BRAF

BRAF alterations in NSCLC

Acquired BRAF alterations are seen in 4-5% of patients with advanced non-small cell lung cancer (NSCLC). BRAF V600E point mutation is the most frequent BRAF alteration and is seen in about 50% of these cases. BRAF V600E mutation has been associated with poor response to platinum-based chemotherapy as well as poor outcomes compared to BRAF non-V600E mutations or BRAF wild type.

Single agent BRAF V600E tyrosine kinase inhibitors such as dabrafenib and vemurafenib have been studied in BRAF V600E positive NSCLC. Single agent dabrafenib was associated with a response rate of 33%, PFS 5.5 months and OS 12.7 months. Vemurafenib was similarly associated with a response rate of 37-45%, PFS 5.2-6.5 months, and OS 9.3-15.4 months. Subsequently, adopting the success of combined BRAF and MEK inhibition seen in melanoma, two studies evaluated the efficacy of dabrafenib and trametinib combination in BRAF V600E positive NSCLC. In a non-randomized, single arm, phase II study of 57 previously treated patients with advanced NSCLC whose tumors harbored BRAF V600E mutation, dabrafenib and trametinib was associated with an ORR of 63·2% (36 of 57; 95% CI 49·3–75·6). In previously untreated patients with BRAF V600E mutation positive NSCLC, a single-arm phase II study of 36 patients showed an ORR of 64% (95% CI 46-79) with dabrafenib and trametinib. Dabrafenib and trametinib have intracranial activity and penetrate the blood-brain barrier. In a multicohort phase II trial of 125 patients with metastatic melanoma with intracranial metastases, the combination resulted in an intracranial response rate between 44-59%. Based on these two studies, the combination of dabrafenib and trametinib was granted approval for the treatment of patients with advanced NSCLC whose tumors harbor BRAF V600E mutation.

Dabrafenib is dosed at 150 mg orally twice a day while trametinib is dosed at 2 mg orally once daily. Both medications are to be taken at least 1 hour before or 2 hours after a meal.

The most common adverse events (>20% incidence) associated with dabrafenib are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. Secondary skin cancer is a unique but important adverse event that can be seen in 7 to 19% of patients treated with dabrafenib. The most common adverse events (>20% incidence) associated with trametinib are rash, diarrhea, and lymphedema. Combined blockade is most commonly associated (>20%) with pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia. The combination is also associated with a higher incidence of basal cell carcinoma of the skin (9%) than single agent dabrafenib (2%) but a lower rate of squamous cell carcinoma than single agent dabrafenib.

Dabrafenib Dose Modifications

• Initial Dose : 150 mg twice daily

• First dose reduction: 100 mg twice daily

• Second dose reduction: 75 mg twice daily

• Third dose reduction: 50 mg twice daily

Criteria for dose interruptions:

• Greater than 20% absolute decrease in LVEF

• Symptomatic heart failure

• Grade 3 or grade 4 dermatologic toxicity

• Fever greater than 39.0 °C

• Grade 3 hemorrhage

• Uveitis, iritis, iridocyclitis

Criteria for discontinuation:

• Severe cutaneous adverse reactions

• Grade 4 hemorrhage

• Retinal vein occlusion

• Persistent uveitis, iritis, iridocyclitis

• Life-threatening pulmonary embolism

• Recurrent grade 4 adverse reactions

• New primary RAS-mutation positive non-cutaneous malignancy