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Biological challenges of BRAF inhibitor therapy.

ABSTRACT: Activating mutations in BRAF, a constituent of the map kinase pathway, were first discovered as being most prevalent in melanoma in 2002. Only recently have potent and selective, orally available inhibitors of BRAF emerged for clinical testing and demonstrated clear evidence of tumor regression in the majority of patients whose tumors harbor a BRAF mutation. While these early observations suggest that the BRAF targeted therapy will become part of the standard treatment paradigm for patients with advanced melanoma, it is also clear that a majority of these responses are incomplete and temporary. Therefore, the focus of the melanoma field has shifted to understanding the limits of the first generation of selective BRAF inhibitors with regard to safety and efficacy, the context of somatic genetic changes that accompany BRAF, and the combination regimens that target distinct elements of melanoma pathophysiology.

SUBMITTER: Puzanov I

PROVIDER: S-EPMC5528282 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Biological challenges of BRAF inhibitor therapy.

Puzanov Igor I Burnett Patrick P Flaherty Keith T KT

Molecular oncology 20110216 2

Activating mutations in BRAF, a constituent of the map kinase pathway, were first discovered as being most prevalent in melanoma in 2002. Only recently have potent and selective, orally available inhibitors of BRAF emerged for clinical testing and demonstrated clear evidence of tumor regression in the majority of patients whose tumors harbor a BRAF mutation. While these early observations suggest that the BRAF targeted therapy will become part of the standard treatment paradigm for patients with ...[more]

PMID: 21393075

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Project description:The toxicity spectrum between Chinese and Caucasian patients with melanoma who were treated with BRAF inhibitors (BRAFi) may differ. The purpose of the present study was to assess the safety and tolerability of BRAFi and BRAFi-based combination therapies [MEK inhibitors (MEKi) or anti-programmed death-1 (PD-1) antibody] in Chinese patients with BRAF V600E/K mutation-positive metastatic melanoma. We also investigated whether treatment-related adverse events (AEs) correlated with the prognosis. This retrospective study collected data from 43 patients with BRAF V600E/K mutation-positive metastatic melanoma from a single Chinese cancer center. Of the 43 patients, 12 patients received BRAFi monotherapy, 12 patients received BRAFi+MEKi, and 19 patients received BRAFi combined with the anti-PD-1 antibody. The median follow-up time was 19 months. In the BRAFi group, the most common AEs were rashes, palmoplantar erythrodysesthesia, and arthralgia. Four out of 12 (30%) patients experienced grade 3-4 treatment-related AEs. All grades of AEs in the BRAFi+MEKi group were similar to the BRAFi group, except for higher pyrexia (58.3%) and fewer cutaneous AEs. Three out of 12 (25%) patients experienced grade 3-4 AEs, especially pyrexia (16.7%). In the BRAFi+anti-PD-1 antibody group, AEs were similar to the BRAFi group, except for an increased aminotransferase level (36.8%), increased bilirubin (31.6%), and hypothyroidism (15.8%). Eleven out of 19 (57.9%) patients experienced grade 3-4 AEs and four out of 19 (21%) patients discontinued the therapy due to AEs. Treatment-related hepatotoxicity (trHE), defined as an increase in either alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin levels, was the only AE identified as a significant poor-prognosis indicator in this study. The median progression-free survival of patients with trHE (41.9%) was 8 months, whereas it was 18 months for those without trHE [p = 0.046, hazard ratio (HR) = 2.116]. Moreover, this association was independent of medication regimens (p = 0.014, HR = 2.971). The overall response rate of patients with trHE was significantly lower than those without trHE (44.4 vs. 60.0%, p = 0.024), and we observed a similar trend in patients treated with BRAFi, BRAFi+MEKi, and BRAFi+anti-PD-1 antibody. In conclusion, BRAFi and BRAFi-based combination therapies were tolerable with reversible AEs in Chinese patients with melanoma. The trHE in patients receiving BRAFi and BRAFi-based regimens might indicate a poor therapy-related prognosis.

Dataset Information

Biological challenges of BRAF inhibitor therapy.

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Biological challenges of BRAF inhibitor therapy.

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