Advanced/Metastatic Gastric or GEJ Adenocarcinoma — HER2-Positive

Evidence-based treatment sequencing for advanced or metastatic gastric and gastroesophageal junction adenocarcinoma harboring HER2 overexpression (IHC 3+ or IHC 2+/ISH+) or gene amplification: frontline trastuzumab plus chemotherapy with pembrolizumab or the ToGA chemotherapy backbone, then fam-trastuzumab deruxtecan or ramucirumab + paclitaxel, then clinical trial or salvage.

HER2 confirmed (IHC 3+ or IHC 2+/ISH+) and PD-L1 CPS assessed — first-line systemic therapy selection

• HER2-positive — chemo-immunotherapy + trastuzumab combination → Trastuzumab + fluoropyrimidine/platinum chemotherapy + pembrolizumab
• Trastuzumab + chemotherapy backbone (no checkpoint inhibitor) → Trastuzumab + cisplatin + fluoropyrimidine (capecitabine or 5-FU)

1L: Trastuzumab + fluoropyrimidine/platinum chemotherapy + pembrolizumab

Preferred frontline standard of care for HER2-positive advanced gastric/GEJ cancer; KEYNOTE-811 showed benefit from adding pembrolizumab, most pronounced in PD-L1 CPS >= 1. Monitor for immune-related adverse events, cardiotoxicity (LVEF surveillance with trastuzumab), and platinum/fluoropyrimidine toxicities.

• Disease progression → Disease progression following frontline anti-HER2 therapy

1L: Trastuzumab + cisplatin + fluoropyrimidine (capecitabine or 5-FU)

Foundational frontline anti-HER2 regimen established by ToGA; an option when checkpoint inhibition is not used (e.g. PD-L1 low/negative or contraindication). Baseline and serial LVEF monitoring for trastuzumab-related cardiotoxicity.

• Disease progression → Disease progression following frontline anti-HER2 therapy

Disease progression following frontline anti-HER2 therapy

• HER2-positive, post-trastuzumab progression → Fam-trastuzumab deruxtecan (T-DXd)
• Cytotoxic salvage preference / T-DXd deferred → Ramucirumab + paclitaxel

2L: Fam-trastuzumab deruxtecan (T-DXd)

Preferred targeted antibody-drug conjugate for HER2-positive advanced gastric/GEJ cancer after progression on a prior trastuzumab-based regimen (DESTINY-Gastric). Monitor closely for interstitial lung disease/pneumonitis, nausea, and myelosuppression.

• Subsequent progression → Clinical trial referral or salvage regimens

2L: Ramucirumab + paclitaxel

Standard second-line cytotoxic and anti-angiogenic option when antibody-drug conjugate therapy is contraindicated or deferred. Monitor for hypertension, proteinuria, bleeding, and neuropathy.

• Subsequent progression → Clinical trial referral or salvage regimens

3L+: Clinical trial referral or salvage regimens

Evaluate for clinical trials or alternative multi-agent salvage therapy (e.g. trifluridine-tipiracil, taxane- or irinotecan-based chemotherapy) based on prior exposure and performance status.