A Research Guide for
Facing Gastric Cancer (Stomach Cancer)

FDA-APPROVED Zolbetuximab is a monoclonal antibody targeting claudin 18.2 (CLDN18.2), a protein expressed on the surface of approximately 38% of gastric cancers. FDA-approved in 2024 in combination with chemotherapy for first-line treatment of CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma. The SPOTLIGHT trial showed improved median PFS (10.6 vs. 8.7 months) and OS (18.2 vs. 15.5 months) when zolbetuximab was added to mFOLFOX6. The GLOW trial confirmed benefit with CAPOX.

FDA-APPROVED The KEYNOTE-859 trial established pembrolizumab plus chemotherapy as a first-line standard for advanced HER2-negative gastric/GEJ cancer. In the overall population, adding pembrolizumab to chemotherapy improved median OS from 11.5 to 12.9 months. The benefit was most pronounced in patients with PD-L1 CPS ≥10, where median OS improved from 11.6 to 15.7 months.

FDA-APPROVED CheckMate 649 was the first large trial to show that adding a checkpoint inhibitor (nivolumab) to chemotherapy improved overall survival in first-line advanced gastric cancer. In patients with PD-L1 CPS ≥5, median OS improved from 11.1 to 14.4 months. Nivolumab + chemotherapy is now a standard first-line regimen alongside pembrolizumab + chemotherapy.

FDA-APPROVED Trastuzumab deruxtecan (T-DXd, Enhertu) is an antibody-drug conjugate that showed remarkable activity in HER2-positive gastric cancer. The DESTINY-Gastric01 trial demonstrated an objective response rate of 51% in previously treated patients (versus 14% with chemotherapy alone), with median OS of 12.5 vs. 8.4 months. It is now FDA-approved for HER2-positive gastric/GEJ cancer after prior trastuzumab-based treatment.

FDA APPROVED 2025 On November 25, 2025, the FDA approved durvalumab (Imfinzi) plus FLOT chemotherapy given before and after surgery, followed by durvalumab alone, for resectable gastric or gastroesophageal junction (GEJ) cancer — the first perioperative immunotherapy approved for this setting. Approval was based on the phase 3 MATTERHORN trial (NCT04592913), which showed a 29% reduction in the risk of disease progression, recurrence, or death and a higher rate of complete tumor disappearance (pathologic complete response 19.2% vs 7.2%) when durvalumab was added to FLOT. A separate trial, KEYNOTE-585, evaluated pembrolizumab plus chemotherapy in this setting and improved pathologic complete response rates, but pembrolizumab is not FDA-approved for perioperative gastric cancer.

Upper endoscopy (esophagogastroduodenoscopy, or EGD) is the primary diagnostic test. A flexible lighted scope is passed through the mouth into the stomach, allowing the doctor to directly visualize the stomach lining and take tissue samples (biopsies) from any suspicious areas. Multiple biopsies (at least 6–8) from different parts of the tumor are recommended to ensure adequate tissue for both histologic diagnosis and biomarker testing. The procedure takes approximately 15–30 minutes and is done under sedation.

A contrast-enhanced CT scan of the chest, abdomen, and pelvis is performed in all patients to evaluate the extent of disease: tumor size, lymph node involvement, and presence of distant metastases (liver, peritoneum, lungs, distant lymph nodes). This is the standard staging imaging study.

Endoscopic ultrasound uses an ultrasound probe at the tip of an endoscope to assess the depth of tumor invasion through the stomach wall layers and evaluate nearby lymph nodes. EUS is important for accurate T-staging and is particularly useful when deciding whether the cancer can be surgically removed and whether preoperative chemotherapy is needed.

PET-CT combines metabolic imaging (which detects areas of high sugar uptake, a hallmark of cancer) with CT anatomy. PET-CT is useful for detecting distant metastases not seen on CT alone and for evaluating treatment response. However, not all gastric cancers are PET-avid — diffuse-type and signet ring cell cancers may not light up well on PET, limiting its sensitivity for these subtypes.

For patients with locally advanced gastric cancer (T3 or higher) being considered for curative surgery, a diagnostic laparoscopy (minimally invasive look inside the abdomen) with peritoneal washings is recommended. This detects peritoneal carcinomatosis (cancer seeding in the abdominal cavity) that is not visible on CT or PET scans. Positive peritoneal cytology indicates stage IV disease even without visible peritoneal deposits, which changes the treatment approach from curative to palliative.

HER2 is a growth receptor protein that is overexpressed in approximately 15–20% of gastric cancers. HER2-positive gastric cancer is treated with trastuzumab (Herceptin) added to first-line chemotherapy, and with trastuzumab deruxtecan (Enhertu) in later lines. Testing is performed by immunohistochemistry (IHC) and FISH (fluorescence in situ hybridization). Scoring differs from breast cancer: gastric HER2 IHC 3+ is positive; IHC 2+ requires reflex FISH testing to confirm.

Why it matters: If HER2-positive, trastuzumab must be added to your chemotherapy backbone from the start. Missing HER2-positive status means missing a highly effective targeted therapy.

PD-L1 is a protein that tumors can use to evade the immune system. In gastric cancer, PD-L1 expression is measured using the Combined Positive Score (CPS), which counts PD-L1-positive tumor cells, lymphocytes, and macrophages. A higher CPS predicts greater benefit from immunotherapy.

• CPS ≥1: Some benefit from adding checkpoint inhibitors to chemotherapy
• CPS ≥5: Clinically meaningful benefit from immunotherapy (key threshold in CheckMate 649)
• CPS ≥10: Largest benefit from immunotherapy (key threshold in KEYNOTE-859)

Claudin 18.2 is a tight junction protein expressed on normal gastric mucosa and retained in many gastric cancers. Approximately 38% of gastric cancers have CLDN18.2 expression (≥75% of tumor cells staining positive by IHC using the VENTANA CLDN18 assay). CLDN18.2-positive, HER2-negative patients are eligible for zolbetuximab (Vyloy) added to first-line chemotherapy.

Why it matters: CLDN18.2 testing is relatively new. If your oncologist has not tested for CLDN18.2, ask about it, especially if you are HER2-negative.

MSI-high (MSI-H) or mismatch repair deficient (dMMR) gastric cancers have a defective DNA repair system, creating many mutations that make the cancer more visible to the immune system. MSI-H/dMMR gastric cancers respond exceptionally well to checkpoint immunotherapy, with some patients achieving durable, long-lasting responses. MSI-H status also suggests possible Lynch syndrome (hereditary), which has implications for family screening.

Pembrolizumab monotherapy: Pembrolizumab is FDA-approved for any MSI-H/dMMR solid tumor, including gastric cancer, that has progressed on prior therapy. Response rates in MSI-H gastric cancer can exceed 40–50%.

• FGFR2b overexpression: The protein FGFR2b is overexpressed (by IHC) in roughly a third of advanced gastric cancers — this is the marker used to select patients for bemarituzumab (an anti-FGFR2b antibody), and is broader than FGFR2 gene amplification (~5–10%, detected by NGS/FISH). In the FIGHT trial, adding bemarituzumab to chemotherapy improved outcomes in FGFR2b-positive patients; the phase III FORTITUDE-101 trial has now met its primary survival endpoint at interim analysis. Bemarituzumab is not yet FDA-approved.
• NTRK fusions: Rare (<1%) but actionable. Larotrectinib and entrectinib are FDA-approved for any NTRK fusion-positive solid tumor.
• TMB-High: Pembrolizumab is FDA-approved for tumors with TMB ≥10 mutations/megabase.
• Next-generation sequencing (NGS): Comprehensive genomic profiling can identify rare targetable mutations and may help identify clinical trial options.

• What stage is my cancer, and has it spread beyond the stomach?
• What are my HER2, PD-L1 CPS, CLDN18.2, and MSI/dMMR results?
• Is my tumor the intestinal or diffuse histologic type?
• Is surgery an option for me?
• Do I need diagnostic laparoscopy before proceeding with treatment?
• Should I be tested for hereditary cancer syndromes (CDH1, Lynch syndrome)?
• What is the plan if imaging does not clearly show metastatic disease?
• Is there a clinical trial for my specific tumor profile?

• Endoscopic mucosal resection (EMR) / Endoscopic submucosal dissection (ESD): For very early-stage cancers (T1a) confined to the mucosa, without lymph node involvement, favorable histology (well-differentiated, no lymphovascular invasion). Common in Japan and Korea where screening detects many early cancers. Preserves the stomach.
• Subtotal (distal) gastrectomy: Removal of the lower portion of the stomach. Used for cancers in the antrum or body that can be completely removed with adequate margins. Preferred over total gastrectomy when feasible because quality of life is better.
• Total gastrectomy: Removal of the entire stomach. Required for proximal cancers, diffuse-type cancers, large tumors, or when adequate margins cannot be achieved with subtotal gastrectomy. The esophagus is connected directly to the small intestine (Roux-en-Y reconstruction).
• Prophylactic total gastrectomy: For patients with confirmed CDH1 germline mutations (hereditary diffuse gastric cancer). Recommended even without detectable cancer because of very high lifetime cancer risk.

Adequate lymph node dissection is critical for both staging accuracy and cancer cure. The standard of care varies by region:

• D2 lymphadenectomy: The international standard recommended by NCCN, ESMO, and JGCA. Involves removal of perigastric lymph nodes plus those along the major arterial vessels. At least 16 lymph nodes should be examined pathologically.
• D1 lymphadenectomy: Removal of perigastric lymph nodes only. Less extensive but associated with higher local recurrence.
• Why this matters: The extent of lymph node dissection is one of the strongest surgical factors affecting outcomes. Centers that routinely perform D2 dissection report better staging accuracy and often better survival. This is a key reason to seek treatment at a high-volume center.

Laparoscopic and robotic gastrectomy are increasingly performed for gastric cancer, particularly in East Asia. Multiple randomized trials (KLASS-02, CLASS-01, JLSSG0901) have demonstrated comparable oncologic outcomes with shorter recovery times and fewer complications compared to open surgery for select patients. Minimally invasive approaches are now included in NCCN guidelines as appropriate options when performed by experienced surgeons.

STANDARD OF CARE The FLOT4-AIO trial established FLOT (5-FU, leucovorin, oxaliplatin, docetaxel) as the preferred perioperative regimen in the West. FLOT given as 4 cycles before surgery and 4 cycles after surgery improved median overall survival from 35 to 50 months compared to the previous standard (ECF/ECX). FLOT is now the NCCN category 1 recommendation for perioperative chemotherapy.

In Japan and Korea, where screening detects more early-stage cancers and D2 dissection is standard, adjuvant (post-surgery only) chemotherapy is the established approach:

• S-1 (tegafur + gimeracil + oteracil): Standard adjuvant for stage II–III in Japan (ACTS-GC trial)
• CAPOX (capecitabine + oxaliplatin): Standard adjuvant in Korea (CLASSIC trial)
• S-1 + docetaxel: Shown to improve outcomes in stage III (JACCRO GC-07 trial)

Adjuvant chemoradiation (chemotherapy + radiation after surgery) was established by the INT-0116/Macdonald trial and is still used in some situations, particularly when less than D2 lymphadenectomy was performed or when margins are close or positive. However, perioperative FLOT has largely supplanted adjuvant chemoradiation as the preferred approach in the US and Europe when surgery is planned at a center performing D2 dissection.

FDA-APPROVED For GEJ and esophageal cancers that received neoadjuvant chemoradiation and did not achieve a pathologic complete response, adjuvant nivolumab for 1 year doubled disease-free survival (22.4 vs. 11.0 months) in the CheckMate 577 trial. This is relevant for cancers at the gastroesophageal junction.

• Is my cancer surgically resectable?
• Do I need chemotherapy before surgery? What regimen?
• Will I have a partial or total gastrectomy?
• What extent of lymph node dissection (D1 vs. D2) do you perform?
• How many gastrectomies does this center perform per year?
• Should I have diagnostic laparoscopy before starting treatment?
• What is the plan for chemotherapy after surgery?
• Am I eligible for a perioperative immunotherapy trial?
• What nutritional support will I receive after surgery?
• What are the expected side effects of the chemotherapy regimen?

STANDARD OF CARE For HER2-negative advanced gastric cancer:

• Nivolumab + FOLFOX or CAPOX (CheckMate 649): Median OS 14.4 months vs. 11.1 months for chemotherapy alone (CPS ≥5)
• Pembrolizumab + 5-FU/platinum (KEYNOTE-859): Median OS 12.9 months overall; 15.7 months for CPS ≥10

Both are acceptable first-line options. Choice between nivolumab and pembrolizumab often depends on institutional preference and insurance coverage.

FDA-APPROVED For CLDN18.2-positive (≥75% tumor cells staining 2+ or 3+ by VENTANA assay), HER2-negative advanced gastric cancer:

• Zolbetuximab + mFOLFOX6 (SPOTLIGHT): Median PFS 10.6 vs. 8.7 months; median OS 18.2 vs. 15.5 months
• Zolbetuximab + CAPOX (GLOW): Median PFS 8.2 vs. 6.8 months; median OS 14.4 vs. 12.2 months

Key side effects: Nausea and vomiting are common with zolbetuximab, particularly during the first few infusions. Aggressive anti-emetic prophylaxis is important.

STANDARD OF CARE For HER2-positive advanced gastric cancer:

• Trastuzumab + 5-FU/platinum chemotherapy (ToGA trial): Median OS improved from 11.1 to 13.8 months. Trastuzumab is a monoclonal antibody targeting HER2.
• Adding pembrolizumab: The KEYNOTE-811 trial showed that adding pembrolizumab to trastuzumab + chemotherapy improved PFS. Triplet therapy (pembrolizumab + trastuzumab + chemo) is now an option for HER2-positive, PD-L1 CPS ≥1 tumors.

Heart monitoring: Trastuzumab can affect heart function. Regular echocardiograms or MUGA scans are required during treatment.

Gastric cancers that are MSI-H/dMMR (∼5–8%) respond exceptionally well to checkpoint immunotherapy. Treatment options include:

• Pembrolizumab + chemotherapy first-line (included in KEYNOTE-859; MSI-H patients had the largest benefit)
• Pembrolizumab monotherapy for MSI-H tumors that progress on prior treatment (tumor-agnostic FDA approval)
• Nivolumab-based regimens

Some oncologists are discussing whether MSI-H gastric cancer patients might benefit from immunotherapy alone (without chemotherapy) in the first-line setting, though this is not yet standard outside of clinical trials.

FDA-APPROVED Ramucirumab is a monoclonal antibody targeting VEGFR2, which blocks new blood vessel growth to tumors. The RAINBOW trial showed that ramucirumab + paclitaxel improved median OS from 7.4 to 9.6 months compared to paclitaxel alone. Ramucirumab is also approved as a single agent (REGARD trial). It is the established second-line standard for HER2-negative gastric cancer.

FDA-APPROVED For HER2-positive gastric cancer after prior trastuzumab, T-DXd (Enhertu) achieved an objective response rate of 51% compared to 14% with physician’s choice chemotherapy. Median OS was 12.5 vs. 8.4 months.

FDA-APPROVED TAS-102 (trifluridine/tipiracil, Lonsurf) is an oral chemotherapy option for patients who have progressed on at least 2 prior lines. The TAGS trial showed a modest survival benefit (5.7 vs. 3.6 months). Adding bevacizumab may improve outcomes further based on preliminary data.

Irinotecan (alone or in combination) is used as a second-line or later-line option, particularly in Asia. Common regimens include irinotecan monotherapy, irinotecan + 5-FU, and FOLFIRI. Irinotecan is metabolized differently based on UGT1A1 polymorphisms — patients who are UGT1A1 *28/*28 (homozygous) are at higher risk of severe toxicity and may need dose reductions.

• What treatment is recommended for my specific biomarker profile?
• Am I eligible for immunotherapy? What was my PD-L1 CPS score?
• Is my tumor CLDN18.2-positive? Am I eligible for zolbetuximab?
• What second-line options are available when first-line treatment stops working?
• Should I be retested for biomarkers at progression?
• Is there a clinical trial I should consider?
• What is the goal of treatment — to control the disease, relieve symptoms, or both?
• How will we monitor whether treatment is working?
• What support is available for nutrition and symptom management?

• Dumping syndrome: Occurs when food moves too quickly from the stomach remnant into the small intestine. Causes nausea, cramping, diarrhea, dizziness, and sweating after eating. Managed by eating small, frequent meals; avoiding liquids with meals; limiting simple sugars; lying down after meals.
• Weight loss: Most patients lose 10–20% of body weight after gastrectomy. Work with a dietitian experienced in post-gastrectomy nutrition. High-calorie, high-protein foods in small portions.
• Vitamin and mineral deficiencies: Total gastrectomy patients must receive lifelong vitamin B12 injections (monthly). Iron supplementation is often needed. Calcium and vitamin D supplementation to prevent bone loss. Folate monitoring.
• Pancreatic enzyme insufficiency: Some patients develop poor fat absorption. Pancreatic enzyme replacement (Creon) may improve digestion and reduce steatorrhea.

• Nausea/vomiting: Common with platinum-based chemotherapy and zolbetuximab. Aggressive anti-emetic regimens (ondansetron, dexamethasone, NK1 receptor antagonists) are essential.
• Peripheral neuropathy: Tingling, numbness, or pain in hands/feet from oxaliplatin. Usually improves after stopping but can be permanent. Report symptoms early so doses can be adjusted.
• Fatigue: The most common side effect. Regular light exercise actually helps reduce fatigue. Treat underlying anemia if present.
• Diarrhea: Common with 5-FU, capecitabine, and irinotecan. Loperamide is first-line treatment. Severe diarrhea may require IV fluids and hospitalization.
• Immune-related side effects: Checkpoint inhibitors (pembrolizumab, nivolumab) can cause inflammation in any organ. Report new symptoms promptly — most immune side effects are manageable if caught early.

• Stent placement: For tumors causing obstruction at the gastric inlet or outlet, a self-expanding metal stent can be placed endoscopically to restore the ability to eat.
• Bypass surgery: Gastrojejunostomy to bypass an obstructing tumor that cannot be stented.
• Bleeding control: Endoscopic treatment (cauterization, clipping) or radiation therapy for tumor-related bleeding.
• Ascites management: Peritoneal carcinomatosis often causes fluid accumulation (ascites). Paracentesis (needle drainage) provides temporary relief. Tunneled peritoneal catheters allow drainage at home.

• NCCN (US): Comprehensive treatment algorithms, updated at least annually
• ESMO (Europe): Clinical practice guidelines; ESMO Magnitude of Clinical Benefit Scale (MCBS) rates new therapies
• JGCA (Japan): Japanese Gastric Cancer Association, 6th edition guidelines (2023). Reflects the most extensive surgical experience globally, including D2 dissection standards and ESD for early cancer
• KGCA (Korea): Korean guidelines emphasizing screening and surgical standards
• NICE (UK): Technology appraisals for NHS access
• Health Canada / CADTH: Canadian drug access pathway

FAILED Despite success in colorectal cancer, bevacizumab (anti-VEGF antibody) added to chemotherapy failed to improve overall survival in the AVAGAST phase III trial for first-line advanced gastric cancer. A modest PFS benefit was seen but no OS benefit, particularly in Asian patients. Bevacizumab is not approved for gastric cancer.

FAILED The LOGiC and TyTAN trials testing lapatinib (oral HER2 inhibitor) in HER2-positive gastric cancer did not meet their primary endpoints. Unlike trastuzumab, lapatinib has not been adopted for gastric cancer.

FAILED Adding pertuzumab to trastuzumab + chemotherapy (dual HER2 blockade, successful in breast cancer) did not significantly improve overall survival in the JACOB trial for first-line HER2-positive gastric cancer. Unlike breast cancer, dual HER2 blockade has not been adopted in gastric cancer.

NOT SUPPORTED The T-ACT trial demonstrated that continuing trastuzumab beyond first-line progression (adding it to paclitaxel in the second line) did not improve survival compared to paclitaxel alone in HER2-positive gastric cancer. This is different from breast cancer practice and underscores that HER2 biology differs between these cancers. Trastuzumab deruxtecan (Enhertu) is the preferred second-line HER2-targeted option.

FAILED The GRANITE-1 trial testing everolimus (mTOR inhibitor) as salvage therapy in advanced gastric cancer failed to improve overall survival compared to placebo. mTOR inhibition has not shown clinical utility in gastric cancer.

• Prepare for a learning curve. Eating after a partial or total gastrectomy is fundamentally different. The patient must learn to eat 6–8 small meals per day instead of 3 large ones. This is not optional — it prevents dumping syndrome and malnutrition.
• Keep a food diary. Track what foods are tolerated and which cause problems. Each person is different.
• High-protein, nutrient-dense foods. Focus on quality over quantity. Every bite needs to count nutritionally.
• Separate liquids from solids. Drink fluids 30–60 minutes before or after meals, not during.
• Vitamin B12 injections are mandatory after total gastrectomy. Without a stomach, B12 cannot be absorbed from food. Monthly injections prevent irreversible nerve damage.

• Weight loss is expected. Most patients lose significant weight after gastrectomy. This can be distressing for both patient and caregiver. Work closely with a dietitian.
• Body image changes. Changes in eating habits, weight, and physical ability can affect self-image and mood. Professional psychological support is beneficial.
• Caregiver burnout. Managing complex dietary needs, multiple medications, and frequent medical appointments is exhausting. Ask for help. Use cancer center support services.
• Support organizations: Debbie’s Dream Foundation (debbiedream.org), No Stomach For Cancer (nostomachforcancer.org), and the Hope for Stomach Cancer Foundation provide patient and caregiver resources.