Teaching pack: HER2-positive gastric cancer

HER2 positivity is defined in stomach cancer as immunohistochemistry 3+ or 2+ with amplification on in situ hybridisation, and every advanced gastric or junctional adenocarcinoma is tested at diagnosis. HER2-positive tumours are more often intestinal type and sit more often at the junction than in the distal stomach; staining is heterogeneous, so biopsies from several sites are recommended and a negative result on a small sample can be wrong.

ToGA (Lancet 2010) added trastuzumab to cisplatin and a fluoropyrimidine and extended median overall survival from 11.1 to 13.8 months, and to 16.0 months in patients with strong HER2 expression; it made trastuzumab the first targeted therapy in stomach cancer. KEYNOTE-811 then added pembrolizumab to trastuzumab and chemotherapy, raising response rates and improving survival in PD-L1-positive tumours, so the triplet is now first-line standard where PD-L1 is expressed. Zanidatamab, a bispecific HER2 antibody, is being tested against trastuzumab in the same setting in HERIZON-GEA-01.

• ToGA made HER2 the first biomarker in stomach cancer and trastuzumab-chemotherapy the standard first line for fifteen years.
• Trastuzumab deruxtecan gives a second HER2-directed line with a real survival gain, unlike lapatinib and trastuzumab emtansine before it.
• Pembrolizumab added to trastuzumab and chemotherapy is now the first-line triplet in PD-L1-positive tumours.

1. 2010ToGA: trastuzumab plus chemotherapy extends survival in HER2-positive gastric cancer
2. 2017GATSBY: trastuzumab emtansine fails in the second line
3. 2020DESTINY-Gastric01: trastuzumab deruxtecan beats chemotherapy after trastuzumab
4. 2021FDA approves trastuzumab deruxtecan for HER2-positive gastric cancer; KEYNOTE-811 adds pembrolizumab first line
5. 2025DESTINY-Gastric04: trastuzumab deruxtecan beats ramucirumab-paclitaxel in the second line

• Zanidatamab (treatment)
• HERIZON-GEA-01 (trial)
• Disitamab vedotin (treatment)
• HER2 sequence in gastric cancer: zanidatamab/trastuzumab + chemo ± PD-1 → T-DXd (pairing)
• Trastuzumab deruxtecan (treatment)

• 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=920): Progression-free survival: 12.4 months vs 12.4 months vs 8.1 months
• KEYNOTE-811 (phase 3, n=738): Progression-free survival (second interim analysis): 10 months vs 8.1 months, HR 0.72
• DESTINY-Gastric01 (phase 2, n=233): Objective response (independent central review): 51% vs 14%
• A Phase Ⅲ Study of Rilvegostomig in Combination With Fluoropyrimidine and Trastuzumab Deruxtecan as the First-line Treatment for HER2-positive Gastric Cancer (phase 3, n=840): result not yet recorded

• HER2 heterogeneity and loss after treatment make a single biopsy unreliable.
• No HER2-directed therapy has yet improved cure rates in resectable disease.
• Interstitial lung disease with trastuzumab deruxtecan needs early recognition.

1. What does 'triple-negative' mean in breast cancer?
   Answer

   The tumour lacks the three receptors other breast cancers can be treated through: oestrogen receptor, progesterone receptor, and HER2 (IHC 0-1+ or 2+/ISH-negative).
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. 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.
5. What is the bystander effect in ADCs?
   Answer

   A released, membrane-permeable payload diffuses out of the targeted cell and kills neighbouring cells that lack the antigen; requires a cleavable linker and permeable payload (DXd, MMAE, SN-38), explaining T-DXd's activity in HER2-low disease and T-DM1's lack of it.
6. What should I ask before starting an ADC such as Enhertu?
   Answer

   How lung inflammation (ILD) will be monitored and what symptoms to report immediately; HER2 status and how it was scored; expected nausea, hair loss, and blood counts; dosing schedule (every three weeks); how response will be assessed and when; what comes next if it stops working.

• ToGA (Lancet 2010): https://pubmed.ncbi.nlm.nih.gov/20728210/
• DESTINY-Gastric01 (NEJM 2020): https://www.nejm.org/doi/full/10.1056/NEJMoa2004413
• Wikipedia: https://en.wikipedia.org/wiki/Stomach_cancer
• Wikipedia: https://en.wikipedia.org/wiki/Stomach_cancer