Abstract 3454
Background
The clinical benefit of combined treatment with BRAF- and MEK-inhibitors (BRAFi; MEKi) in BRAFV600 mutant (BRAFm) melanoma is limited due to resistance after 6-14 months, associated with emerging secondary mutations. Withholding of treatment leads to reversible hyperactivation of the MAPK pathway, causing transient growth arrest and increase in Reactive Oxygen Species (ROS) in preclinical studies. Treatment of BRAFi/MEKi resistant melanoma cells with vorinostat leads to a further increase in ROS, effectively killing BRAFi resistant cells. In vivo, switch from BRAFi to vorinostat in BRAFi resistant BRAFm melanoma resulted in a decline in tumor volume. Six patients with resistant BRAFm melanoma were treated with vorinostat 360 mg QD continuously. These patients revealed regression of mutant clones and progression of BRAFi sensitive clones. Tumor biopsies showed newly developed secondary MAPK pathway mutations, e.g. NRASQ61H and KRASG12C amplifications at start and a complete absence of these resistant mutations after two weeks of vorinostat. Based on these findings we postulate that BRAFi resistant BRAFm melanoma cells can be eliminated by a short treatment with vorinostat due to killing of tumor cells harboring a secondary mutation in the MAPK pathway. In vitro experiments confirmed this hypothesis.
Trial design
This is a proof of concept study to determine the efficacy of sequential treatment with vorinostat and BRAFi/MEKi in BRAFi resistant BRAFm melanoma. Patients with age ≥ 18 years, WHO performance 0-2 and progression on BRAFi/MEKi are eligible. 26 evaluable patients with resistant BRAFm melanoma will be treated with vorinostat 360 mg continuously for 2 weeks and thereafter switch back to BRAFi/MEKi. The primary aim is to demonstrate ≥ 30% anti-tumor response of progressive lesions according to RECIST 1.1 upon sequenced treatment with vorinostat and BRAFi/MEKi. Secondary endpoints are to demonstrate that emerging resistant clones with a secondary mutation in the MAPK pathway can be detected by ctDNA analysis and purged by short term treatment with vorinostat. Blood and tumor biopsies will be taken for pharmacokinetic, pharmacodynamic and pharmacogenetic exploratory analyses.
Clinical trial identification
NCT02836548.
Editorial acknowledgement
Legal entity responsible for the study
The Netherlands Cancer Institute.
Funding
Oncode.
Disclosure
J.H.M. Schellens: Shareholder / Stockholder / Stock options, and patent holder on oral taxenes: Modra Pharmaceutical. All other authors have declared no conflicts of interest.
Resources from the same session
4278 - Clinical factors and overall survival (OS) associated with patterns of metastases (mets) in melanoma patients (pts).
Presenter: Ines Pires da Silva
Session: Poster Display session 3
Resources:
Abstract
4370 - Continental differences in pathologic response with neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO) in patients with macroscopic stage III melanoma in the phase 2 OpACIN-neo trial.
Presenter: Irene Reijers
Session: Poster Display session 3
Resources:
Abstract
3230 - Comparable responses of melanoma at primary site and synchronous lymph node metastases upon neoadjuvant ipilimumab (IPI) and nivolumab (NIVO)
Presenter: Judith Versluis
Session: Poster Display session 3
Resources:
Abstract
3171 - Adjuvant Therapies for Stage III Melanoma: Benchmarks for Bringing Clinical Trials to Clinical Practice
Presenter: Tina HIEKEN
Session: Poster Display session 3
Resources:
Abstract
3493 - Mixture-cure modeling for resected stage III/IV melanoma in the phase 3 CheckMate 238 trial
Presenter: Jeffrey Weber
Session: Poster Display session 3
Resources:
Abstract
3036 - An open-label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib for patients with unresectable advanced BRAFV600-mutant melanoma: a subgroup analysis of patients with brain metastasis
Presenter: Caroline Dutriaux
Session: Poster Display session 3
Resources:
Abstract
2233 - Adverse event (AE) kinetics in patients (pts) treated with dabrafenib + trametinib (D + T) in the metastatic and adjuvant setting
Presenter: Jean Jacques Grob
Session: Poster Display session 3
Resources:
Abstract
2435 - A Single Arm, Open Label, Phase II, Multicenter Study to Assess the Detection of the BRAF V600 Mutation on cfDNA from Plasma in Patients with Advanced Melanoma
Presenter: Piotr Rutkowski
Session: Poster Display session 3
Resources:
Abstract
1766 - Efficacy and Safety of Dabrafenib and Trametinib in Patients with Metastatic BRAFV600 Mutation-positive Melanoma in the Real-World Setting – Interim results of the non-interventional COMBI-r study
Presenter: Carola Berking
Session: Poster Display session 3
Resources:
Abstract
2131 - Trial update: A randomized Phase Ib/II study of the selective small molecule Axl inhibitor Bemcentinib (BGB324) in combination with either dabrafenib/trametinib (D/T) or pembrolizumab in patients with metastatic melanoma
Presenter: Oddbjørn Straume
Session: Poster Display session 3
Resources:
Abstract