Background
Development of resistance after median 12-14 months limits the clinical benefit of BRAF and MEK inhibitors in BRAF V600 mutated melanoma. This acquired resistance is frequently caused by reactivation of the MAPK pathway by secondary mutations. It has been shown that short-term treatment (14d) with vorinostat was able to initiate apoptosis of the resistant tumor cells. We aimed to assess the anti-tumor activity of sequential treatment with vorinostat and BRAFi/MEKi in patients with BRAF V600 melanoma who progressed after initial response to BRAFi/MEKi.
Methods
Eligible patients with BRAFi/MEKi resistant BRAF V600 melanoma were treated with vorinostat 360 mg once daily in a 14-day cycle, followed by BRAFi/MEKi. In patients with clinical benefit upon treatment, additional cycles of vorinostat were allowed. The primary endpoint was an anti-tumor response rate of progressive lesions of at least 30% according to RECIST 1.1. Secondary endpoints included safety and tolerability, pharmacokinetics of vorinostat and translational molecular analyses.
Results
25 patients (16M/9F, median age 56 years) with advanced, progressive BRAFi/MEKi resistant BRAF V600 melanoma have initiated treatment with vorinostat. 21 patients were evaluable for response. Best objective response: 4 PR (confirmed in 3 pts, duration of response 6.2, 9.3 and 18.6 months), 4 SD (confirmed in 1 pt, duration 9.3 months) and 13 PD. Four patients received ≥ 2 cycles of vorinostat and 1 patient had an objective response upon this retreatment. Common reported adverse events were fatigue (24%), nausea (20%) and vomiting (12%) and were only grade 1/2. Preliminary results of ctDNA analysis (in first 6 pts) showed emerging secondary mutations in NRAS in two patients at time of BRAFi/MEKi resistance. Elimination of the NRAS mutation by vorinostat treatment was observed in one patient (best overall response: PD).
Conclusions
Intermittent treatment with vorinostat in patients with resistant BRAF V600 mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable anti-tumor responses were observed in a minority of patients (14%). Translational research aiming to find predictive biomarkers for response is ongoing.
Clinical trial identification
NCT02836548.
Legal entity responsible for the study
The authors.
Funding
This investigator-initiated trial is financially supported by Oncode Institute and an ERC proof of concept grant.
Disclosure
J.H. Beijnen: Financial Interests, Personal and Institutional, Funding, Employment/Ownership Interests: Modra Pharmaceuticals; Financial Interests, Institutional, Funding, Research funding: Neon Therapeutics. All other authors have declared no conflicts of interest.
