What is the third line of treatment for metastatic gastric cancer?

Third-Line Treatment for Metastatic Gastric Cancer

Trifluridine-tipiracil is the recommended third-line treatment for metastatic gastric cancer based on the strongest evidence from the phase III TAGS trial. 1

Evidence-Based Treatment Algorithm for Third-Line Therapy

First-Line Considerations

Before reaching third-line therapy, patients typically receive:

• First-line: Platinum-based combinations (cisplatin/oxaliplatin + fluoropyrimidine)
• Second-line: Ramucirumab + paclitaxel (preferred) or single-agent ramucirumab, taxanes, or irinotecan

Third-Line Treatment Options (in order of evidence strength)

1. Trifluridine-tipiracil (TAS-102)

   • Strongest evidence base from phase III TAGS trial
   • Category 1 recommendation
   • Improved median OS by 2.1 months (5.7 vs 3.6 months) compared to placebo
   • No objective responses but disease stabilization benefit
   • Common grade 3-4 toxicities: neutropenia (38%), leukopenia (21%), anemia (19%) 1

2. Alternative options if trifluridine-tipiracil unavailable:

   • Taxane (if not used in second-line)
   • Irinotecan (if not used in second-line)
   • FOLFIRI (if not previously used) 1

3. Molecular-guided therapy (if applicable):

   • HER2-positive tumors: Trastuzumab deruxtecan for patients who progressed on prior trastuzumab therapy
   • MSI-H/dMMR tumors: Pembrolizumab (preferred if available) 1

Patient Selection Factors for Third-Line Therapy

Third-line therapy should be considered for patients with:

• ECOG performance status 0-1
• Adequate organ function
• Longer progression-free survival in previous lines (particularly first-line PFS ≥6.9 months and second-line PFS ≥3.5 months)
• Previous surgical resection (positive prognostic factor)
• Age <70 years (though carefully selected older patients may benefit) 2, 3

Efficacy Expectations

• Median overall survival after initiating third-line therapy: approximately 6 months 2
• Disease control rather than objective response is the primary goal
• Benefit is greatest in patients who had longer PFS in previous lines of therapy 3

Common Pitfalls and Caveats

1. Toxicity management is critical:

   • Trifluridine-tipiracil causes significant hematologic toxicity requiring close monitoring
   • Patients with moderate renal impairment (especially those ≥65 years) require careful dose adjustment 1

2. Patient selection is crucial:

   • Third-line therapy should be reserved for patients with good performance status
   • Patients with rapid progression through first and second lines (<3 months) have limited benefit 2, 3

3. Quality of life considerations:

   • Limited quality of life data available for third-line therapies
   • Balance potential survival benefit against treatment toxicity 4

The evidence clearly supports offering third-line therapy to appropriately selected patients with metastatic gastric cancer, with trifluridine-tipiracil having the strongest evidence base for improved survival outcomes.