Vemurafenib and HSP90 for BRAF positive peeps with unresectable melanoma

Folks have been looking at many meds to add to targeted therapy so that melanoma peeps (who happen to be BRAF positive....about 1/2 of us) will not develop resistance to the positive effects of those drugs.  They have been looking at HSP90 (heat shock protein 90) as well as ricolinostat (an HDAC6 inhibitor) for some time now.  Here are some prior reports:  Heat Shock Protein 

Now, there's this: 

Combined BRAF and HSP90 inhibition in patients with unresectable BRAF V600E mutant melanoma. Eroglu, Chen, Gibney, Weber, et al. Clin Cancer Res. 2018 Apr 19. 

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.

Vemurafenib (960 mg PO BID) combined with escalating doses of XL888 (30, 45, 90 or 135 mg PO 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.
Objective responses were observed in 15/20 evaluable patients (75%), with 3 complete and 12 partial responses. Median progression-free and overall survival were 9.2 months (95%) and 34.6 months, 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' PBMCs showed increased day 8 HSP70 expression compared to baseline in the three cohorts with XL888 doses greater than/= to45 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.

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.

Thanks, ratties.  We'll have to see if this moves any further along and/or if they will finally combine it with a BRAF/MEK combo which we already know does better than BRAFi alone! - c