{"entity":{"id":"idea-biomarker-quadruplet-gastric","kind":"idea","name":"Biomarker-directed first-line quadruplets in gastric cancer","aka":[],"tldr":"Stomach cancer now has three add-on biomarkers (HER2, PD-L1, Claudin 18.2) that often overlap. Test whether combining two add-ons beats picking one.","summary":"Gastric cancer now has three first-line add-on biomarkers, HER2, PD-L1 and Claudin 18.2, which sometimes overlap. This idea asks whether tumours that are both CLDN18.2-positive and PD-L1 CPS 5 or higher do better with chemotherapy plus zolbetuximab plus PD-1 blockade than with chemotherapy plus a PD-1 inhibitor alone. The rationale is that the two add-ons act through non-overlapping mechanisms, antibody-dependent cellular cytotoxicity versus T-cell release, and zolbetuximab-induced cell death may increase antigen presentation. Zolbetuximab with nivolumab is under study in ILUSTRO, HERIZON-GEA-01 combined zanidatamab with tislelizumab, and the proposed test is a randomised phase 3 in double-positive patients, at an early clinical stage.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03504397: SPOTLIGHT & GLOW","url":"https://clinicaltrials.gov/study/NCT03504397"},{"label":"ClinicalTrials.gov NCT02872116: CheckMate 649","url":"https://clinicaltrials.gov/study/NCT02872116"}],"tags":[],"related":[],"cancers":["gastric"],"sections":[],"technologies":[],"targets":["cldn18-2","pd1","her2"],"drugs":["zolbetuximab","nivolumab","zanidatamab","tislelizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["spotlight-glow","checkmate-649","herizon-gea-01"],"people":[],"bottlenecks":[],"keyPapers":["paper-yarden-sliwkowski-erbb-network-nrmcb-2001"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"In CLDN18.2-positive, PD-L1 CPS ≥5 tumours, chemotherapy + zolbetuximab + PD-1 blockade improves OS over chemotherapy + PD-1 alone without prohibitive toxicity.","rationale":"Non-overlapping mechanisms (ADCC vs T-cell release); zolbetuximab-induced cell death may increase antigen presentation.","test":"Randomised phase 3 in double-positive patients; OS primary; ctDNA and CLDN18.2 heterogeneity as stratifiers.","maturity":"early-clinical"},"route":"/ideas/idea-biomarker-quadruplet-gastric/","neighbours":{"cancer":[{"id":"gastric-cldn18-2-positive","kind":"cancer","name":"Claudin 18.2-positive gastric cancer","route":"/cancers/gastric-cldn18-2-positive/"},{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"gastric-pdl1-high","kind":"cancer","name":"PD-L1-high gastric cancer","route":"/cancers/gastric-pdl1-high/"}],"target":[{"id":"cldn18-2","kind":"target","name":"Claudin 18.2","route":"/targets/cldn18-2/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"tislelizumab","kind":"drug","name":"Tislelizumab","route":"/drugs/tislelizumab/"},{"id":"zanidatamab","kind":"drug","name":"Zanidatamab","route":"/drugs/zanidatamab/"},{"id":"zolbetuximab","kind":"drug","name":"Zolbetuximab","route":"/drugs/zolbetuximab/"}],"trial":[{"id":"checkmate-649","kind":"trial","name":"CheckMate 649","route":"/trials/checkmate-649/"},{"id":"herizon-gea-01","kind":"trial","name":"HERIZON-GEA-01","route":"/trials/herizon-gea-01/"},{"id":"spotlight-glow","kind":"trial","name":"SPOTLIGHT & GLOW","route":"/trials/spotlight-glow/"}],"paper":[{"id":"paper-yarden-sliwkowski-erbb-network-nrmcb-2001","kind":"paper","name":"Yarden and Sliwkowski 2001: untangling the ErbB signalling network","route":"/key-papers/paper-yarden-sliwkowski-erbb-network-nrmcb-2001/"}]}}