Impact of BRAF mutation and effectiveness of BRAF inhibitor on the brain metastases in patients with metastatic melanoma.

Abstract

9048 Background: Brain metastases continue to be the major cause of morbidity and mortality in patients with metastatic melanoma. The impact of BRAF mutations and effectiveness of BRAF inhibitors on the brain metastases in these patients is lacking. Methods: Preclinical studies were conducted to assessthe steady-state brain and plasma distribution of vemurafenib, a BRAF inhibitor in FVB wild-type and Mdr1a/b-/-Bcrp1-/- mice deficient in the drug efflux transporters, p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). A retrospective analysis of patients with metastatic melanoma treated at University of Minnesota from August 2011 to December 2012 was conducted. A similar analysis of cases treated at Mayo Clinic is underway. Results: The preclinical studies in mice show that both P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib. Retrospective analysis was performed on 57 patients with Stage IIIc /IV cutaneous and mucosal melanoma. Patients with BRAF mutation had a higher incidence rate of brain metastases compared to patients without BRAF mutation, although it was not statistically significant (Incidence ratio=1.56; 95% CI=0.70-3.48; P=0.27). Vemurafenib neither reduced the incidence of brain metastases (Incidence ratio = 0.89; 95% CI: 0.30-2.60; P=0.83) nor made significant difference in overall survival. It was observed that treatment with BRAF inhibitor led to improvement in extracranial disease but did not affect progression of intracranial disease. Conclusions: In concordance with preclinical data which indicates that P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib, the retrospective analysis shows that there is improvement in extracranial disease but progression in intracranial disease with treatment with BRAF inhibitor in patients with metastatic malignant melanoma with BRAF mutation. Development of BRAF inhibitors that are not substrates for P-gp and BCRP or concomitant use of P-gp and BCRP inhibitors with vemurafenib, may be needed in order to control or prevent intracranial disease in these patients. Further analysis to improve statistical power of our observation is underway.

Update on benefit of immunotherapy and targeted therapy in melanoma: the changing landscape

“…A retrospective study showed that vemurafenib did not reduce the incidence of brain metastases. 41 In the Phase I and II studies of vemurafenib, 38% of patients required dose reduction of the drug because of toxic effects, the most common being rash, fatigue, arthralgia, alopecia, photosensitivity, nausea, and diarrhea. 40 Of note, vemurafenib is associated with unique cutaneous toxicities, specifically photosensitivity or eruptive squamous cell carcinoma.…”

International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors

“…Vemurafenib was associated with a relative reduction of 63% in risk of death and of 74% in the risk of disease progression ( p < 0.001 for both comparisons) 1526 . These data, along with additional subsequent studies, have pushed BRAF inhibitor therapy to the forefront of locally advanced and metastatic cutaneous melanoma 1527–1531 …”