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Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor GSK2118436 (GSK436).
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2011
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Pten MutationPathologyCancer BiologyTumor BiologyPten AlterationOncologyCancer Cell BiologyMolecular DiagnosticsRadiation OncologyMolecular OncologyCancer ResearchMelanomaMetastatic MelanomaTumor Genetic AnalysesCancer GeneticsBraf MutationCancer GenomicsBraf Inhibitor Gsk2118436Medicine
8501 Background: GSK436 is a highly potent, selective ATP-competitive BRAF inhibitor. BRF112680, a first in human study, assessed safety, pharmacokinetics, pharmacodynamics, and efficacy. Efficacy of single-agent GSK436 was demonstrated in BRAF V600 mutation-positive (mut+) metastatic melanoma patients (pts), with an unconfirmed response rate (RR) of 77% in V600E mut+ pts and 44% in V600K mut+ pts (based on October 2010 data cut). This study evaluates the relationship of genetic alterations in target genes to RR. Methods: To date, samples from 38 pts have been evaluated; 5 pts had samples at pre-treatment (preTx) and progression, 32 pts had a preTx sample only, and 1 pt had a progression sample only. Tumor DNA was evaluated by Sequenom (SEQ) for a targeted panel of mutations in 11 genes (AKT1, BRAF, CDK4, CDKN2A, CTNNB1, GNAQ, GNA11, KIT, MEK1, MEK2, NRAS). PTEN mutation and copy number were derived by sequencing and array CGH (Agilent 1M) or MPLA, respectively. Results: BRAF mutation status was confirmed in all pt samples via SEQ. At preTx, 30 tumors were BRAF V600E, and 7 were V600K. The BRAF mut was retained in the 5 pts with both preTx and progression samples; in 3/5 the ratio of mut:wt decreased in the progression sample. To date, a PTEN alteration (mutation, hemizygous or homozygous deletion) was observed in 9/37 preTx sample pts (24%); 8 of which were V600E+. Pts with a PTEN alteration had lower RR (1/9=11%) compared with pts in which no PTEN alteration was observed (15/28=54%). In addition to the BRAF mutation, we observed in separate preTx samples mutations in MEK2 and CDK4; both patients had SD. An additional pt with a BRAF and β-catenin mutation had PR. Conclusions: These data support genetic characterization of melanomas for mutations outside of BRAF as predictors of RR to BRAF inhibition; the V600 mutation type itself is strongly predictive. Our data suggest that alterations in PTEN may be associated with a decrease in RR to GSK436. Mutations in the MAPK signaling pathway (MEK2) and outside it (CDK4) have been identified, which may also be associated with RR. Additional analyses are being performed to identify further predictors of response to BRAF inhibition.