Phase I study of vemurafenib (VEM) and cobimetinib (COB) with heat shock protein 90 (HSP90) inhibitor XL888 in advanced BRAFV600 mutant melanoma.

Abstract

9553 Background: Resistance to BRAF+MEK inhibitors(i) in BRAF-mutant melanoma is common. Multiple resistance mechanisms involve HSP90 clients, and a phase 1 study of VEM with XL888 showed PFS rates similar to the combination of BRAF+MEKi (Eroglu, CCR, 2018). Methods: Combination of VEM (960 mg PO BID) and COB (60 mg QD for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60 or 90 mg PO twice weekly) was investigated in a phase 1 study of advanced melanoma, with a modified Ji dose escalation design. Dose-limiting toxicity (DLT) was defined as related grade ≥3 adverse event or inability to deliver 75% of XL888 in first 4 weeks. Results: 25 pts (9 female, median age 62, 15 with M1C disease, 6 with prior anti-PD-1 therapy) were enrolled. After 2 DLTs (rash and acute kidney injury) in first cohort, a lower dose of VEM 720 mg BID and COB 40 mg, with the same XL888 cohorts was investigated. 3 DLTs (rash) in 12 pts were observed in the XL888 60 mg cohort, which was determined as the maximum tolerated dose. Most common grade 3 toxicities included diarrhea (8), hypertension (6), rash (5), alkaline phosphate/GGT elevation (4). 11 patients required dose reductions of VEM and/or COB. Objective responses (PR/CR) were observed in 18 of 25 pts (72%; 95% CI: 51-88%). Median PFS was 8.1 months (4.7 – NA); median overall survival was not reached, with 1-year OS of 71% (45-86%). Single cell RNA-Seq (10X genomics) was performed on baseline and on-treatment tumor biopsies; 8 days of treatment was associated with an increase in immune cell influx (CD4+ and CD8+) and a decrease in number of melanoma cells. At day 8, one patient (now without progression for nearly 2 years) had no tumor cells remaining with only immune cells and stromal fibroblasts left. Further analyses will be presented. Serial plasma BRAF circulating tumor (ct)DNA levels were obtained, with decrease in ctDNA levels corresponding with response and 83% of patients with disease progression showing an elevation in ctDNA from baseline. Conclusions: VEM/COB plus XL888 had significant toxicity, requiring dose-reductions that may have contributed to the low PFS rate despite high response rate. Caution must be used in combination of BRAF+MEKi with other agents. Clinical trial information: NCT02721459.