# Biomarker-directed first-line quadruplets in gastric cancer

Source: https://onco.cc/ideas/idea-biomarker-quadruplet-gastric/  
OnCo record `idea-biomarker-quadruplet-gastric` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-07
- 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.
- Proposed test: Randomised phase 3 in double-positive patients; OS primary; ctDNA and CLDN18.2 heterogeneity as stratifiers.
- Maturity: early-clinical

## Sources

- ClinicalTrials.gov NCT03504397: SPOTLIGHT & GLOW: https://clinicaltrials.gov/study/NCT03504397
- ClinicalTrials.gov NCT02872116: CheckMate 649: https://clinicaltrials.gov/study/NCT02872116

## Connected records

- cancers: [Claudin 18.2-positive gastric cancer](https://onco.cc/cancers/gastric-cldn18-2-positive/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [PD-L1-high gastric cancer](https://onco.cc/cancers/gastric-pdl1-high/)
- targets: [Claudin 18.2](https://onco.cc/targets/cldn18-2/), [HER2](https://onco.cc/targets/her2/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Nivolumab](https://onco.cc/drugs/nivolumab/), [Tislelizumab](https://onco.cc/drugs/tislelizumab/), [Zanidatamab](https://onco.cc/drugs/zanidatamab/), [Zolbetuximab](https://onco.cc/drugs/zolbetuximab/)
- trials: [CheckMate 649](https://onco.cc/trials/checkmate-649/), [HERIZON-GEA-01](https://onco.cc/trials/herizon-gea-01/), [SPOTLIGHT & GLOW](https://onco.cc/trials/spotlight-glow/)
- key papers: [Yarden and Sliwkowski 2001: untangling the ErbB signalling network](https://onco.cc/key-papers/paper-yarden-sliwkowski-erbb-network-nrmcb-2001/)

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