A Better Option For Advanced HER2+ Gastric and GEJ Cancers
- Researchers reported that the targeted drug trastuzumab deruxtecan (T-DXd) outperformed the standard chemotherapy mix of ramucirumab plus paclitaxel when used as second-line treatment for advanced stomach or gastroesophageal junction (GEJ) cancers carrying high levels of HER2 protein.
- “This really confirms that after first-line therapy, that this is the preferred agent in the second-line,” Dr. Sofya Pintova, a gastrointestinal medical oncologist at Mount Sinai Hospital in New York, tells SurvivorNet Connect. “It’s a confirmatory study.”
Promising new data for people with advanced stomach or gastroesophageal junction (GEJ) cancer was presented at 2025’s American Society of Clinical Oncology (ASCO) meeting. Researchers reported that the targeted drug trastuzumab deruxtecan (T-DXd) outperformed the standard chemotherapy mix of ramucirumab plus paclitaxel when used as second-line treatment for tumors carrying high levels of HER2 protein.
The findings came from DESTINY-Gastric04, a global phase III study that followed nearly 500 volunteers across three continents.
“This really confirms that after first-line therapy, that this is the preferred agent in the second-line,” Dr. Sofya Pintova, a gastrointestinal medical oncologist at Mount Sinai Hospital in New York City, tells SurvivorNet Connect. “It’s a confirmatory study.”
The median overall survival (OS) when using trastuzumab deruxtecan was 14.7 months compared to 11.4 months for the current standard treatment approach. Using the drug also reduced the risk of death by nearly 30% and disease progression by 26%.
A Breakthrough For An Aggressive Cancer
HER2+ gastric and GEJ cancers behave aggressively. Although first-line therapy that combines trastuzumab (brand name Herceptin) with chemotherapy helps many patients, the cancer often grows again within a year. Before this promising research, the most common next step was using paclitaxel paired with ramucirumab. That combination offers a few extra months, but its benefits flatten quickly.
Trastuzumab deruxtecan, often shortened to T-DXd and sold as Enhertu, is an antibody-drug conjugate.
The DESTINY-Gastric04 results show that switching to T-DXd after trastuzumab fails or stops working can help keep patients alive longer and shrink tumors more often than the previous standard. For patients facing limited options, this fresh weapon brings a longer period of control and renewed hope.
Nancy Ghattas, head of the immuno-oncology and gastrointestinal (GI) tumor franchise for drugmaker AstraZeneca, touts the findings as the first major development for these patients in 20 years.
“To put things in perspective, one out of four [patients] progress in one year, even after surgery and chemotherapy,” Ghattas tells SurvivorNet Connect. “…When we are bringing in this new therapy, which is practice-changing, potentially becoming a new standard of care that can reduce that progression by 29%, that is extra months and years of hope for patients.”
The DESTINY-Gastric04 Trial
Researchers enrolled 494 adults from hospitals in Asia, Europe, and South America.
Each participant had:
- Unresectable or metastatic gastric or GEJ adenocarcinoma
- Disease that worsened after a first-line regimen containing trastuzumab
- A high HER2 score confirmed by tissue testing
Doctors randomly assigned volunteers, in a one-to-one fashion, to one of two groups:
- Experimental arm: T-DXd given as an intravenous infusion every three weeks at 6.4 mg per kilogram of body weight
- Control arm: Ramucirumab 8 mg per kilogram on days 1 and 15 of each 28-day cycle plus paclitaxel 80 mg per square meter on days 1, 8, and 15
Treatment continued until the cancer grew, side effects became unacceptable, or the patient chose to stop.
The primary endpoint was overall survival. Secondary endpoints included PFS, ORR, how long responses lasted, disease-control rate, and safety.
An independent data committee reviewed the numbers at a planned checkpoint in March 2025. The benefit was so clear that the committee recommended amending the study early so every participant could consider crossing over to the T-DXd treatment approach.
What Did The Data Show?
T-DXd led to median overall survival of 14.7 months vs. 11.4 months in the control group of the study (who received the current standard), reducing the risk of death by nearly 30% and disease progression by 26%.
Progression-free survival was 6.7 months for patients taking T-DXd compared to 5.6 months in the control group — and the objective response rate was 44.3% vs. 29.1%.
While the progression-free survival and objective response rates do show improvements with T-DXd, they are not considered statistically significant. Still, the data does confirm that the T-DXd approach should be considered in the second-line setting.
