What is the recommended treatment protocol for Lonsurf (trifluridine/tipiracil) chemotherapy in patients with metastatic colorectal cancer?

Lonsurf (Trifluridine/Tipiracil) Treatment Protocol for Metastatic Colorectal Cancer

Trifluridine/tipiracil (Lonsurf) is recommended as a third-line or later treatment option for patients with metastatic colorectal cancer who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and if RAS wild-type, anti-EGFR therapy. 1, 2

Indication and Patient Selection

• Indicated for patients with metastatic colorectal cancer who have progressed on or are not candidates for:

  • Fluoropyrimidine-based chemotherapy (5-FU, capecitabine)
  • Oxaliplatin-based regimens
  • Irinotecan-based regimens
  • Anti-VEGF biological therapy (bevacizumab)
  • Anti-EGFR therapy (if RAS wild-type) 1

• Typically used as third-line or later therapy after failure of standard treatments 2

Dosing Protocol

Standard Dosing

• Recommended dose: 35 mg/m² orally twice daily (based on trifluridine component)
• Schedule: Days 1-5 and 8-12 of each 28-day cycle
• Administration: Take with food
• Maximum dose: 80 mg per dose
• Continue until: Disease progression or unacceptable toxicity 1

Dose Calculation

• Round dose to nearest 5 mg increment
• Dosing is based on body surface area (BSA) as follows:
  • BSA < 1.07 m²: 35 mg twice daily
  • BSA 1.07-1.22 m²: 40 mg twice daily
  • BSA 1.23-1.37 m²: 45 mg twice daily
  • BSA 1.38-1.52 m²: 50 mg twice daily
  • BSA 1.53-1.68 m²: 55 mg twice daily
  • BSA 1.69-1.83 m²: 60 mg twice daily
  • BSA 1.84-1.98 m²: 65 mg twice daily
  • BSA 1.99-2.14 m²: 70 mg twice daily
  • BSA 2.15-2.29 m²: 75 mg twice daily
  • BSA ≥ 2.30 m²: 80 mg twice daily 1

Special Populations

• Severe renal impairment (CrCl 15-29 mL/min):

  • Reduce dose to 20 mg/m² twice daily
  • Follow same schedule (Days 1-5 and 8-12 of each 28-day cycle) 1

• Hepatic impairment:

  • Do not initiate treatment in patients with baseline moderate or severe hepatic impairment 1

Monitoring and Dose Modifications

Monitoring

• Complete blood count (CBC) prior to each cycle and on Day 15 of each cycle 1
• Clinical assessment for toxicities before each cycle

Dose Modifications for Adverse Reactions

Withhold treatment for any of the following:

• Absolute neutrophil count (ANC) < 500/mm³ or febrile neutropenia
• Platelets < 50,000/mm³
• Grade 3 or 4 non-hematologic adverse reactions 1

Reduce dose by 5 mg/m²/dose after recovery for:

• Febrile neutropenia
• Grade 4 neutropenia (recovered to ≥ 1,500/mm³) or thrombocytopenia (recovered to ≥ 75,000/mm³) causing > 1 week delay in starting next cycle
• Grade 3 or 4 non-hematologic adverse reactions except for controlled nausea/vomiting or responsive diarrhea 1

Important limitations:

• Maximum of 3 dose reductions permitted
• Permanently discontinue if unable to tolerate 20 mg/m² twice daily
• Do not re-escalate dose after reduction 1

Combination Therapy

• Lonsurf may be used as a single agent or in combination with bevacizumab 1
• When used in combination with bevacizumab, refer to bevacizumab prescribing information for its dosing and modifications 1

Management of Common Adverse Events

Hematologic Toxicities

• Neutropenia: Most common grade 3-4 adverse event

  • Monitor CBC closely
  • Consider G-CSF for severe neutropenia (though rarely needed in clinical practice) 3
  • Dose reduction or temporary interruption may be required

• Anemia and Thrombocytopenia:

  • More common in patients ≥65 years old 1
  • Manage according to standard clinical practice

Non-Hematologic Toxicities

• Gastrointestinal:

  • Nausea/vomiting: Manage with antiemetics
  • Diarrhea: Treat with loperamide (most commonly used supportive therapy) 3
  • Constipation: One of the most common grade ≥3 toxicities requiring intervention 3

• Fatigue: Most commonly reported symptom (33.8% of patients) 3

  • Supportive care and dose modifications as needed

Expected Outcomes

• Progression-free survival (PFS): Approximately 2.2-3.2 months 3, 4, 5
• Overall survival (OS): Approximately 5.8-6.6 months 4, 5
• Response pattern:
  • Disease control rather than objective response is the primary benefit
  • A subset of patients (approximately 12.5%) may experience PFS >9 months, particularly those with left-sided and RAS wild-type disease 5

Important Clinical Considerations

• Treatment sequencing: Ensure patients have received all standard therapies before initiating Lonsurf 2
• Patient selection: Consider performance status and ability to tolerate treatment
• Pill burden: Patients may need to take multiple tablets per dose based on BSA
• Drug handling: Lonsurf is a cytotoxic drug requiring special handling procedures 1
• Missed doses: Instruct patients not to retake missed or vomited doses, but continue with next scheduled dose 1

Alternative Third-Line Options

For context, other third-line options for metastatic colorectal cancer include:

• Regorafenib (alternative to trifluridine/tipiracil with similar indication) 2
• Encorafenib + cetuximab (for BRAF V600E-mutated tumors) 2
• Anti-EGFR monotherapy (for RAS/BRAF wild-type patients not previously exposed) 2

The choice between these options should be based on molecular profiling, prior therapies, and patient-specific factors.