What is the next line of chemotherapy for a patient with metastatic HER2-positive gastric cancer who has progressed after first-line XELOX (oxaliplatin, capecitabine) and Trastuzumab (trastuzumab)?

Second-Line Treatment for HER2-Positive Metastatic Gastric Cancer After Progression on XELOX-Trastuzumab

Fam-trastuzumab deruxtecan-nxki is the optimal second-line treatment for patients with HER2-positive metastatic gastric cancer who have progressed after first-line XELOX plus trastuzumab therapy. 1, 2

Evidence-Based Treatment Algorithm

First-Line Assessment

1. Confirm disease progression on XELOX-trastuzumab
2. Verify HER2 status with repeat biopsy if possible (HER2 loss occurs in ~35% of patients after first-line therapy) 3

Second-Line Treatment Options (Ranked by Efficacy)

For Confirmed HER2-Positive Disease:

1. First Choice: Fam-trastuzumab deruxtecan-nxki

   • Superior overall survival (14.7 vs 11.4 months) compared to ramucirumab plus paclitaxel 1
   • Higher objective response rate (44.3% vs 29.1%) 1
   • FDA approved for HER2-positive tumors after trastuzumab-based therapy 2

2. Alternative: Ramucirumab plus paclitaxel

   • Category 1 recommendation (preferred) 2
   • Median OS of 9.63 months vs 7.36 months for paclitaxel alone 2
   • Higher response rate (28% vs 6%) compared to paclitaxel alone 2

3. Other Options:

   • Trastuzumab plus ramucirumab and paclitaxel (investigational)
     • Median PFS of 7.1 months and OS of 13.6 months 3
     • Objective response rate of 54% 3
   • Single-agent docetaxel (category 1) 2
   • Single-agent paclitaxel (category 1) 2
   • Single-agent irinotecan (category 1) 2
   • FOLFIRI (if not used in first-line) 2

For HER2-Negative Disease (if HER2 loss confirmed):

• Ramucirumab plus paclitaxel (category 1, preferred) 2
• Single-agent ramucirumab (category 1) 2
• Single-agent taxanes or irinotecan 2

Monitoring and Management Considerations

Efficacy Monitoring

• Radiographic assessment every 6-8 weeks
• Clinical evaluation for symptom improvement

Toxicity Management

• For fam-trastuzumab deruxtecan-nxki:

  • Monitor for interstitial lung disease/pneumonitis (occurs in ~14% of patients, mostly grade 1-2) 1
  • Regular pulmonary function assessment
  • Monitor for neutropenia (grade 3-4 in 51%) 2
  • Monitor for anemia (grade 3-4 in 38%) 2

• For ramucirumab-based regimens:

  • Monitor for hypertension (more common than with placebo) 2
  • Monitor for neutropenia (common with ramucirumab plus paclitaxel) 2

Special Considerations

Treatment Selection Factors

• Patient performance status
• Comorbidities (especially cardiac and pulmonary)
• Prior toxicities from first-line treatment
• Patient preference regarding treatment schedule and side effect profile

Common Pitfalls to Avoid

1. Failing to re-test HER2 status after progression on first-line therapy
2. Overlooking interstitial lung disease with fam-trastuzumab deruxtecan-nxki
3. Continuing trastuzumab beyond progression without adding new agents (no evidence supports this approach) 2
4. Delaying second-line therapy in patients with good performance status

Third-Line Options

If progression occurs after second-line therapy, consider:

• Trifluridine and tipiracil (category 1 for third-line or subsequent therapy) 2
• Clinical trial enrollment
• Any unused second-line options from above

The evidence strongly supports fam-trastuzumab deruxtecan-nxki as the most effective second-line treatment for HER2-positive gastric cancer after progression on trastuzumab-based therapy, with significant survival advantage over the previous standard of ramucirumab plus paclitaxel.