Vemurafenib

Zelboraf.

Prevents BRAF mutations from activating the MAP kinase signaling pathway, leading to decreased cell growth and death of melanoma cells.

Its antitumor activity against BRAF V600E mutant cells is associated with the inhibition of oncogenic MAPK signaling, with inhibition of the phosphorylated ERK, a downstream effector of BRAF that is active when phosphorylated.

BRAF mutations are present in 40-60% of melanomas.

BRAF mutations typically involve substitution of glutamic acid for valine at position 600 and are known as V600 mutations.

Adverse reactions mainly dermatological.

May increase LFTs, or prolong QT interval.

In a phase 2 study this agent is a 53% response rate in metastatic melanoma.

In a phase 2 trial of vemurafenib in patients previously treated with BRAF V600 mutant metastatic melanoma involving 132 patients with a median follow-up of 12.9 months was associated with an overall response rate of 53%, 6% complete response, median duration of response, 6.7 months and median progression free survival 6.8 months, and median survival of 15.9 months (Sosman JA et al).

Patients with BRAF V600E gene mutations in melanoma have a 63% reduced relative risk of death compared with dacarbazine treated patients, and a 74% reduction in the risk of disease progression (Chapman PB et al).

Dose 960 mg orally BID.

Patients respond rapidly, but resistance emerges rapidly, as well.

Most responding patients relapse within the drug-resistant disease.

Intermittent dosing strategy may over common development of resistance.

BRAF inhibitor, which blocks the active conformation of BRAF kinase, is associated with a higher rate of objective tumor responses and improved overall survival in melanoma patients, as compared to standard chemotherapy.

Vemurafenib Demonstrates Antitumor Activity in Papillary Thyroid Cancer

In a phase II clinical trial, the BRAF inhibitor vemurafenib demonstrated antitumor activity in patients with BRAFV600E-mutated papillary thyroid cancer who were either tyrosine kinase inhibitor (TKI) treatment naïve or had received prior TKI treatments.

Median progression-free survival (PFS) in treatment-naïve patients treated with vemurafenib was 15.6 months.

Approximately 50% of patients with PTC have tumors with activating

BRAFV600E mutations in papillary cancer of the thyroid is an indicator of poor prognosis.

Oral vemurafenib at 960 mg tablets twice daily.

Across several previous studies, the BRAFV600E mutation has been reported to be associated with several negative prognostic clinicopathologic features as well as an increase in overall mortality in patients with papillary cancer of the thyroid.

25% of patients experience partial response to treatment 75% have stable disease to treatment.

As nearly 50% of patients with papillary cancer of the thyroid in the U.S. are BRAFV600E-mutation positive.

BRAF inhibitors can increase phosphorylated ERK with wild type BRAF that harbor upstream pathway activation of oncogenic RAS or upregulated receptor tyrosine kinases and paradoxically activate the MAPK pathway.

Well differentiated cutaneous squamous cell carcinomas and keratoacanthomas develop in approximately 15-30% of patients treated with type I BRAF inhibitors, such as vemurafenib.

Mutations in RAS are frequenting cutaneous squamous cell carcinomas and in keratoacanthomas that develop in patients treated with vemurafenib, associated with paradoxical activation of MAPk (Su F et al).

Vemurafenib is highly effective in patients with relapsed or refactory hairy cell leukemia.

Vemurafenib given in a short course from 16 to 18 weeks is highly effective with a relapsed or refractory hairy cell leukemia with overall response rates around 96%.

Vemurafenib associated with a complete response rate of 35-42%.