Overview of Gastric Cancer Treatment

Gastric and gastroesophageal junction (GEJ) adenocarcinomas remain challenging malignancies with poor prognosis in advanced stages. Treatment has evolved significantly with molecular subtyping based on HER2, PD-L1, MSI-H/dMMR, and Claudin 18.2 expression guiding targeted therapy and immunotherapy selection. Standard first-line chemotherapy consists of platinum/fluoropyrimidine doublets, with addition of trastuzumab for HER2-positive disease and checkpoint inhibitors for PD-L1 CPS ≥1 or MSI-H tumors showing significant survival improvements.

Treatment Approach by Molecular Subtype

HER2-Positive (15% of cases)

  • First-line: Trastuzumab + platinum/fluoropyrimidine (FOLFOX or XELOX)
  • Second-line: Trastuzumab deruxtecan (T-DXd) - breakthrough therapy
  • Later lines: Tucatinib + trastuzumab

PD-L1 CPS ≥1 or MSI-H/dMMR

  • First-line: Nivolumab or pembrolizumab + chemotherapy
  • MSI-H: Pembrolizumab monotherapy is highly effective
  • Later lines: Nivolumab monotherapy

Claudin 18.2 Positive (30-40% of cases)

  • First-line: Zolbetuximab + chemotherapy (recently approved)
  • Must have ≥75% tumor cells with moderate-to-strong staining

Unselected Population

  • First-line: Platinum/fluoropyrimidine doublet ± ramucirumab
  • Second-line: Ramucirumab + paclitaxel or FOLFIRI
  • Later lines: Regorafenib, trifluridine/tipiracil

Epidemiology & Impact

Gastric cancer is the fifth most common cancer worldwide with approximately 1.1 million new cases annually, though rates are much lower in the United States (approximately 30,300 cases in 2025). Incidence varies dramatically by geography, with rates in East Asia 5-6 times higher than in North America, reflecting H. pylori prevalence and dietary factors. In the US, incidence has been rising 0.8% per year, with notable increases in non-cardia gastric cancer among younger adults. Key risk factors include H. pylori infection, smoking, high-salt diets, family history, and hereditary diffuse gastric cancer (CDH1 mutations). Overall 5-year survival is approximately 36%.

Molecular Biology & Biomarkers

Gastric adenocarcinoma has four TCGA molecular subtypes: EBV-positive (approximately 9%, high PD-L1), microsatellite unstable (22%, immunotherapy responsive), genomically stable (20%, CDH1/RHOA mutations), and chromosomally unstable (50%, receptor tyrosine kinase amplifications). HER2 overexpression (15-20%) guides trastuzumab therapy. PD-L1 CPS identifies immunotherapy candidates. Claudin 18.2, expressed in approximately 38% of cases, is targeted by zolbetuximab. Comprehensive biomarker testing (HER2, PD-L1, MSI, Claudin 18.2) is now recommended at diagnosis.

Evolving Treatment Landscape

CheckMate 649 established nivolumab plus chemotherapy as preferred first-line treatment, with survival improvement particularly in PD-L1 CPS 5 or higher tumors. For HER2-positive tumors, trastuzumab plus chemotherapy is standard, with trastuzumab deruxtecan showing remarkable activity including in lower HER2 expression. Zolbetuximab targeting Claudin 18.2 improved survival in the SPOTLIGHT and GLOW trials. Perioperative FLOT is standard for resectable disease.

Approved Gastric Cancer Therapies

Enhertu
trastuzumab deruxtecan
FDA Approved 2021 HER2+ Second-line
Approved Indications (US/FDA)
Treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
Dosing Schedule
5.4 mg/kg IV over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. First infusion over 90 minutes to monitor for infusion reactions.
Clinical Evidence
DESTINY-Gastric01 trial: T-DXd achieved significantly improved objective response rate (51% vs 14%), PFS (5.6 vs 3.5 months), and OS (12.5 vs 8.4 months, HR 0.59) vs physician's choice chemotherapy in HER2+ gastric cancer after trastuzumab failure. T-DXd is an antibody-drug conjugate with potent topoisomerase I inhibitor payload and bystander killing effect. Main adverse events include interstitial lung disease (ILD)/pneumonitis requiring close monitoring, nausea, decreased appetite, and cytopenias.
Manufacturer
Daiichi Sankyo/AZ
Approval Year
2021
Pivotal Trial
NCT03329690 ↗
Key Publication
Shitara et al. NEJM 2020 ↗
Herceptin
trastuzumab
FDA Approved 2010 HER2+ Frontline
Approved Indications (US/FDA)
Treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease, in combination with cisplatin and capecitabine or 5-fluorouracil.
Dosing Schedule
Loading dose: 8 mg/kg IV over 90 minutes
Maintenance: 6 mg/kg IV every 3 weeks over 30-90 minutes
Continue until disease progression
Clinical Evidence
ToGA trial: Adding trastuzumab to chemotherapy (cisplatin + fluoropyrimidine) improved median OS from 11.1 to 13.8 months (HR 0.74) in HER2+ advanced gastric/GEJ cancer. Benefit was greatest in tumors with IHC 3+ or IHC 2+/FISH+ (median OS 16 months). This established trastuzumab + chemotherapy as standard first-line therapy for HER2+ disease. Main adverse events are cardiac dysfunction (requires LVEF monitoring), infusion reactions, and increased chemotherapy-related toxicities.
Manufacturer
Genentech
Approval Year
2010
Pivotal Trial
ToGA ↗
Key Publication
Bang et al. Lancet 2010 (ToGA) ↗
Opdivo
nivolumab
FDA Approved 2021 Multiple Lines
Approved Indications (US/FDA)
First-line treatment in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma; Treatment of advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma after prior fluoropyrimidine- and platinum-containing chemotherapy (monotherapy).
Dosing Schedule
First-line (with chemo): 360 mg IV every 3 weeks or 240 mg IV every 2 weeks
Monotherapy: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks
Continue until disease progression or unacceptable toxicity
Clinical Evidence
CheckMate 649: Nivolumab + chemotherapy vs chemotherapy alone significantly improved OS (14.4 vs 11.1 months, HR 0.71) and PFS (7.7 vs 6.0 months) in first-line gastric/GEJ/esophageal adenocarcinoma with PD-L1 CPS ≥5. Benefit seen in all PD-L1 CPS ≥1. CheckMate 032: Nivolumab monotherapy achieved 12% ORR in heavily pretreated patients. Main toxicities include immune-related adverse events affecting multiple organ systems.
Manufacturer
Bristol Myers Squibb
Approval Year
2021
Pivotal Trial
NCT02872116 ↗
Key Publication
Janjigian et al. Lancet 2021 ↗
Cyramza
ramucirumab
FDA Approved 2014 Second-line
Approved Indications (US/FDA)
Treatment of advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy, as a single agent or in combination with paclitaxel.
Dosing Schedule
Monotherapy: 8 mg/kg IV every 2 weeks
With Paclitaxel: Ramucirumab 8 mg/kg IV on days 1 and 15 + paclitaxel 80 mg/m² IV on days 1, 8, 15 of 28-day cycle
Clinical Evidence
REGARD trial: Ramucirumab monotherapy improved OS (5.2 vs 3.8 months, HR 0.78) vs best supportive care in second-line gastric cancer. RAINBOW trial: Ramucirumab + paclitaxel improved OS (9.6 vs 7.4 months, HR 0.81) vs paclitaxel alone. Ramucirumab is a VEGFR2 antagonist that inhibits angiogenesis. Main adverse events include hypertension, bleeding, arterial thromboembolic events, infusion reactions, and impaired wound healing.
Manufacturer
Eli Lilly
Approval Year
2014
Pivotal Trials
NCT00917384 ↗
Key Publication
Fuchs et al. Lancet 2014 (REGARD) ↗