{"entity":{"id":"gastric-her2-positive","kind":"cancer","name":"HER2-positive gastric cancer","aka":["HER2-positive gastro-oesophageal adenocarcinoma","ERBB2-amplified gastric cancer","HER2+ GEA"],"tldr":"HER2-positive gastric cancer overexpresses the HER2 growth receptor and is treated with trastuzumab added to chemotherapy, now usually with pembrolizumab as well. After progression the antibody-drug conjugate trastuzumab deruxtecan gives responses that plain chemotherapy cannot.","summary":"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.\n\nToGA (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.\n\nDESTINY-Gastric01 (NEJM 2020) showed that trastuzumab deruxtecan, an antibody-drug conjugate carrying a topoisomerase inhibitor payload, produced responses in 51 percent of previously treated patients against 14 percent with chemotherapy and improved median survival from 8.4 to 12.5 months, earning FDA approval in 2021. DESTINY-Gastric04 confirmed the benefit in the second line against ramucirumab and paclitaxel, with median survival of 14.7 against 11.4 months. Interstitial lung disease is the toxicity that needs watching. HER2 expression is often lost after trastuzumab, so a fresh biopsy before second-line HER2 therapy is advised.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Stomach_cancer","links":[{"label":"ToGA (Lancet 2010)","url":"https://pubmed.ncbi.nlm.nih.gov/20728210/"},{"label":"DESTINY-Gastric01 (NEJM 2020)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2004413"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Stomach_cancer"}],"tags":["subtype-page"],"related":["gastric-cldn18-2-positive","early-gastric-cancer","gastric-msi-high","gastric-pdl1-high"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["destiny-gastric01","destiny-gastric02","keynote-811","gatsby"],"people":[],"bottlenecks":[],"keyPapers":["paper-toga-trastuzumab-gastric-lancet-2010","paper-flot4-lancet-2019","paper-keynote-811-janjigian-lancet-2023","paper-destiny-gastric01-nejm-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About one in six advanced gastric and junctional adenocarcinomas, commoner in intestinal-type and junctional tumours than in diffuse-type disease; it was the first molecular subgroup of stomach cancer to get its own treatment.","subtypes":["HER2 3+ by immunohistochemistry","HER2 2+ with amplification on in situ hybridisation","HER2-positive, PD-L1 CPS 1 or above (trastuzumab, pembrolizumab and chemotherapy)","HER2-positive junctional adenocarcinoma","HER2 loss after trastuzumab"],"biomarkers":["HER2 by immunohistochemistry and in situ hybridisation (multiple biopsy sites)","PD-L1 combined positive score (decides pembrolizumab in first line)","HER2 status on repeat biopsy at progression","ERBB2 amplification on plasma ctDNA (trials)"],"standardOfCare":[{"setting":"Advanced, first line","approach":"Trastuzumab with a platinum and a fluoropyrimidine (ToGA), plus pembrolizumab when PD-L1 CPS is 1 or above (KEYNOTE-811).","refs":["toga","trastuzumab","pembrolizumab","cisplatin","oxaliplatin","capecitabine","fluorouracil","her2","her2-gastric-sequence"]},{"setting":"Second line","approach":"Trastuzumab deruxtecan (DESTINY-Gastric01 and DESTINY-Gastric04); ramucirumab with paclitaxel where the conjugate is unavailable.","refs":["trastuzumab-deruxtecan","destiny-gastric04","ramucirumab","paclitaxel"]},{"setting":"Later lines","approach":"Trifluridine-tipiracil; trials of zanidatamab and other HER2 agents.","refs":["trifluridine-tipiracil","zanidatamab","herizon-gea-01"]},{"setting":"Localised disease","approach":"Perioperative FLOT and gastrectomy as for HER2-negative disease; adding HER2 therapy before surgery is unproven.","refs":["flot","gastrectomy"]}],"stateOfArt":["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."],"history":[{"year":2010,"title":"ToGA: trastuzumab plus chemotherapy extends survival in HER2-positive gastric cancer","refs":["toga","trastuzumab"]},{"year":2017,"title":"GATSBY: trastuzumab emtansine fails in the second line","refs":[]},{"year":2020,"title":"DESTINY-Gastric01: trastuzumab deruxtecan beats chemotherapy after trastuzumab","refs":["trastuzumab-deruxtecan"]},{"year":2021,"title":"FDA approves trastuzumab deruxtecan for HER2-positive gastric cancer; KEYNOTE-811 adds pembrolizumab first line","refs":["trastuzumab-deruxtecan","pembrolizumab"]},{"year":2025,"title":"DESTINY-Gastric04: trastuzumab deruxtecan beats ramucirumab-paclitaxel in the second line","refs":["destiny-gastric04"]}],"pipeline":["zanidatamab","herizon-gea-01","disitamab-vedotin","her2-gastric-sequence","trastuzumab-deruxtecan"],"openProblems":["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."],"parent":"gastric"},"route":"/cancers/gastric-her2-positive/","neighbours":{"cancer":[{"id":"gastric-cldn18-2-positive","kind":"cancer","name":"Claudin 18.2-positive gastric cancer","route":"/cancers/gastric-cldn18-2-positive/"},{"id":"early-gastric-cancer","kind":"cancer","name":"Early gastric cancer","route":"/cancers/early-gastric-cancer/"},{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"gastric-msi-high","kind":"cancer","name":"Microsatellite-unstable (MSI-high) gastric cancer","route":"/cancers/gastric-msi-high/"},{"id":"gastric-pdl1-high","kind":"cancer","name":"PD-L1-high gastric cancer","route":"/cancers/gastric-pdl1-high/"}],"trial":[{"id":"nct05619016","kind":"trial","name":"[68Ga]Ga-ABY-025 PET for Quantification of HER2-status in Solid Tumors","route":"/trials/nct05619016/"},{"id":"nct06532006","kind":"trial","name":"A Phase Ⅲ Clinical Study of HLX22 in Combination With Trastuzumab and Chemotherapy for the Treatment of Gastroesophageal Junction and Gastric Cancer","route":"/trials/nct06532006/"},{"id":"nct06764875","kind":"trial","name":"A Phase Ⅲ Study of Rilvegostomig in Combination With Fluoropyrimidine and Trastuzumab Deruxtecan as the First-line Treatment for HER2-positive Gastric Cancer","route":"/trials/nct06764875/"},{"id":"aspen-06","kind":"trial","name":"A Study of Evorpacept (ALX148) in Patients With Advanced HER2+ Gastric Cancer (ASPEN-06)","route":"/trials/aspen-06/"},{"id":"nct04492488","kind":"trial","name":"A Study of MRG002 in Patients with HER2-Positive Advanced Solid Tumors and Locally Advanced or Metastatic Gastric/Gastroesophageal Junction (GEJ) Cancer","route":"/trials/nct04492488/"},{"id":"nct06271837","kind":"trial","name":"A Study of T-DXd as Monotherapy or in Combination With Anti-cancer Agents in Patients With Selected HER2-expressing Tumors","route":"/trials/nct06271837/"},{"id":"nct04082364","kind":"trial","name":"Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer","route":"/trials/nct04082364/"},{"id":"destiny-gastric01","kind":"trial","name":"DESTINY-Gastric01","route":"/trials/destiny-gastric01/"},{"id":"destiny-gastric02","kind":"trial","name":"DESTINY-Gastric02","route":"/trials/destiny-gastric02/"},{"id":"destiny-gastric04","kind":"trial","name":"DESTINY-Gastric04","route":"/trials/destiny-gastric04/"},{"id":"nct06221748","kind":"trial","name":"DV Combined With Cadonilimab in Subjects With HER2-expressing Gastric Cancer and Gastroesophageal Junction Adenocarcinoma After Progression on First-line Therapy","route":"/trials/nct06221748/"},{"id":"gatsby","kind":"trial","name":"GATSBY","route":"/trials/gatsby/"},{"id":"herizon-gea-01","kind":"trial","name":"HERIZON-GEA-01","route":"/trials/herizon-gea-01/"},{"id":"keynote-811","kind":"trial","name":"KEYNOTE-811","route":"/trials/keynote-811/"},{"id":"nct05427383","kind":"trial","name":"KN026 in Combination With Chemotherapy in HER2 Positive Gastric Cancer Subjects Who Have Failed First-line Therapy","route":"/trials/nct05427383/"},{"id":"nct06155383","kind":"trial","name":"Perioperative Disitamab Vedotin Plus Toripalimab and XELOX in Gastric or Gastroesophageal Junction Adenocarcinoma.","route":"/trials/nct06155383/"},{"id":"nct05671822","kind":"trial","name":"Ph1b/2 Study of the Safety and Efficacy of SHR-A1811 Combinations in Advanced HER2 Expression Gastric Cancer","route":"/trials/nct05671822/"},{"id":"nct04379596","kind":"trial","name":"Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03)","route":"/trials/nct04379596/"},{"id":"nct06123494","kind":"trial","name":"SHR-A1811 for Subjects With Her2-positive Gastric Cancer and Gastroesophageal Junction Adenocarcinoma After Progression on or After First-line Anti-HER2 Therapy-containing Regimen","route":"/trials/nct06123494/"},{"id":"nct06731478","kind":"trial","name":"Study of TDXd, Chemotherapy, Pembrolizumab, and Trastuzumab in First-Line Metastatic HER2-Positive Gastric or Gastroesophageal Junction Cancer","route":"/trials/nct06731478/"},{"id":"nct05771584","kind":"trial","name":"Therapeutic Cancer Vaccine (AST-301, pNGVL3-hICD) in Gastric Cancer","route":"/trials/nct05771584/"},{"id":"nct06504732","kind":"trial","name":"To Evaluate IAH0968 in Combination With CAPEOX in HER2-positive Gastric Cancer","route":"/trials/nct06504732/"},{"id":"toga","kind":"trial","name":"ToGA","route":"/trials/toga/"}],"paper":[{"id":"paper-destiny-gastric01-nejm-2020","kind":"paper","name":"DESTINY-Gastric01: trastuzumab deruxtecan in previously treated HER2-positive gastric cancer","route":"/key-papers/paper-destiny-gastric01-nejm-2020/"},{"id":"paper-flot4-lancet-2019","kind":"paper","name":"FLOT4-AIO: perioperative FLOT versus ECF/ECX for resectable gastric or gastro-oesophageal junction adenocarcinoma","route":"/key-papers/paper-flot4-lancet-2019/"},{"id":"paper-keynote-811-janjigian-lancet-2023","kind":"paper","name":"KEYNOTE-811: pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma","route":"/key-papers/paper-keynote-811-janjigian-lancet-2023/"},{"id":"paper-toga-trastuzumab-gastric-lancet-2010","kind":"paper","name":"ToGA (Bang 2010): trastuzumab with chemotherapy for HER2-positive advanced gastric cancer","route":"/key-papers/paper-toga-trastuzumab-gastric-lancet-2010/"}],"drug":[{"id":"capecitabine","kind":"drug","name":"Capecitabine","route":"/drugs/capecitabine/"},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"disitamab-vedotin","kind":"drug","name":"Disitamab vedotin","route":"/drugs/disitamab-vedotin/"},{"id":"flot","kind":"drug","name":"FLOT (5-FU, leucovorin, oxaliplatin, docetaxel)","route":"/drugs/flot/"},{"id":"fluorouracil","kind":"drug","name":"Fluorouracil (5-FU)","route":"/drugs/fluorouracil/"},{"id":"oxaliplatin","kind":"drug","name":"Oxaliplatin","route":"/drugs/oxaliplatin/"},{"id":"paclitaxel","kind":"drug","name":"Paclitaxel / nab-paclitaxel","route":"/drugs/paclitaxel/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"ramucirumab","kind":"drug","name":"Ramucirumab","route":"/drugs/ramucirumab/"},{"id":"trastuzumab","kind":"drug","name":"Trastuzumab","route":"/drugs/trastuzumab/"},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"},{"id":"trifluridine-tipiracil","kind":"drug","name":"Trifluridine/tipiracil","route":"/drugs/trifluridine-tipiracil/"},{"id":"zanidatamab","kind":"drug","name":"Zanidatamab","route":"/drugs/zanidatamab/"}],"pairing":[{"id":"her2-gastric-sequence","kind":"pairing","name":"HER2 sequence in gastric cancer: zanidatamab/trastuzumab + chemo ± PD-1 → T-DXd","route":"/pairings/her2-gastric-sequence/"}],"target":[{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"}],"term":[{"id":"gastrectomy","kind":"term","name":"Gastrectomy","route":"/terms/gastrectomy/"}],"person":[{"id":"peter-thuss-patience","kind":"person","name":"Peter Thuss-Patience","route":"/people/peter-thuss-patience/"},{"id":"salah-eddin-al-batran","kind":"person","name":"Salah-Eddin Al-Batran","route":"/people/salah-eddin-al-batran/"}],"biomarker":[{"id":"her2-ihc-2-plus","kind":"biomarker","name":"HER2 IHC 2+ (equivocal, reflex to ISH)","route":"/biomarkers/her2-ihc-2-plus/"},{"id":"her2-ihc-3-plus","kind":"biomarker","name":"HER2 IHC 3+ (HER2-positive by immunohistochemistry)","route":"/biomarkers/her2-ihc-3-plus/"},{"id":"her2-ish-amplified","kind":"biomarker","name":"HER2 ISH amplified (ERBB2 gene amplification)","route":"/biomarkers/her2-ish-amplified/"},{"id":"pd-l1-cps","kind":"biomarker","name":"PD-L1 CPS (combined positive score)","route":"/biomarkers/pd-l1-cps/"}]}}