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Clin Cancer Res. 2018 Nov 15;24(22):5516-5524. doi: 10.1158/1078-0432.CCR-18-0565. Epub 2018 Apr 19.

Combined BRAF and HSP90 Inhibition in Patients with Unresectable BRAF V600E-Mutant Melanoma.

Author information

1
Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
2
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida.
3
Georgetown Lombardi Comprehensive Cancer Center, Washington, District of Columbia.
4
NYU Langone Medical Center, New York, New York.
5
Winship Cancer Institute of Emory University School of Medicine, Atlanta, Georgia.
6
Department of Tumor Biology, Moffitt Cancer Center, Tampa, Florida.
7
Department of Proteomics, Moffitt Cancer Center, Tampa, Florida.
8
Molecular Oncology, Moffitt Cancer Center, Tampa, Florida.
9
Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida. keiran.smalley@moffitt.org.

Abstract

Purpose: BRAF inhibitors are clinically active in patients with advanced BRAFV600-mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888.Patients and Methods: Vemurafenib (960 mg p.o. b.i.d.) combined with escalating doses of XL888 (30, 45, 90, or 135 mg p.o. twice weekly) was investigated in 21 patients with advanced BRAFV600-mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity.Results: Objective responses were observed in 15 of 20 evaluable patients [75%; 95% confidence interval (CI), 51%-91%], with 3 complete and 12 partial responses. Median progression-free survival and overall survival were 9.2 months (95% CI, 3.8-not reached) and 34.6 months (6.2-not reached), respectively. The most common grade 3/4 toxicities were skin toxicities, such as rash (n = 4, 19%) and cutaneous squamous cell carcinomas (n = 3, 14%), along with diarrhea (n = 3, 14%). Pharmacodynamic analysis of patients' peripheral blood mononuclear cells (PBMC) showed increased day 8 HSP70 expression compared with baseline in the three cohorts with XL888 doses ≥45 mg. Diverse effects of vemurafenib-XL888 upon intratumoral HSP client protein expression were noted, with the expression of multiple proteins (including ERBB3 and BAD) modulated on therapy.Conclusions: XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAFV600-mutant melanoma, with a tolerable side-effect profile. HSP90 inhibitors warrant further evaluation in combination with current standard-of-care BRAF plus MEK inhibitors in BRAFV600-mutant melanoma. Clin Cancer Res; 24(22); 5516-24. ©2018 AACR See related commentary by Sullivan, p. 5496.

PMID:
29674508
PMCID:
PMC6195480
[Available on 2019-11-15]
DOI:
10.1158/1078-0432.CCR-18-0565

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