A Proof-of-Concept Study of Sequential Treatment with the HDAC Inhibitor Vorinostat following BRAF and MEK Inhibitors in BRAFV600-Mutated Melanoma.
Clin Cancer Res
; 30(15): 3157-3166, 2024 Aug 01.
Article
in En
| MEDLINE
| ID: mdl-38739109
ABSTRACT
PURPOSE:
The development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi. PATIENTS ANDMETHODS:
Patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma were treated with vorinostat 360 mg once daily for 14 days followed by BRAFi/MEKi. The primary endpoint was an objective response rate of progressive lesions of at least 30% according to Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included progression-free survival, overall survival, safety, pharmacokinetics of vorinostat, and translational molecular analyses using ctDNA and tumor biopsies.RESULTS:
Of the 26 patients with progressive BRAFi/MEKi-resistant BRAFV600-mutated melanoma receiving treatment with vorinostat, 22 patients were evaluable for response. The objective response rate was 9%, with one complete response for 31.2 months and one partial response for 14.9 months. Median progression-free survival and overall survival were 1.4 and 5.4 months, respectively. Common adverse events were fatigue (23%) and nausea (19%). ctDNA analysis showed emerging secondary mutations in NRAS and MEK in eight patients at the time of BRAFi/MEKi resistance. Elimination of these mutations by vorinostat treatment was observed in three patients.CONCLUSIONS:
Intermittent treatment with vorinostat in patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable antitumor responses were observed in a minority of patients (9%).
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antineoplastic Combined Chemotherapy Protocols
/
Proto-Oncogene Proteins B-raf
/
Protein Kinase Inhibitors
/
Histone Deacetylase Inhibitors
/
Vorinostat
/
Melanoma
/
Mutation
Limits:
Adult
/
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Clin Cancer Res
/
Clin. cancer res
/
Clinical cancer research
Year:
2024
Document type:
Article