Phase 1 trial of combined BRAF, MEK, and heat-shock protein 90 inhibition in advanced BRAF V600-mutant melanoma

Resistance to BRAF and MEK inhibitors in BRAF V600-mutant melanoma is common. Multiple resistance mechanisms involve heat-shock protein 90 (HSP90) clients. A phase I trial at Moffitt Cancer Center (Tampa, FL) evaluated the combination of the BRAF inhibitor vemurafenib, the MEK inhibitor cobimetinib, and the HSP inhibitor XL888 for advanced BRAF V600-mutant melanoma. The combination resulted in a high response rate (76%) but also in significant toxicity. The authors conclude that caution must be used when combining HSP90 inhibitors with BRAF and MEK inhibitors.