Metastatic Stomach Cancer: What to Ask

Stage IV is not the branching point here. The tumor's biology is.

NCI says people with metastatic gastric adenocarcinoma should consider testing for three things. HER2 amplification. Defective mismatch repair, or microsatellite instability. And PD-L1 combined positive score. A fourth, claudin 18.2, has since joined them.

Those four results split the disease into different treatment paths. Two people with identical scans can be offered different drugs on this basis alone. So the first practical question is not what stage this is. It is whether all four tests have been run and reported.

Most gastric cancers are. The backbone here is chemotherapy, usually fluorouracil or capecitabine with oxaliplatin.

The change of the last few years was adding a checkpoint drug. CheckMate-649 randomized 1,581 people. One arm got nivolumab with chemotherapy. That meant nivolumab with CAPOX every 3 weeks, or with FOLFOX every 2 weeks, at the amount matched to each schedule. The other got chemotherapy alone.

Median overall survival was 14.0 months with nivolumab added. It was 11.3 months without. In the subgroup with PD-L1 CPS of 5 or more, the figures were 14.4 and 11.1 months.

That is why the CPS number matters. It does not switch the drug off. It changes the size of the expected gain.

The definition is precise. HER2-positive means 3+ staining on immunohistochemistry, or 2+ with a positive FISH test.

It is also uncommon. In the ToGA trial, 3,665 tumors were tested and 810 were positive. That is about 22%.

ToGA established the drug. Median overall survival was 13.8 months with trastuzumab added to cisplatin plus fluorouracil or capecitabine. It was 11.1 months with chemotherapy alone. Cardiac toxicity was rare in both arms.

KEYNOTE-811 added a checkpoint drug on top. It randomized 434 people to chemotherapy and trastuzumab every 3 weeks, with or without pembrolizumab on the same schedule. At the first interim analysis, the objective response rate was 74.4% with pembrolizumab and 51.9% without. Grade 3 or higher events ran at about 57% in both arms, though a third of those in the pembrolizumab arm were immune-related.

For people who cannot tolerate pembrolizumab, NCI notes trastuzumab may be combined with cisplatin and fluorouracil or capecitabine.

Claudin 18.2 is a protein in the tight junctions between stomach lining cells. Some cancers keep it. Zolbetuximab targets it.

Two phase III trials tested adding it to chemotherapy in claudin 18.2-positive, HER2-negative disease. GLOW randomized 507 people to CAPOX with zolbetuximab or placebo. Median progression-free survival was 8.21 months against 6.80. Median overall survival was 14.39 months against 12.16.

SPOTLIGHT randomized 565 people to mFOLFOX6 with zolbetuximab or placebo. Median progression-free survival was 10.61 months against 8.67, with a reduced risk of death. A combined analysis of both trials found no harm to quality of life.

The gains are measured in weeks to months. They are also real, randomized, and only available to people whose tumor was tested.

NCI is blunt here. There is no standard treatment option after progression on first-line palliative chemotherapy.

What exists is a list of accepted regimens. Paclitaxel with or without ramucirumab. Docetaxel. Irinotecan, with or without fluorouracil and leucovorin.

The ramucirumab data are specific. In RAINBOW, 665 people got paclitaxel on days 1, 8 and 15 of a 28-day cycle, plus ramucirumab or placebo on days 1 and 15. Median overall survival was 9.6 months against 7.4. Ramucirumab alone, in REGARD, gave 5.2 months against 3.8.

Two biomarker-driven options sit alongside. Pembrolizumab is approved for dMMR or MSI-high tumors. Trastuzumab deruxtecan is approved for HER2-positive disease after a trastuzumab-based regimen. In DESTINY-Gastric01, given by vein every 3 weeks, the objective response rate was 51% against 14% for chemotherapy, and overall survival was 12.5 against 8.4 months. Its toxicity list is worth reading before starting: grade 3 to 4 neutropenia in 51%, grade 3 to 4 anemia in 38%, and drug-related interstitial lung disease in 10%.

Third line has one FDA-approved option. In TAGS, trifluridine and tipiracil tablets taken twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle — at a strength your oncologist calculates from your body size — gave median overall survival of 5.7 months against 3.6 for placebo.

Checkpoint drugs are not interchangeable here, and the record includes negatives.

KEYNOTE-062 randomized 763 people with untreated advanced gastric cancer and a PD-L1 CPS of 1 or more. It compared pembrolizumab alone, pembrolizumab with chemotherapy, and chemotherapy alone. The final results showed no superiority for either pembrolizumab arm over chemotherapy alone. In the subgroup with CPS of 10 or more, median overall survival was 17.4 months with pembrolizumab alone against 10.8 months with chemotherapy. NCI notes the statistical plan did not test that difference further, so it is a signal rather than a conclusion.

There is also an approval that was taken back. Pembrolizumab had been approved as third-line treatment for gastric and gastroesophageal junction cancers with a CPS of 1 or more. NCI records that this approval was withdrawn after first-line therapy changed to combined chemotherapy and PD-1 blockade.

Systemic drugs do not fix a mechanical problem, and stomach cancer creates mechanical problems.

NCI lists the tools directly. For gastric obstruction, endoluminal laser therapy, an endoluminal stent, or a gastrojejunostomy may help. Palliative radiation therapy may relieve bleeding, pain, and obstruction. Palliative resection is reserved for continued bleeding or obstruction.

These run in parallel with drug treatment, not after it. Raising an eating or bleeding problem early keeps that option open. More on this track is in palliative care.

The most useful item is the pathology report itself, with all four biomarker results on it. Second is a weight history, because nutrition drives what treatment is tolerable. Third is a list of everything currently taken.

For background, see stomach cancer and biomarker testing and precision medicine.

• Call 911 or go to an emergency department if you vomit blood or something that looks like coffee grounds, pass black tarry stools, or feel faint and clammy with either. Bleeding is one of the two problems NCI names palliative resection for, and it can be brisk.
• Call your care team immediately, at any hour, if your temperature reaches 100.4°F (38°C) or higher while you are on chemotherapy. CDC treats a fever during chemotherapy as a medical emergency, because the drugs leave too few white cells to contain an infection, and hours matter. If you cannot get through fast, head to an emergency department and tell them you are having chemotherapy.
• Call your care team the same day if you cannot keep fluids down, food comes back up soon after eating, or your belly is swollen and you have stopped passing gas. Those point to the obstruction that a stent, laser or gastrojejunostomy is meant to relieve. Call the same day too for a new dry cough or breathlessness if you are on trastuzumab deruxtecan, because lung inflammation occurred in about 1 in 10 people on that drug.
• Call your care team within a day or two if swallowing is getting harder, you are eating less each week, or weight is falling. Nutrition decides what treatment you can tolerate, so this is worth raising before the next scheduled visit.

• NCI PDQ — Gastric Cancer Treatment (Health Professional Version)
• NCI PDQ — Gastric Cancer Treatment (Patient Version)
• NCI — Bleeding and Bruising (Thrombocytopenia) During Cancer Treatment
• CDC — Fever and Cancer Treatment, accessed August 13, 2026