% vs 50.3% vs 38.8%

mDoR: 20.7 mos vs 14.3 mos vs 8.3 mos

Safety

Grade >=3 AE: diarrhea (24.8% vs 20.0% vs 12.9%), hypokalemia (22.1% vs 18.7% vs 10.9%), anemia (15.6% vs 15.1% vs 18.9%), neutropenia (10.9% vs 7.9% vs 11.9%), decreased appetite (7.8% vs 6.6% vs 5.6%), vomiting (5.4% vs 3.6% vs 3.6%)

Serious AEs: 58.5% vs 49.2% vs 42.4%

AE leading to discontinuation of HER2-targeted therapy: 13.3% vs 10.5% vs 5.6%

Grade 5 drug-related deaths: 2.4% vs 0.3% vs 1.3%