An Exciting Option For Difficult-To-Treat HER2+ Gastric Cancer: What New Data Means For Patients

The findings came from DESTINY-Gastric04, a global phase III study that followed nearly 500 volunteers across three continents.

This approach was already approved as a treatment down the line for patients with HER2+ gastric cancer, but the study indicates it has a use earlier on as well.

“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. “It’s a confirmatory study.”

The median overall survival, or 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-positive (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, a traditional chemotherapy drug, paired with ramucirumab, an antibody that blocks blood-vessel growth around tumors. 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. Picture it as a guided missile: the antibody part hones in on the HER2 protein while the attached chemotherapy part stays quiet until the missile docks on the cancer cell. Then, it attacks.

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 families 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. “…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.”

Understanding The Data: Terms To Know

When cancer research is presented, sometimes the terminology can be a bit hard to follow. You may be confused about whether the research applies to your case or is its relevant for a loved one facing cancer.

Below are some key terms to understand before we break down the data from the trial.

• HER2-positive means the cancer cells make extra copies of the HER2 gene or protein. That extra HER2 acts like a stuck accelerator, driving cancer growth.
• Antibody-drug conjugate (ADC) is a lab-made antibody linked to a miniature chemotherapy payload. The antibody finds the cancer and attaches to it, and the payload destroys it from inside.
• Second-line therapy is the next treatment used after the first routine approach no longer works.
• Overall survival (OS) measures how long people live after starting the study drug. It is the gold-standard measuring point in cancer trials.
• Progression-free survival (PFS) counts the months a patient lives without the cancer growing or getting worse.
• Objective response rate (ORR) shows how many patients in the trial have their tumors shrink by at least 30% or disappear.

The DESTINY-Gastric04 Trial

Researchers enrolled 494 adults from hospitals in Asia, Europe, and South America. Each participant had:

• Unresectable (cannot be removed with surgery) 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 — the main aspect researchers wanted to measure — 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.

Questions To Ask Your Doctor

• Am I eligible to be treated with trastuzumab deruxtecan (or Enhertu)?
• How often will I need heart and lung checks while undergoing treatment with Enhertu?
• What side effects should I look out for?
• If the approach works, how long can I stay on the medication?
• What are the options if the cancer grows again?

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