What therapy can an elderly lady with metastatic splenic flexure cancer to the liver, harboring a BRAF (B-Raf proto-oncogene) V600E mutation, without detectable KRAS (Kirsten rat sarcoma viral oncogene homolog) or NRAS (neuroblastoma RAS viral oncogene homolog) mutations, and with impaired renal function, presumed DYPD (dihydropyrimidine dehydrogenase) deficiency, and intolerance to capecitabine (Xeloda) and bevacizumab (Avastin), be switched to?

Recommended Treatment Switch for BRAF V600E-Mutant Metastatic Colorectal Cancer with DYPD Deficiency and Renal Impairment

Switch to encorafenib plus cetuximab as the optimal second-line therapy for this patient with BRAF V600E-mutant metastatic colorectal cancer who cannot tolerate fluoropyrimidine-based chemotherapy. 1, 2

Primary Recommendation: BRAF-Targeted Therapy

Encorafenib plus cetuximab represents the only chemotherapy-free targeted option and is specifically indicated for previously treated BRAF V600E-mutant metastatic colorectal cancer. 1, 3 This combination:

• Achieved median overall survival of 9.3 months versus 5.9 months with standard chemotherapy (HR 0.61) in the BEACON CRC trial 2
• Demonstrated objective response rate of 19.5% compared to 1.8% with chemotherapy alone 2
• Provides a chemotherapy-free option, which is critical given the presumed DYPD deficiency that contraindicates fluoropyrimidines 1, 4
• Can be used in second-line setting with Level I, Grade A evidence 1, 5

Why This Avoids the Patient's Contraindications

This regimen completely avoids fluoropyrimidines (capecitabine/5-FU), which are contraindicated in DYPD deficiency and were already poorly tolerated. 1, 4 The combination also:

• Does not require oxaliplatin, which the patient already failed on CAPOX 1
• Avoids bevacizumab, which the patient could not tolerate and carries increased stroke risk in elderly patients 1
• Does not require dose adjustment for renal impairment in the same way fluoropyrimidines do 1

Alternative Consideration: Irinotecan-Based Regimen

If encorafenib plus cetuximab is not accessible, FOLFIRI (without bevacizumab) represents the next best option, though it still contains 5-FU. 1 However:

• This requires careful consideration given presumed DYPD deficiency 1
• Infusional 5-FU may be better tolerated than capecitabine in partial DYPD deficiency 1
• Irinotecan should be used with caution and dose reduction given potential renal impairment 1
• Single-agent irinotecan plus cetuximab could be considered if the patient cannot tolerate any fluoropyrimidine 1

Critical Molecular Testing Confirmation

Confirm BRAF V600E mutation status on tumor tissue (primary or metastasis) using an FDA-approved test or CLIA-approved facility before initiating BRAF-targeted therapy. 1 Additionally:

• Verify RAS wild-type status (KRAS/NRAS not detected) to ensure appropriateness of cetuximab 1
• Consider HER2 testing, as HER2 amplification occurs in 5-14% of RAS/BRAF wild-type tumors and may predict resistance to EGFR inhibitors 1
• Confirm microsatellite stability status, as MSI-H/dMMR tumors should receive checkpoint inhibitors preferentially 1

Management of Adverse Events with Encorafenib-Cetuximab

The most common adverse events with encorafenib plus cetuximab include dermatologic toxicities, gastrointestinal events, and fatigue, which are generally manageable. 4, 3 Key monitoring includes:

• Grade ≥3 adverse events occurred in 57.4% of patients on the doublet regimen 2
• Dermatologic toxicities from cetuximab require prophylactic skin care and topical treatments 4
• Renal function monitoring is essential given pre-existing renal impairment 4
• The safety profile is more favorable than triplet chemotherapy regimens 2

Why Not Other Options

Anti-EGFR monotherapy (cetuximab or panitumumab alone) shows minimal activity in BRAF V600E-mutant disease when used after progression on first-line therapy. 1 The evidence shows:

• BRAF V600E mutation makes response to anti-EGFR antibodies as single agents highly unlikely 1
• Single-agent BRAF inhibitors have only 5% response rates in colorectal cancer 1
• BRAF inhibition must be combined with EGFR blockade to overcome resistance mechanisms 1

FOLFOXIRI plus bevacizumab is not appropriate for this elderly patient with renal failure, bevacizumab intolerance, and presumed DYPD deficiency. 1 Guidelines specifically state:

• Triplets should not be used in patients >75 years old, PS2, or significant comorbidities 1
• Insufficient evidence supports clear benefit of triplet over doublet in BRAF V600E-mutant disease 1
• The regimen contains high-dose fluoropyrimidines contraindicated in DYPD deficiency 1

Common Pitfalls to Avoid

• Do not use single-agent capecitabine as salvage therapy after fluoropyrimidine failure—this is ineffective and not recommended 1
• Do not continue bevacizumab after progression or intolerance—there are insufficient data to support this practice 1
• Do not use panitumumab after cetuximab failure or vice versa—there is no compelling rationale for sequential anti-EGFR antibodies 1
• Do not combine anti-VEGF and anti-EGFR antibodies—this increases toxicity without benefit 1