Is regorafenib (regorafenib) contraindicated in 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, who has developed hyperbilirubinemia (elevated total bilirubin) while on encorafenib (encorafenib) plus cetuximab (cetuximab)?

Regorafenib and Elevated Bilirubin: Not an Absolute Contraindication

Regorafenib is not absolutely contraindicated in patients with elevated total bilirubin, but the etiology of hyperbilirubinemia must be determined before proceeding, and specific management protocols should be followed based on whether the elevation is drug-induced versus disease progression. 1

Determining the Etiology of Hyperbilirubinemia

The critical first step is distinguishing between two fundamentally different scenarios:

• Progressive liver metastases causing biliary obstruction or hepatic dysfunction: This represents disease progression and warrants switching to alternative therapy rather than continuing current treatment 1

• Drug-related hyperbilirubinemia without disease progression: This is manageable with dose modifications and monitoring 1

Obtain repeat imaging to assess for progression of liver metastases, as radiographic evidence of hepatic disease progression while on encorafenib plus cetuximab mandates permanent discontinuation and transition to alternative therapy. 1

Management Algorithm Based on Etiology

If Hyperbilirubinemia is Due to Progressive Disease

Switch to regorafenib, fruquintinib, or trifluridine/tipiracil (TAS-102) as third-line options for BRAF-mutant, MMR-proficient metastatic colorectal cancer. 1 Regorafenib is specifically recommended as a standard option for fit patients with refractory disease after progression on standard chemotherapy, with demonstrated improvement in median overall survival (6.4 months versus 5.0 months with placebo) and progression-free survival in phase III trials. 2

• TAS-102 combined with bevacizumab may provide improved outcomes compared to TAS-102 alone 1
• Regorafenib has shown activity in refractory metastatic colorectal cancer regardless of KRAS mutation status 2

If Hyperbilirubinemia is Drug-Related Without Progression

Hold both encorafenib and cetuximab until bilirubin returns to ≤Grade 1 (≤1.5× upper limit of normal), then resume encorafenib at a reduced dose of 200 mg daily instead of the standard 300 mg daily. 1

• Check bilirubin and complete hepatic function panel weekly during the dose-hold period 1
• Continue weekly monitoring for the first month after resuming treatment 1
• Obtain repeat imaging every 6-8 weeks to ensure disease control is maintained during dose modifications 1

Absolute Contraindications for Regorafenib

Permanently discontinue encorafenib plus cetuximab and do not initiate regorafenib in the following scenarios: 1

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

Regorafenib Safety Profile in Context of Liver Dysfunction

While regorafenib commonly causes elevated liver enzymes as an adverse event, this does not represent an absolute contraindication to its use:

• The most common grade 3 adverse events with regorafenib include hand-foot syndrome, hypertension, increased liver enzymes, and rash 2
• In real-world studies, hyperbilirubinemia occurred in 43% of patients (any grade) and 9% experienced grade 3-4 hyperbilirubinemia 3
• Severe and fatal liver toxicity occurred in only 0.3% of 1,100 patients treated with regorafenib across all trials 2

Monitor liver function tests closely when initiating regorafenib in patients with baseline hepatic dysfunction, and consider starting at a reduced dose (80-120 mg daily) rather than the standard 160 mg daily to minimize hepatotoxicity. 4, 3

Clinical Context for This Patient

Given this patient's BRAF V600E mutation, MMR proficiency, and KRAS wild-type status with progression on encorafenib plus cetuximab:

• If imaging confirms progressive liver metastases: Transition to regorafenib (160 mg daily for 3 weeks of each 4-week cycle, with dose reduction to 120 mg or 80 mg if needed for tolerability) 2, 3

• If imaging shows stable disease and hyperbilirubinemia is drug-related: Hold encorafenib/cetuximab, allow bilirubin to normalize, then resume at reduced doses with intensive monitoring 1

The decision should be based on objective radiographic assessment of disease status, not bilirubin levels alone, as elevated bilirubin in the setting of progressive liver metastases indicates treatment failure rather than manageable toxicity. 1