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
6008 - Quality of life in previously untreated patients with advanced renal cell carcinoma (aRCC) in CheckMate 214: updated results
Presenter: David Cella
Session: Poster Display session 3
Resources:
Abstract
3630 - Results of phase 1 clinical trial of high doses of Seleno-L-methionine (SLM) in sequential combination with Axitinib in previously treated and relapsed clear cell renal carcinoma (ccRCC) patients
Presenter: Yousef Zakharia
Session: Poster Display session 3
Resources:
Abstract
2356 - Safety and Efficacy of CDX-014 , an Antibody-Drug Conjugate against T Cell immunoglobulin mucin-1 (TIM-1), in advanced Renal Cell Carcinoma
Presenter: Bradley McGregor
Session: Poster Display session 3
Resources:
Abstract
1028 - SPAZO2 (SOGUG): Outcomes and prognostic significance of IMDC intermediate prognosis subclassification in metastatic renal cell carcinoma (mRCC) in patients treated with 1st-line pazopanib (1stPz).
Presenter: Begona P. Valderrama
Session: Poster Display session 3
Resources:
Abstract
2293 - Effect of Antacid Intake on the Therapeutic Efficacy of Sunitinib (SUN) in Metastatic Renal Cell Carcinoma (mRCC) Patients (pts): a Sub-Analysis of the STAR-TOR Registry
Presenter: Katrin Schlack
Session: Poster Display session 3
Resources:
Abstract
1451 - Randomized phase 3 trial of avelumab + axitinib vs sunitinib as first-line treatment for advanced renal cell carcinoma: JAVELIN Renal 101 Japanese subgroup analysis
Presenter: Motohide Uemura
Session: Poster Display session 3
Resources:
Abstract
4399 - Overall and progression-free survival according to MSKCC scores in 1st line sunitinib treatment of metastatic renal cell carcinoma (mRCC)
Presenter: Jindrich Finek
Session: Poster Display session 3
Resources:
Abstract
1344 - Combination therapy with checkpoint inhibitors for first-line treatment of advanced renal cell carcinoma: A systematic review and meta-analysis of randomized controlled trials
Presenter: Kyaw Thein
Session: Poster Display session 3
Resources:
Abstract
3462 - A phase II trial of TKI induction followed by a randomized comparison between nivolumab or TKI continuation in renal cell carcinoma (NIVOSWITCH)
Presenter: Viktor Grünwald
Session: Poster Display session 3
Resources:
Abstract
5268 - Nivolumab (N) treatment beyond progression in a real-world cohort of patients (pts) with metastatic renal cell carcinoma (mRCC)
Presenter: Sophie Hans
Session: Poster Display session 3
Resources:
Abstract