What is the recommended third-line treatment for a patient with progressive disease, BRAF V600E mutation, MMR proficiency, KRAS wild-type status, and a history of hyperbilirubinemia on encorafenib plus cetuximab?

Third-Line Treatment for Progressive BRAF V600E-Mutated mCRC with Hyperbilirubinemia

For a patient with BRAF V600E-mutated, MMR-proficient, KRAS wild-type metastatic colorectal cancer who develops progressive disease and hyperbilirubinemia on encorafenib plus cetuximab, you should first determine if the hyperbilirubinemia is due to progressive liver metastases or drug toxicity—if it's progressive disease, switch to regorafenib, fruquintinib, or trifluridine/tipiracil (TAS-102) as third-line therapy. 1, 2, 3

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 represent true disease progression and warrant switching to alternative systemic therapy 2, 3
• Drug-related hyperbilirubinemia without disease progression allows for dose modification and continuation of encorafenib plus cetuximab 2, 3

Obtain repeat imaging (CT chest/abdomen/pelvis with contrast) to assess for hepatic disease progression, new liver lesions, or biliary obstruction 3

Management Algorithm Based on Etiology

If Progressive Disease (Most Likely Scenario)

Switch to one of the following third-line options:

• Regorafenib 160 mg orally daily (days 1-21 of 28-day cycle) is recommended for patients pre-treated with fluoropyrimidines, oxaliplatin, irinotecan, and biologics 1

  • Regorafenib demonstrated improved median OS (6.4 vs 5.0 months with placebo) and PFS in phase III trials regardless of KRAS mutation status 2
  • Consider dose-escalation approach: 80 mg daily week 1,120 mg daily week 2, then 160 mg daily week 3 to minimize hepatotoxicity 1, 2
  • Common grade 3+ adverse events include hand-foot syndrome, hypertension, elevated liver enzymes, and rash 1

• Trifluridine/tipiracil (TAS-102) 35 mg/m² orally twice daily (days 1-5 and 8-12 of 28-day cycle) is recommended with similar indications 1

  • TAS-102 demonstrated improved PFS and OS in refractory mCRC with primarily hematologic toxicity (neutropenia, leukopenia) 1
  • Consider adding bevacizumab to TAS-102, as combination therapy significantly prolonged OS and PFS compared to TAS-102 monotherapy 1, 3

• Fruquintinib is approved for patients who previously received or are unsuitable for anti-VEGF and anti-EGFR treatment 1

If Drug-Related Hyperbilirubinemia Without Progression

Hold both encorafenib and cetuximab until bilirubin returns to ≤Grade 1 (≤1.5× ULN), then resume encorafenib at reduced dose of 200 mg daily (instead of standard 300 mg daily) 2, 3, 4

• Check bilirubin and hepatic function panel weekly during dose-hold period and for the first month after resuming treatment 3
• Obtain repeat imaging every 6-8 weeks to ensure disease control is maintained during dose modifications 3

Permanent Discontinuation Criteria

Permanently discontinue encorafenib plus cetuximab if any of the following occur:

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

Important Clinical Context

Why Encorafenib Plus Cetuximab Was Appropriate Second-Line

For BRAF V600E-mutated, pre-treated mCRC patients, encorafenib-cetuximab is recommended as the best option in second or third line 1

• The BEACON CRC trial demonstrated median OS of 9.3 months with encorafenib plus cetuximab versus 5.9 months with chemotherapy plus cetuximab (HR 0.60) 1, 4, 5
• Confirmed ORR was 19.5% for the doublet versus 1.8% for control 4, 5
• This represents the only chemotherapy-free targeted therapy approved for BRAF V600E-mutated mCRC 6

Regorafenib Safety in Context of Liver Dysfunction

Regorafenib commonly causes elevated liver enzymes as an adverse event, but this does not represent an absolute contraindication 2

• 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 2
• Starting at reduced dose (80-120 mg daily) rather than standard 160 mg daily minimizes hepatotoxicity 2

Alternative Considerations

If the patient cannot tolerate standard chemotherapy due to severely impaired hepatic metabolism, consider cetuximab plus bevacizumab, which has achieved partial remission and normalization of bilirubin in case reports 3

Reintroduction of initial induction therapy can be considered after second-line therapy, as long as the patient did not progress during the induction course of first-line chemotherapy 1