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Cancer ; 130(2): 232-243, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37776537

RESUMO

BACKGROUND: Resistance to BRAF and MEK inhibitors in BRAF V600-mutant melanoma is common. Multiple resistance mechanisms involve heat-shock protein 90 (HSP90) clients, and a phase 1 study of vemurafenib with the HSP90 inhibitor XL888 in patients with advanced melanoma showed activity equivalent to that of BRAF and MEK inhibitors. METHODS: Vemurafenib (960 mg orally twice daily) and cobimetinib (60 mg orally once daily for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60, or 90 mg orally twice weekly) was investigated in a phase 1 trial of advanced melanoma, with a modified Ji dose-escalation design. RESULTS: Twenty-five patients were enrolled. After two dose-limiting toxicities (DLTs) (rash and acute kidney injury) in the first cohort, lower doses of vemurafenib (720 mg) and cobimetinib (40 mg) were investigated with the same XL888 doses. Three DLTs (rash) were observed in 12 patients in the XL888 60-mg cohort, and this was determined as the maximum tolerated dose. Objective responses were observed in 19 patients (76%), and the median progression-free survival was 7.6 months, with a 5-year progression-free survival rate of 20%. The median overall survival was 41.7 months, with a 5-year overall survival rate of 37%. Single-cell RNA sequencing was performed on baseline and on-treatment biopsies; treatment was associated with increased immune cell influx (CD4-positive and CD8-positive T cells) and decreased melanoma cells. CONCLUSIONS: Combined vemurafenib and cobimetinib plus XL888 had significant toxicity, requiring frequent dose reductions, which may have contributed to the relatively low progression-free survival despite a high tumor response rate. Given overlapping toxicities, caution must be used when combining HSP90 inhibitors with BRAF and MEK inhibitors.


Assuntos
Exantema , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Vemurafenib , Proteínas Proto-Oncogênicas B-raf , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
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