Is it safe to start trifluridine/tipiracil (Lonsurf) in a patient with BRAF V600E-mutated, MMR-proficient, KRAS wild-type metastatic colorectal cancer and severe hyperbilirubinemia?

Trifluridine/Tipiracil Should NOT Be Started with 13x Elevated Bilirubin

Trifluridine/tipiracil (Lonsurf) is contraindicated in patients with severe hepatic impairment, and a bilirubin elevation of 13 times the upper limit of normal represents severe hepatic dysfunction that precludes safe initiation of this agent. While the provided evidence does not contain specific FDA labeling information for trifluridine/tipiracil regarding hepatic impairment, the magnitude of hyperbilirubinemia described (13x elevated) indicates severe liver dysfunction that would make any cytotoxic chemotherapy extremely hazardous.

Clinical Reasoning

Severity of Hepatic Impairment

• A 13-fold elevation in bilirubin represents severe hepatic dysfunction, far exceeding the threshold for safe administration of most chemotherapeutic agents 1, 2
• For context, irinotecan (a commonly used agent in colorectal cancer) should be used with extreme caution and reduced doses even with mild bilirubin elevations, and guidelines specifically warn about its use in patients with elevated serum bilirubin 3
• The degree of hyperbilirubinemia in this case suggests either severe intrinsic liver disease or extensive hepatic metastatic burden, both of which dramatically increase toxicity risk 3

Drug Metabolism and Safety Concerns

• Trifluridine/tipiracil is metabolized hepatically, and severe hepatic impairment would be expected to significantly alter drug clearance and increase systemic exposure 1, 2
• The most common grade ≥3 adverse events with trifluridine/tipiracil include neutropenia, anemia, leukopenia, and thrombocytopenia—all of which would be substantially more dangerous in a patient with severe hepatic dysfunction 1, 2
• Patients with compromised hepatic function have reduced synthetic capacity for clotting factors and are at higher risk for bleeding complications when combined with chemotherapy-induced thrombocytopenia 2

Alternative Management Strategy

Immediate Priorities

• Address the underlying cause of hyperbilirubinemia first before considering any systemic chemotherapy 3
• Evaluate for biliary obstruction (from tumor or other causes) that might be amenable to stenting or surgical decompression
• Assess hepatic synthetic function (INR, albumin) and overall performance status to determine if the patient is even a candidate for any systemic therapy

Treatment Options for BRAF V600E-Mutant mCRC

• If hepatic function improves to acceptable levels, encorafenib plus cetuximab is the recommended targeted therapy for previously treated BRAF V600E-mutant metastatic colorectal cancer, with demonstrated OS benefit (median 9.3 months vs 5.9 months for chemotherapy) 3, 4
• This regimen showed improved outcomes compared to standard chemotherapy in the BEACON CRC trial and is now considered standard of care for this molecular subtype after progression on first-line therapy 3, 4
• The doublet of encorafenib plus cetuximab had a more favorable toxicity profile than triplet therapy (grade ≥3 adverse events in 57.4% vs 65.8%), which may be particularly relevant in a patient with compromised hepatic function 4

When Trifluridine/Tipiracil Could Be Considered

• Trifluridine/tipiracil (with or without bevacizumab) is indicated for patients with mCRC who have progressed through fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy 5, 1, 2
• This agent should only be considered if bilirubin normalizes or returns to near-normal levels (specific thresholds not provided in evidence, but clinical judgment suggests <2-3x ULN maximum)
• The combination of trifluridine/tipiracil with bevacizumab is preferred over monotherapy when feasible, with OS improvement from 7.5 to 10.8 months 5

Critical Pitfalls to Avoid

• Do not initiate any cytotoxic chemotherapy with severe hyperbilirubinemia—the risk of life-threatening toxicity far outweighs any potential benefit 3
• Do not assume that oral agents like trifluridine/tipiracil are "safer" in hepatic dysfunction—they still undergo hepatic metabolism and can cause severe myelosuppression 1, 2
• For this specific patient with BRAF V600E mutation, MMR-proficient disease, recognize that this molecular subtype has historically poor prognosis (median OS 13.4 months in BRAF-mutant subgroup vs 37.1 months in wild-type) 3
• Do not use single-agent capecitabine, mitomycin, gemcitabine, or interferons as salvage therapy—these have not shown efficacy in refractory mCRC 3

Summary Algorithm

1. Hold all systemic chemotherapy until bilirubin improves
2. Investigate and treat reversible causes of hyperbilirubinemia (biliary obstruction, etc.)
3. Reassess hepatic function after intervention
4. If bilirubin normalizes and patient has adequate performance status:
   • Consider encorafenib plus cetuximab as preferred option for BRAF V600E-mutant disease 3, 4
   • Reserve trifluridine/tipiracil (± bevacizumab) for later-line therapy after progression 5
5. If bilirubin remains significantly elevated, focus on best supportive care rather than systemic therapy