Advanced Gastric / GEJ Adenocarcinoma: Systemic Therapy

Advanced Gastric / GEJ Adenocarcinoma: overview

This algorithm sequences systemic therapy for advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma, with first-line treatment selected by biomarker.

In the first line, HER2-positive disease receives trastuzumab plus chemotherapy plus pembrolizumab (KEYNOTE-811). PD-L1-positive disease receives nivolumab plus chemotherapy (CheckMate 649). Claudin 18.2 (CLDN18.2)-positive disease receives zolbetuximab plus chemotherapy (SPOTLIGHT/GLOW). Biomarker-negative disease is treated with a chemotherapy doublet (FOLFOX or CAPOX), which also serves as the backbone for the other first-line regimens. In the second line, ramucirumab plus paclitaxel is the antiangiogenic standard, supported by RAINBOW, which prolonged overall and progression-free survival over paclitaxel alone. HER2-positive disease may instead receive trastuzumab deruxtecan, supported by DESTINY-Gastric01, which improved response and overall survival versus chemotherapy, with interstitial lung disease requiring close monitoring. In the third line and beyond, trifluridine/tipiracil is supported by TAGS, which improved overall survival over placebo, and single-agent chemotherapy or a clinical trial is chosen according to fitness.

Trials behind this algorithm

• KEYNOTE-811 trial Janjigian YY et al, Nature, 2021; PMID: 34912120
• Checkmate 649 trial Janjigian et al. , Lancet, 2021, PMID: 34102137
• RAINBOW Wilke et al, Lancet Onc, PMID: 25240821
• DESTINY-Gastric01 Shitara K et al, NEJM, 2020; PMID: 32469182
• TAGS Shitara K et al, Lancet Oncol, 2018; PMID: 30355453

Background reading: Esophageal and gastric cancer board review notes.