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
2881 - Impact of corticosteroids and antibiotics on efficacy of immune-checkpoint inhibitors in advanced non-small cell lung cancer
Presenter: Joaquin Mosquera Martinez
Session: Poster Display session 3
Resources:
Abstract
3186 - The landscape of immuno-oncology clinical trials in China
Presenter: Dawei Wu
Session: Poster Display session 3
Resources:
Abstract
3468 - Clinical Significance of Immune-related Creatine Phosphokinase Increase Associated with Anti PD1/PD-L1 immunotherapies.
Presenter: Samia Hajem
Session: Poster Display session 3
Resources:
Abstract
3836 - Thyroid toxicity and anti-thyroid antibodies as predictive markers for patients treated with anti-PD1 checkpoint therapy
Presenter: Wim Meer
Session: Poster Display session 3
Resources:
Abstract
1343 - Treatment-related adverse events and tolerability in patients with advanced renal cell carcinoma treated with first-line combination therapy with checkpoint inhibitors
Presenter: Thura Win Htut
Session: Poster Display session 3
Resources:
Abstract
5783 - Immune-related adverse events (irAEs) with single-agent PD-1 vs PD-L1 inhibitors: a meta-analysis of 8,730 patients from clinical trials
Presenter: Guru Sonpavde
Session: Poster Display session 3
Resources:
Abstract
5422 - EULAR recommendations for the diagnosis and the management of rheumatic immune-related adverse events due to cancer immunotherapy
Presenter: Marie Kostine
Session: Poster Display session 3
Resources:
Abstract
1202 - Radiographic characteristics and poor prognostic factors of interstitial lung disease (ILD) in nivolumab-treated patients with non-small cell lung cancer (NSCLC)
Presenter: Shinichi Sasaki
Session: Poster Display session 3
Resources:
Abstract
2749 - Use of Checkpoint Inhibitors (CPI) in Allogeneic Stem Cell Transplant Recipients: An Institutional Experience and A Systemic Review of the Literature
Presenter: Chantal Saberian
Session: Poster Display session 3
Resources:
Abstract
3256 - Deep Learning Radiomics distinguishes intrapulmonary Disease from Metastases in Immunotherapy-treated Melanoma Patients
Presenter: Thi Dan Linh Nguyen-Kim
Session: Poster Display session 3
Resources:
Abstract