DESTINY-Gastric01: What the Stomach Cancer Trial Found

An antibody with a payload attached

HER2 is a growth-signal protein, and some tumors carry far too much of it. Trastuzumab is an antibody that latches onto HER2 and interferes with that signal.

Trastuzumab deruxtecan is a different drug built on the same antibody. It is an antibody-drug conjugate, or ADC: an anti-HER2 antibody, a chemotherapy payload, and a chemical linker holding the two together.

The payload is deruxtecan, a topoisomerase I inhibitor. Topoisomerase I is an enzyme cells need to untangle DNA when they copy it. Block it and the cell cannot divide.

The antibody finds HER2 on a cancer cell. The package is pulled inside, the linker is cut, and the payload lands there rather than everywhere.

Why try HER2 again after HER2 has failed

Everyone in this trial had already had trastuzumab, and the cancer grew anyway. Another HER2 drug looks unpromising in that setting.

The payload is why it is not. HER2 here works as an address label, not only a switch to turn off. A tumor that has learned to ignore HER2 signaling still displays the protein, and the address still delivers.

The trial

DESTINY-Gastric01 was an open-label randomized phase 2 trial run in Japan and South Korea. Open-label means nobody was blinded to the assignment.

Everyone had gastric or gastroesophageal junction adenocarcinoma, confirmed HER2-positive by a central laboratory. All had progressed on at least two earlier treatments, including trastuzumab, a fluoropyrimidine drug and a platinum drug.

Of 187 treated patients, 125 got the ADC every three weeks. Sixty-two got the physician's choice of chemotherapy: 55 irinotecan, 7 paclitaxel.

The main measure was objective response, judged by independent reviewers rather than the treating team. That means the tumor shrank by a defined amount on scans.

What happened

Tumors shrank in 51 percent of the ADC group, against 14 percent on chemotherapy, with a p-value below 0.001. The FDA's review of the same trial, counting only confirmed responses, put the figures at 40.5 and 11.3 percent.

Median overall survival was 12.5 months versus 8.4. The hazard ratio for death was 0.59, with a 95 percent confidence interval of 0.39 to 0.88. A hazard ratio below 1 favors the newer drug; 0.59 means the death rate ran about 41 percent lower.

Median progression-free survival, the time before scans showed growth, was 5.6 versus 3.5 months. Responses lasted longer too: a median of 11.3 months against 3.9.

The lung risk that comes with the drug

Blood counts fell often. Severe neutropenia, a shortage of the white cells that fight bacteria, hit 51 percent of the ADC group and 24 percent on chemotherapy. Severe anemia hit 38 percent and 23 percent.

The lungs are the bigger issue. Twelve patients developed drug-related interstitial lung disease or pneumonitis, meaning inflammation and scarring in the tissue between the air sacs. Nine cases were mild or moderate; three were severe. One patient died of drug-related pneumonia.

The US label carries a boxed warning, the FDA's strongest, for interstitial lung disease and for harm to a fetus. A new cough, breathlessness or fever on this drug is therefore urgent, not routine. Our page on targeted therapy side effects covers that habit of watching.

What the FDA approved

On January 15, 2021 the FDA approved fam-trastuzumab deruxtecan-nxki, sold as Enhertu, for adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had already had a trastuzumab-based regimen.

The dose is 6.4 milligrams per kilogram by vein every three weeks, until the disease grows or side effects become unacceptable. The application had priority review and breakthrough therapy designation, and cleared about six weeks early.

Getting to a HER2 answer at all

None of this happens without a biopsy. Stomach cancer is diagnosed by upper endoscopy: a thin lighted tube down the throat, and a tissue sample taken from anything abnormal.

That sample is what gets HER2 tested. NCI lists HER2 alongside PD-L1, microsatellite instability, mismatch repair status and NTRK changes as biomarkers checked in stomach cancer. Our page on targeted therapy explains how such a result steers the plan.

When to get checked

Stomach cancer is quiet early. NCI says symptoms usually begin only after it has spread.

NCI lists as possible early symptoms: indigestion and stomach discomfort, a bloated feeling after eating, mild nausea, loss of appetite, and heartburn.

For advanced disease NCI adds blood in the stool, vomiting, unexplained weight loss, stomach pain, jaundice, fluid buildup in the abdomen, and trouble swallowing.

The signal is persistence. Heartburn for a week is ordinary. Heartburn every day for a month, new trouble swallowing, or black or bloody stool is worth a same-week appointment. Our page on stomach cancer symptoms goes into what each can mean.

What the group numbers show

SEER, the federal cancer statistics program, puts five-year relative survival at 39.8 percent for US stomach cancer diagnosed from 2016 to 2022.

That figure hides most of the story. Split by spread at diagnosis, five-year relative survival runs 78.1 percent while the cancer is confined to the stomach, 39.0 percent with regional lymph nodes involved, and 8.1 percent for distant spread. Thirty-five percent of US cases are already distant when found.

These are averages across a registry population. They are not a forecast for any individual.

What this trial cannot tell you

Every site was in Japan or South Korea. Stomach cancer is more common there and is often found earlier. Whether the same size of benefit appears elsewhere was not tested here.

It was a phase 2 trial with 187 treated patients. Phase 2 asks whether a drug does something; phase 3 settles how much.

The comparison was irinotecan or paclitaxel alone, in people who had already used at least two lines of treatment. That is a low bar by design, and it says nothing about newer combinations given earlier.

And the lung risk is not a footnote. One death in 125 people is a real number in a trial this small.

Sources

• Shitara K and others, Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer, New England Journal of Medicine 2020 (record and abstract via NCBI) — https://pubmed.ncbi.nlm.nih.gov/32469182/
• FDA, FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas — https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-positive-gastric-adenocarcinomas
• NCI, Stomach Cancer Diagnosis — https://www.cancer.gov/types/stomach/diagnosis
• NCI, Symptoms of Stomach Cancer — https://www.cancer.gov/types/stomach/symptoms
• SEER Cancer Stat Facts, Stomach Cancer — https://seer.cancer.gov/statfacts/html/stomach.html

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

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