Teaching pack: Gastric & gastro-oesophageal junction cancer

Gastric and gastro-oesophageal junction adenocarcinoma causes about one million new cases and 660,000 deaths a year, concentrated in East Asia, Eastern Europe, and Latin America, where Helicobacter pylori infection, salt, and smoking drive incidence. Japan and Korea screen endoscopically and cure most cases early; elsewhere two-thirds present with advanced disease and five-year survival is under 30%. Biology splits by the Lauren classification (intestinal vs diffuse) and the TCGA classes (EBV-positive, MSI, genomically stable, chromosomally unstable), and clinically by three actionable biomarkers: HER2 (~15-20%), PD-L1 (CPS ≥5 in ~60%), and Claudin 18.2 (~38% at the approval threshold), with FGFR2b, MSI, and EBV as further strata.

Localised disease is treated with gastrectomy and D2 lymphadenectomy plus perioperative chemotherapy: FLOT in the West, adjuvant S-1 or CAPOX in Asia. MATTERHORN (2025) added durvalumab to FLOT, the first perioperative immunotherapy with an overall survival benefit (3-year OS 68.6%). Advanced disease is stratified at diagnosis: HER2-positive tumours get trastuzumab + chemotherapy + pembrolizumab (KEYNOTE-811) or, after HERIZON-GEA-01, zanidatamab + chemotherapy ± tislelizumab; HER2-negative, PD-L1 CPS ≥5 tumours get nivolumab or pembrolizumab with chemotherapy (CheckMate 649 5-year OS 16% vs 6%); CLDN18.2-positive tumours get zolbetuximab + chemotherapy (SPOTLIGHT/GLOW). Second line: T-DXd for HER2-positive disease (DESTINY-Gastric04, OS 14.7 vs 11.4 months), ramucirumab + paclitaxel otherwise, and from 2026 the CLDN18.2 ADC sonesitatug vedotin (CLARITY-Gastric 01). Third line: trifluridine/tipiracil.

• Biomarker-stratified first line with four possible add-ons.
• First solid-tumour CAR-T approval (China).
• Three first-line biomarkers (HER2, PD-L1, CLDN18.2) each with a phase 3-proven add-on to chemotherapy; testing all three at diagnosis is standard.
• Perioperative durvalumab + FLOT (MATTERHORN) is the first immunotherapy to improve survival in resectable gastric cancer (FDA November 2025).
• Zanidatamab beat trastuzumab head-to-head first line (HERIZON-GEA-01, 2026), the first HER2 advance in first line since ToGA.
• T-DXd has phase 3 proof in second-line HER2-positive disease (DESTINY-Gastric04).

1. 1881Billroth performs the first successful gastrectomy for cancer
2. 1965Lauren describes intestinal and diffuse types
3. 1983Helicobacter pylori identified (Marshall and Warren)
4. 1990Japan and Korea institute endoscopic screening programmes
5. 2006MAGIC: perioperative chemotherapy improves survival (ECF)
6. 2010ToGA: trastuzumab in HER2+ gastric cancer
7. 2010ToGA: trastuzumab, the first targeted therapy in gastric cancer
8. 2014TCGA molecular classification; RAINBOW establishes ramucirumab + paclitaxel
9. 2017Nivolumab third line (ATTRACTION-2); pembrolizumab for MSI-high tumours
10. 2019FLOT4: docetaxel quadruplet becomes perioperative standard; trifluridine/tipiracil third line (TAGS)

• Sonesitatug vedotin (product)
• Satricabtagene autoleucel (product)
• Disitamab vedotin (product)
• Zanidatamab (product)
• FAPI PET (technology)
• HERIZON-GEA-01 (trial)
• CLARITY-Gastric 01 (trial)
• Bemarituzumab (product)
• FORTITUDE-101 (trial)
• Biomarker-directed first-line quadruplets in gastric cancer (idea)
• Peritoneal-directed therapy for gastric cancer (idea)
• HER2 sequence in gastric cancer: zanidatamab/trastuzumab + chemo ± PD-1 → T-DXd (pairing)

• CheckMate 649 (phase 3, n=1,581): Overall survival, PD-L1 CPS ≥5: 14.4 months vs 11.1 months, HR 0.71
• KEYNOTE-859 (phase 3, n=1,579): Overall survival, all randomised: 12.9 months vs 11.5 months, HR 0.78
• RAINBOW (phase 3, n=665): Overall survival: 9.6 months vs 7.4 months, HR 0.81
• ToGA (phase 3, n=594): Overall survival: 13.8 months vs 11.1 months, HR 0.74
• DESTINY-Gastric04 (phase 3, n=494): Overall survival: 14.7 months vs 11.4 months, HR 0.7
• HERIZON-GEA-01 (phase 3, n=914): Progression-free survival: 12.4 months vs 12.4 months vs 8.1 months

• Peritoneal metastasis.
• Heterogeneous CLDN18.2/HER2 expression.
• Screening only in Japan/Korea.
• Peritoneal metastasis is the dominant relapse pattern and is poorly imaged, poorly penetrated by drugs, and excluded from most trials.
• Diffuse-type and genomically stable tumours lack targets and respond poorly to chemotherapy and immunotherapy.
• Biomarker overlap (CLDN18.2 with PD-L1) has no randomised guidance on combination versus sequence.

1. Which new target has an approved antibody, an approved CAR-T in China, and ADCs in phase 3 for gastric cancer?
   Answer

   Claudin 18.2: zolbetuximab (Vyloy), satricabtagene autoleucel (satri-cel, CARsgen, China), and ADCs such as CMG901/AZD0901.
2. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
3. Why does trastuzumab deruxtecan work in 'HER2-low' breast cancers that older HER2 drugs ignored?
   Answer

   Its cleavable linker releases a membrane-permeable topoisomerase-I payload (DXd) at high DAR, so a small amount of HER2 is enough to deliver drug and the payload diffuses to kill neighbouring cells (bystander effect); HER2-low is a delivery address, not a driver. DESTINY-Breast04 and -06 proved it.
4. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
5. In what setting did T-DXd move into early-stage HER2-positive breast cancer in 2026?
   Answer

   Neoadjuvant (DESTINY-Breast11, T-DXd followed by THP, pCR 67.3% vs 56.3%) and post-neoadjuvant residual disease (DESTINY-Breast05, beating T-DM1), both approved Q2 2026.
6. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.

• NCCN Gastric Cancer guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434
• ESMO gastric cancer guideline: https://www.esmo.org/guidelines/guidelines-by-topic/esmo-clinical-practice-guidelines-gastrointestinal-cancers/gastric-cancer
• NCI PDQ gastric cancer treatment: https://www.cancer.gov/types/stomach/hp/stomach-treatment-pdq
• Wikipedia: https://en.wikipedia.org/wiki/Stomach_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434
• Guideline: https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/
• Guideline: https://www.esmo.org/guidelines/guidelines-by-topic/esmo-clinical-practice-guidelines-gastrointestinal-cancers/gastric-cancer