{"entity":{"id":"gastric-pdl1-high","kind":"cancer","name":"PD-L1-high gastric cancer","aka":["PD-L1 CPS 5 or above gastric cancer","PD-L1-positive gastro-oesophageal adenocarcinoma","EBV-positive gastric cancer (PD-L1 high)"],"tldr":"PD-L1-high gastric cancer expresses the immune checkpoint protein PD-L1 on tumour and immune cells, and this is the group in which nivolumab or pembrolizumab added to chemotherapy clearly extends life. The benefit shrinks as the score falls, so regulators now restrict the antibodies to tumours with at least some PD-L1 expression.","summary":"PD-L1 in stomach cancer is scored with the combined positive score, the number of PD-L1-staining tumour cells, lymphocytes and macrophages divided by the number of viable tumour cells, using the 28-8 or 22C3 antibody. Epstein-Barr virus-positive tumours, about one in eleven, express PD-L1 heavily and respond best of all; microsatellite-unstable tumours do too. Scores of 5 or above with the 28-8 assay and 1 or above with 22C3 have become the practical thresholds, and the two assays are not perfectly interchangeable.\n\nCheckMate 649 (Lancet 2021) randomised HER2-negative advanced gastric, junctional and oesophageal adenocarcinoma to nivolumab plus oxaliplatin-fluoropyrimidine chemotherapy or chemotherapy alone; in the combined positive score 5 or above group median overall survival rose from 11.1 to 14.4 months, and in all randomised patients from 11.6 to 13.8 months, with the gain concentrated in tumours with higher scores and persisting at five years. KEYNOTE-859 (Lancet Oncology 2023) did the same with pembrolizumab, improving median survival from 11.5 to 12.9 months overall, from 11.4 to 13.0 months in score 1 or above and from 11.8 to 15.7 months in score 10 or above. Chinese trials with tislelizumab and sintilimab followed the same pattern.\n\nRegulators drew different lines. The FDA first approved nivolumab in 2021 regardless of PD-L1 and pembrolizumab in 2023, then in 2025 narrowed both to tumours with a combined positive score of 1 or above after its advisory committee found no benefit below that score; the European label requires a score of 5 for nivolumab. In resectable disease MATTERHORN added durvalumab to perioperative FLOT and improved event-free survival in all patients, PD-L1 status notwithstanding, so the biomarker matters most in the metastatic setting.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Stomach_cancer","links":[{"label":"CheckMate 649 (Lancet 2021)","url":"https://pubmed.ncbi.nlm.nih.gov/34102137/"},{"label":"KEYNOTE-859 (Lancet Oncology 2023)","url":"https://pubmed.ncbi.nlm.nih.gov/37875143/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Stomach_cancer"}],"tags":["subtype-page"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Roughly six in ten advanced gastric adenocarcinomas have a PD-L1 combined positive score of 1 or above and about half score 5 or above; the higher the score, the larger the survival gain from adding a PD-1 antibody to chemotherapy.","subtypes":["PD-L1 CPS 10 or above (largest benefit)","PD-L1 CPS 5 or above (nivolumab label in Europe)","PD-L1 CPS 1 to 4 (smaller benefit)","EBV-positive gastric cancer (PD-L1 high, immunotherapy-responsive)","PD-L1-negative (chemotherapy alone unless another target is present)"],"biomarkers":["PD-L1 combined positive score (28-8 or 22C3 assay)","Epstein-Barr virus in situ hybridisation","Microsatellite instability and mismatch repair (overlapping responders)","HER2 (must be negative for this pathway)","Claudin 18.2 (competing first-line target)"],"standardOfCare":[{"setting":"Advanced, first line, CPS 5 or above","approach":"Nivolumab with FOLFOX or CAPOX (CheckMate 649) or pembrolizumab with platinum-fluoropyrimidine chemotherapy (KEYNOTE-859).","refs":["checkmate-649","keynote-859","nivolumab","pembrolizumab","folfox","capox","pdl1","cps"]},{"setting":"Advanced, first line, CPS 1 to 4","approach":"PD-1 antibody with chemotherapy is permitted in the United States and offered with a smaller expected gain; chemotherapy alone or zolbetuximab where claudin 18.2 is positive.","refs":["nivolumab","pembrolizumab","zolbetuximab","cps"]},{"setting":"Resectable stage II to III","approach":"Perioperative FLOT with durvalumab (MATTERHORN), given irrespective of PD-L1 score.","refs":["matterhorn","durvalumab","flot"]},{"setting":"Second line","approach":"Ramucirumab with paclitaxel (RAINBOW); no established role for continued PD-1 blockade.","refs":["rainbow","ramucirumab","paclitaxel"]}],"stateOfArt":["Nivolumab and pembrolizumab with chemotherapy are the first-line standard for PD-L1-expressing HER2-negative disease, with five-year survivors in CheckMate 649.","The combined positive score is one of the few checkpoint biomarkers with a clear dose-response across trials.","Durvalumab with FLOT brought immunotherapy into curative-intent treatment without needing the biomarker."],"history":[{"year":2017,"title":"KEYNOTE-059 and ATTRACTION-2: PD-1 antibodies active in late-line gastric cancer","refs":["pembrolizumab","nivolumab"]},{"year":2021,"title":"CheckMate 649: nivolumab plus chemotherapy extends survival; FDA approval","refs":["checkmate-649","nivolumab"]},{"year":2023,"title":"KEYNOTE-859: pembrolizumab plus chemotherapy extends survival","refs":["keynote-859","pembrolizumab"]},{"year":2025,"title":"FDA restricts first-line PD-1 antibodies to PD-L1 CPS 1 or above; MATTERHORN positive with durvalumab and FLOT","refs":["matterhorn","durvalumab"]}],"pipeline":["matterhorn","tislelizumab","idea-biomarker-quadruplet-gastric","gotistobart","azd7789"],"openProblems":["Two assays with different thresholds leave patients near the cut-off in an uncertain position.","Most patients still progress within a year on chemo-immunotherapy.","How to combine PD-1 blockade with claudin 18.2 or HER2 therapy when targets overlap."],"parent":"gastric"},"route":"/cancers/gastric-pdl1-high/","neighbours":{"drug":[{"id":"azd7789","kind":"drug","name":"AZD7789","route":"/drugs/azd7789/"},{"id":"capox","kind":"drug","name":"CAPOX (capecitabine, oxaliplatin)","route":"/drugs/capox/"},{"id":"durvalumab","kind":"drug","name":"Durvalumab","route":"/drugs/durvalumab/"},{"id":"flot","kind":"drug","name":"FLOT (5-FU, leucovorin, oxaliplatin, docetaxel)","route":"/drugs/flot/"},{"id":"folfox","kind":"drug","name":"FOLFOX (5-FU, leucovorin, oxaliplatin)","route":"/drugs/folfox/"},{"id":"gotistobart","kind":"drug","name":"Gotistobart","route":"/drugs/gotistobart/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"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":"tislelizumab","kind":"drug","name":"Tislelizumab","route":"/drugs/tislelizumab/"},{"id":"zolbetuximab","kind":"drug","name":"Zolbetuximab","route":"/drugs/zolbetuximab/"}],"trial":[{"id":"checkmate-649","kind":"trial","name":"CheckMate 649","route":"/trials/checkmate-649/"},{"id":"keynote-859","kind":"trial","name":"KEYNOTE-859","route":"/trials/keynote-859/"},{"id":"matterhorn","kind":"trial","name":"MATTERHORN","route":"/trials/matterhorn/"},{"id":"rainbow","kind":"trial","name":"RAINBOW","route":"/trials/rainbow/"}],"idea":[{"id":"idea-biomarker-quadruplet-gastric","kind":"idea","name":"Biomarker-directed first-line quadruplets in gastric cancer","route":"/ideas/idea-biomarker-quadruplet-gastric/"}],"target":[{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"term":[{"id":"cps","kind":"term","name":"Combined positive score (CPS)","route":"/terms/cps/"}],"cancer":[{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"}]}}