Combined BRAF and HSP90 Inhibition in Patients with Unresectable BRAFV600E-Mutant Melanoma

被引:54
|
作者
Eroglu, Zeynep [1 ]
Chen, Y. Ann [2 ]
Gibney, Geoffrey T. [3 ]
Weber, Jeffrey S. [4 ]
Kudchadkar, Ragini R. [5 ]
Khushalani, Nikhil I. [1 ]
Markowitz, Joseph [1 ]
Brohl, Andrew S. [1 ]
Tetteh, Leticia F. [1 ]
Ramadan, Howida [1 ]
Arnone, Gina [1 ]
Li, Jiannong [2 ]
Zhao, Xiuhua [1 ]
Sharma, Ritin [6 ]
Darville, Lancia N. F. [7 ]
Fang, Bin [7 ]
Smalley, Inna [6 ]
Messina, Jane L. [1 ]
Koomen, John M. [8 ]
Sondak, Vernon K. [1 ]
Smalley, Keiran S. M. [1 ,6 ]
机构
[1] H Lee Moffitt Canc Ctr & Res Inst, Dept Cutaneous Oncol, Tampa, FL USA
[2] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA
[3] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA
[4] NYU, Langone Med Ctr, New York, NY USA
[5] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA USA
[6] H Lee Moffitt Canc Ctr & Res Inst, Dept Tumor Biol, Tampa, FL USA
[7] H Lee Moffitt Canc Ctr & Res Inst, Dept Prote, Tampa, FL USA
[8] H Lee Moffitt Canc Ctr & Res Inst, Mol Oncol, Tampa, FL USA
关键词
PHASE-II TRIAL; ACQUIRED-RESISTANCE; TARGETED INHIBITION; MUTANT MELANOMA; MEK INHIBITION; RAF INHIBITORS; DOUBLE-BLIND; VEMURAFENIB; DABRAFENIB; MUTATIONS;
D O I
10.1158/1078-0432.CCR-18-0565
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: BRAF inhibitors are clinically active in patients with advanced BRAF(V600)-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 BRAF(V600)-mutant melanoma. Primary end-points 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 BRAF(V600)-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 BRAF(V600)-mutant melanoma. (C) 2018 AACR. See related commentary by Sullivan, p. 5496
引用
收藏
页码:5516 / 5524
页数:9
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