What is the recommended dosing strategy for regorafenib (Regorafenib) in a patient with BRAF V600E-mutated, MMR (mismatch repair)-proficient, KRAS (Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer and a history of hyperbilirubinemia (elevated bilirubin) on encorafenib (Encorafenib) plus cetuximab (Cetuximab)?

Regorafenib Dosing in Hepatic Impairment

In a patient with BRAF V600E-mutated, MMR-proficient, KRAS wild-type metastatic colorectal cancer developing hyperbilirubinemia on encorafenib plus cetuximab, first determine if the elevated bilirubin represents progressive liver disease versus drug-related toxicity; if due to disease progression, switch to regorafenib at standard dosing (160 mg daily), but if drug-related without progression, hold encorafenib/cetuximab and resume at reduced doses once bilirubin normalizes. 1, 2

Determining the Etiology of Hyperbilirubinemia

The critical first step is distinguishing between two fundamentally different scenarios that require opposite management approaches 1, 2:

• Progressive liver metastases causing biliary obstruction or hepatic dysfunction represent disease progression and warrant switching therapy entirely 1, 2
• Drug-related hyperbilirubinemia without disease progression requires temporary dose holds and subsequent dose reductions of the current regimen 2

Obtain repeat imaging (CT or MRI) to assess for new or enlarging liver metastases, biliary obstruction, or other signs of disease progression 2. Check hepatic function panel weekly during evaluation 2.

Management Algorithm Based on Etiology

If Hyperbilirubinemia is Due to Progressive Disease:

Switch to alternative systemic therapy immediately rather than attempting dose modifications of encorafenib/cetuximab 1, 2:

• Regorafenib is recommended as a standard third-line option for BRAF V600E-mutated, MMR-proficient metastatic colorectal cancer after failure of prior therapies 3
• Alternative options include fruquintinib or trifluridine/tipiracil (TAS-102), with TAS-102 plus bevacizumab showing improved outcomes 3, 2
• For this specific patient population (BRAF-mutant, MMR-proficient), encorafenib-cetuximab was the optimal second-line choice, so regorafenib represents the logical next step 3

If Hyperbilirubinemia is Drug-Related Without Progression:

Hold both encorafenib and cetuximab until bilirubin returns to ≤Grade 1 (≤1.5× upper limit of normal) 2:

• Resume encorafenib at reduced dose of 200 mg daily (instead of standard 300 mg daily) 2
• Resume cetuximab at standard dosing 2
• Monitor bilirubin and hepatic function panel weekly for the first month after resuming treatment 2
• Obtain repeat imaging every 6-8 weeks to ensure disease control is maintained 2

Permanently discontinue encorafenib/cetuximab if any of the following occur 2:

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

Regorafenib Dosing and Hepatic Considerations

Standard Dosing Approach:

Regorafenib standard dose is 160 mg orally once daily for 3 weeks of each 4-week cycle 3:

• The drug has demonstrated improved overall survival (6.4 months versus 5.0 months with placebo) and progression-free survival in phase III trials regardless of KRAS mutation status 1
• In Asian populations, including Chinese patients, regorafenib showed greater survival benefit than in Western populations 3

Dose-Escalation Strategy for Better Tolerability:

Consider starting with a dose-escalation approach for the first cycle to minimize toxicity 3, 1:

• Week 1: 80 mg daily
• Week 2: 120 mg daily
• Week 3: 160 mg daily (target dose)
• Continue at 160 mg daily for subsequent cycles if tolerated

This escalation strategy is particularly relevant given the patient's history of hepatobiliary toxicity on prior therapy 3.

Hepatic Monitoring with Regorafenib:

Regorafenib commonly causes elevated liver enzymes but this does not represent an absolute contraindication 1:

• Severe and fatal liver toxicity occurs in only 0.3% of patients treated with regorafenib 1
• Monitor liver function tests closely when initiating regorafenib in patients with baseline hepatic dysfunction 1
• Consider starting at reduced dose (80-120 mg daily) rather than standard 160 mg daily if significant baseline hepatic dysfunction persists 1

Clinical Context and Prognosis

Real-world data from patients with BRAF V600E-mutated metastatic colorectal cancer treated with encorafenib/cetuximab show 4, 5:

• Median progression-free survival of 4.5 months and overall survival of 9.2 months 4
• Only 47% of patients receive subsequent therapy after progression on encorafenib/cetuximab 5
• Patients receiving encorafenib/cetuximab in second line (versus third line or beyond) are more likely to receive subsequent therapy (53% versus 30%) and achieve longer post-progression survival 5

Among patients with MMR-proficient tumors receiving treatment after encorafenib/cetuximab failure, combinatory chemotherapy ± anti-VEGF appears superior to regorafenib or trifluridine/tipiracil (median PFS 2.6 versus 2.0 months; post-progression survival 6.5 versus 4.4 months) 5. However, regorafenib remains a guideline-recommended option and may be preferred in patients with poor performance status or those unable to tolerate chemotherapy 3.

Critical Pitfalls to Avoid

• Do not continue encorafenib/cetuximab with dose modifications if imaging shows progressive liver disease – this represents treatment failure requiring a switch in therapy 1, 2
• Do not delay switching to alternative therapy in patients with progressive disease, as attrition rates are high and only 47% receive subsequent treatment after progression 5
• Do not start regorafenib at full dose (160 mg) in patients with significant baseline hepatic dysfunction – use dose-escalation strategy starting at 80 mg daily 3, 1
• Do not assume all hyperbilirubinemia on BRAF inhibitors represents progressive disease – drug-related toxicity without progression can be managed with dose holds and reductions 2, 6