What is Zelboraf (Vemurafenib)?
Zelboraf (vemurafenib) is an FDA-approved oral BRAF kinase inhibitor specifically indicated for treating unresectable or metastatic melanoma with BRAF V600E or V600K mutations, and for Erdheim-Chester Disease (ECD) with BRAF mutations. 1, 2
Mechanism of Action
- Vemurafenib is a selective inhibitor of mutated BRAF kinase, specifically targeting the V600 mutation that occurs in approximately 45% of patients with metastatic melanoma 1
- It blocks aberrant signaling through the mitogen-activated protein kinase (MAPK) pathway caused by the BRAF mutation 3
- The drug is a small-molecule kinase inhibitor available as 240 mg oral tablets 2
FDA-Approved Indications
Melanoma:
- Treatment of unresectable or metastatic melanoma with documented BRAF V600E or V600K mutations 1
- FDA approval occurred in August 2011 based on pivotal phase III trial data 1, 4
- Requires companion diagnostic testing using an FDA-approved test (Cobas 4800 BRAF V600 Mutation Test) or CLIA-approved facility before initiating therapy 1
Erdheim-Chester Disease:
- Treatment of ECD with BRAF mutations 2
Clinical Efficacy Data
Survival Benefits:
- In the pivotal phase III trial of 675 previously untreated patients, vemurafenib demonstrated superior outcomes compared to dacarbazine 1:
Response Characteristics:
- Overall response rate: 40-50% in BRAF V600-mutated patients 1
- Responses occur rapidly, typically within days to weeks of starting treatment 1
- Critical limitation: Median duration of response is only 5-6 months 1
Dosing and Administration
- Standard dose: 960 mg orally twice daily (every 12 hours) 2, 4
- Can be taken with or without food 2
- Tablets should not be crushed or chewed 2
- Steady state achieved after approximately 15-21 days with half-life of ~57 hours 5
Serious Adverse Events and Safety Profile
New Malignancies (Black Box Warning):
- Cutaneous squamous cell carcinoma (cuSCC) and keratoacanthoma occur in 18-24% of patients and require simple excision 1, 4
- New melanoma lesions can develop 2
- Non-cutaneous squamous cell carcinoma may occur 2
- Dermatologic monitoring required before treatment, every 2 months during treatment, and for 6 months after discontinuation 2
Common Adverse Events (≥20%):
- Arthralgia (21% most common non-cutaneous side effect) 1
- Rash and alopecia 4
- Photosensitivity reactions (grade 2-3 in 12% of patients) 1
- Fatigue and nausea 4
- 38% of patients require dose modifications due to adverse events 1
Severe Reactions:
- Hypersensitivity reactions including anaphylaxis 2
- Stevens-Johnson syndrome and toxic epidermal necrolysis 2, 4
- QT prolongation 2, 4
- Liver enzyme abnormalities 4
- Uveitis 4
- Radiation sensitization and recall 2
- Renal failure 2
Critical Clinical Considerations
Patient Selection:
- Only use in patients with confirmed BRAF V600 mutations - vemurafenib is not indicated for wild-type BRAF melanoma 1
- Testing must be performed using FDA-approved diagnostic or CLIA-approved facility 1
- Preferably obtain tissue from metastatic biopsy rather than archival material 1
Contraindications and Precautions:
- Avoid in patients with history of long QT syndrome 2
- Monitor electrolytes (potassium, calcium, magnesium) before and during treatment 2
- Requires sun protection: protective clothing, SPF 30+ sunscreen, and lip balm due to severe photosensitivity 2
- Pregnancy Category D: causes fetal harm; requires effective contraception during treatment and for 2 weeks after final dose 2
- Do not breastfeed during treatment and for 2 weeks after final dose 2
Drug Interactions:
- Substrate and inducer of CYP3A4 5
- Moderate inhibitor of CYP1A2 5
- Substrate and inhibitor of P-glycoprotein and breast cancer resistance protein 5
Resistance and Duration of Benefit
- Resistance mechanisms do not involve secondary BRAF mutations but may include BRAF V600E over-amplification, upregulation of other MAPK cascade components, or activation of alternative growth pathways 3
- The major limitation is short median duration of response (5-6 months), contrasting with ipilimumab which has lower response rates (10-20%) but more durable responses when they occur 1
Current Treatment Paradigm
Preferred Approach:
- NCCN guidelines now recommend BRAF/MEK inhibitor combination therapy (dabrafenib/trametinib or vemurafenib/cobimetinib) as preferred over vemurafenib monotherapy due to superior efficacy 1
- Single-agent vemurafenib remains a category 1 recommendation but combination therapy is preferred when available 1