What are the next steps for a patient with colon cancer, liver metastasis, MMR (mismatch repair) proficiency, BRAF (B-Raf proto-oncogene) mutation, and KRAS (Kirsten rat sarcoma viral oncogene homolog) wild type, currently on encorafenib (encorafenib) plus cetuximab (cetuximab), who develops hyperbilirubinemia (elevated bilirubin)?

Management of Hyperbilirubinemia in a Patient on Encorafenib Plus Cetuximab

For a patient with BRAF V600E-mutated, MMR-proficient, KRAS wild-type metastatic colon cancer developing hyperbilirubinemia while on encorafenib plus cetuximab, immediately assess the severity of liver dysfunction and hold both agents if bilirubin is significantly elevated, then determine if the hyperbilirubinemia is due to disease progression in the liver or drug-related hepatotoxicity before deciding whether to resume treatment at reduced doses or switch to alternative therapy. 1, 2

Immediate Assessment Steps

Determine the Cause of Hyperbilirubinemia

• Obtain total and direct bilirubin levels, along with complete hepatic function panel (AST, ALT, alkaline phosphatase, albumin, INR) to differentiate between cholestatic versus hepatocellular patterns 3
• Perform urgent imaging (CT or MRI) to assess for progressive liver metastases causing biliary obstruction or worsening hepatic replacement 3
• Rule out drug-induced liver injury from encorafenib or cetuximab, though this is less common than disease progression in this clinical context 1

Grade the Severity Using NCI-CTCAE Criteria

• Grade 1 (1.0-1.5× ULN): Continue treatment with close monitoring 1
• Grade 2 (1.5-3.0× ULN): Hold treatment and reassess within 1-2 weeks 1
• Grade 3 (3.0-10× ULN): Hold treatment; consider dose reduction or discontinuation 1
• Grade 4 (>10× ULN): Permanently discontinue both agents 1

Management Algorithm Based on Etiology

If Hyperbilirubinemia is Due to Progressive Liver Metastases

• Consider switching to alternative systemic therapy rather than resuming encorafenib plus cetuximab, as progression on this regimen indicates treatment failure 2, 4
• Third-line options include regorafenib, fruquintinib, or trifluridine/tipiracil (TAS-102), with potential improved outcomes when TAS-102 is combined with bevacizumab 4
• Evaluate for palliative biliary interventions (stenting, drainage) if there is significant biliary obstruction contributing to cholestasis 3
• Reassess for potential surgical resection of liver metastases if oligometastatic disease is present, as NCCN guidelines do not exclude BRAF-mutated patients from curative-intent surgery 2

If Hyperbilirubinemia is Drug-Related Without Disease Progression

• Hold both encorafenib and cetuximab until bilirubin returns to ≤Grade 1 (within 1-2 weeks) 1
• Resume encorafenib at reduced dose (200 mg daily instead of 300 mg daily) if bilirubin improves, per FDA dosing modification guidelines 1
• Resume cetuximab at the same dose (250 mg/m² weekly) once hepatic function stabilizes, as cetuximab dose modifications are typically reserved for infusion reactions and dermatologic toxicity, not hepatotoxicity 1
• If hyperbilirubinemia recurs at reduced encorafenib dose, permanently discontinue the regimen and transition to alternative therapy 1

Special Consideration: Antibody Monotherapy Bridge Strategy

• If bilirubin elevation is severe (Grade 3-4) but imaging shows stable or responding disease, consider temporary cetuximab monotherapy while holding encorafenib until liver function recovers 5, 3
• Case reports demonstrate that cetuximab plus bevacizumab can be effective in patients with severe hyperbilirubinemia when standard chemotherapy is contraindicated due to impaired hepatic metabolism, achieving partial remission and normalization of bilirubin 3
• Once bilirubin normalizes, reintroduce encorafenib at reduced dose (200 mg daily) in combination with cetuximab 5

Critical Monitoring During Dose Modifications

• Check bilirubin and hepatic function panel weekly during the dose-hold period and for the first month after resuming treatment 1
• Obtain repeat imaging every 6-8 weeks to ensure disease control is maintained during dose modifications 2
• Monitor for other signs of hepatic decompensation including coagulopathy, hypoalbuminemia, and encephalopathy 3

When to Permanently Discontinue Encorafenib Plus Cetuximab

• Grade 4 hyperbilirubinemia (>10× ULN) regardless of etiology 1
• Recurrent Grade 3 hyperbilirubinemia despite dose reductions 1
• Radiographic evidence of disease progression in the liver while on treatment 2, 4
• Development of hepatic decompensation (ascites, encephalopathy, variceal bleeding) 3

Common Pitfalls to Avoid

• Do not continue full-dose encorafenib plus cetuximab in the setting of Grade 2 or higher hyperbilirubinemia, as this risks hepatotoxicity and may worsen outcomes 1
• Do not assume hyperbilirubinemia is always drug-related—failure to image and assess for progressive liver metastases may delay appropriate treatment changes 3
• Do not use irinotecan-based chemotherapy as the next line if severe hyperbilirubinemia persists, as irinotecan is contraindicated in significant hepatic dysfunction due to impaired glucuronidation and risk of severe toxicity 3
• Do not add binimetinib (MEK inhibitor) to create triplet therapy in this setting, as the triplet regimen has comparable efficacy to the doublet but significantly worse tolerability, particularly with dermatologic toxicity 2, 6