Combined BRAF and HSP90 Inhibition in Patients with Unresectable <i>BRAF</i> ^V600E-Mutant Melanoma.

Abstract

<b>Purpose:</b> 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.<b>Patients and Methods:</b> 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 endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity.<b>Results:</b> 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 (<i>n</i> = 4, 19%) and cutaneous squamous cell carcinomas (<i>n</i> = 3, 14%), along with diarrhea (<i>n</i> = 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.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 24(22); 5516-24. ©2018 AACR</i> <i>See related commentary by Sullivan, p. 5496</i>.