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
5517 - Molecular fingerprinting in breast cancer (BC) screening using Quantum Optics (QO) technology combined with an artificial intelligence (AI) approach applying the concept of “molecular profiles at n variables (MPnV)”: a prospective pilot study.
Presenter: Jean-Marc Nabholtz
Session: Poster Display session 3
Resources:
Abstract
2152 - Inferring the correlation between incidence rates of melanoma and the average tumor-specific epitope binding ability of HLA class I molecules in different populations
Presenter: Istvan Miklos
Session: Poster Display session 3
Resources:
Abstract
4382 - Thermal Liquid Biopsy as a Valuable Tool in Lung Cancer Screening Programs
Presenter: Alberto Rodrigo
Session: Poster Display session 3
Resources:
Abstract
2465 - Towards a screening test for cancer by circulating DNA analysis
Presenter: Rita Tanos
Session: Poster Display session 3
Resources:
Abstract
3788 - Evaluation of a successful launch of the MammaPrint and BluePrint NGS kit
Presenter: Leonie Delahaye
Session: Poster Display session 3
Resources:
Abstract
3863 - Analysis of prognostic factors on overall survival in elderly women treated for early breast cancer using data mining and machine learning
Presenter: Pierre Heudel
Session: Poster Display session 3
Resources:
Abstract
1993 - Circulating tumor cell detection in epithelial ovarian cancer using dual-component antibodies targeting EpCAM and FRα
Presenter: Na Li
Session: Poster Display session 3
Resources:
Abstract
4281 - CEUS of the breast: Is it feasible in improved performance of BI-RADS evaluation of critical breast lesions?——A multi-center prospective study in China
Presenter: Jun Luo
Session: Poster Display session 3
Resources:
Abstract
2268 - Classification of abnormal findings on ring-type dedicated breast PET for detecting breast cancer
Presenter: Shinsuke Sasada
Session: Poster Display session 3
Resources:
Abstract
4035 - Prediction of benign and malignant breast masses using digital mammograms texture features
Presenter: Cui Yanhua
Session: Poster Display session 3
Resources:
Abstract