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

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 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 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. Clin Cancer Res; 24(22); 5516–24. ©2018 AACR.

See related commentary by Sullivan, p. 5496

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