Abstract 5545
Background
Many advanced melanoma patients are refractory and do not respond to checkpoint inhibition (CI) alone. Epigenetic modulation of tumors to enhance their immunogenicity, alter the tumor microenvironment and thus increase the chance of response to immunotherapy is one clinical approach. In an open label Phase Ib/II multi-center study (‘SENSITIZE’) we investigated the combination of the HDAC inhibitor domatinostat and pembrolizumab in patients with advanced melanoma.
Methods
Advanced stage melanoma patients who were refractory or non-responding to prior checkpoint inhibitor therapy were treated with domatinostat (orally) at increasing dose levels in 3 different dose cohorts in combination with pembrolizumab (2mg/kg) q3w intravenously in a modified “rolling six” study design to evaluate the safety and tolerability of the combination treatment. Tumor assessment was initially performed after 12 weeks. Tumor biopsies were taken for immunohistochemical and gene expression analysis, peripheral blood for PK/PD analysis.
Results
At time of data cut-off on May 8th, 2019 (study ongoing), a total of 23 patients were enrolled into the study. The safety profile indicates that domatinostat-specific adverse events add to the known safety profile of pembrolizumab, but no exacerbation of immune-related adverse events in rate and severity has been observed so far. Domatinostat alone and in combination was considered safe. First signs of efficacy have been observed, including patients one with a partial response and two with stable disease per irRECIST 1.1. Tumor biopsies at baseline showed a domatinostat-induced alteration of the tumor microenvironment including infiltration of CD8+ T cells, the presence of PD-1/ PD-L1 positive cells, and changes on gene expression levels. Furthermore, a dose-dependent PK profile has been observed.
Conclusions
Domatinostat given in combination with pembrolizumab is safe and tolerable and might increase anti-tumor activity in these CI-unresponsive melanoma patients by alteration of the immune tumor microenvironment.
Clinical trial identification
NCT03278665.
Editorial acknowledgement
Legal entity responsible for the study
4SC AG.
Funding
4SC AG.
Disclosure
P.A. Ascierto: Advisory / Consultancy, Travel / Accommodation / Expenses: 4SC. F. Hermann: Full / Part-time employment: 4SC AG. R. Bartz: Full / Part-time employment: 4SC AG. D. Schadendorf: Advisory / Consultancy, Travel / Accommodation / Expenses: 4SC. All other authors have declared no conflicts of interest.
Resources from the same session
4021 - Prospective pathological experience with research biopsies in the context of clinical trials at Vall d’Hebron Institute of Oncology
Presenter: Paolo Nuciforo
Session: Poster Display session 3
Resources:
Abstract
5603 - Development of a comprehensive next-generation targeted sequencing assay for detection of gene-fusions in solid tumors
Presenter: Vinay Mittal
Session: Poster Display session 3
Resources:
Abstract
4952 - Next-generation sequencing for better treatment strategy of cancer of unknown primary (CUP)
Presenter: Kang Kook Lee
Session: Poster Display session 3
Resources:
Abstract
4590 - Circulating-free DNA analysis from long-term surviving metastatic colorectal cancer patients undergoing surgery for resectable disease.
Presenter: Michele Ghidini
Session: Poster Display session 3
Resources:
Abstract
3696 - Ultra-sensitive detection of circulating tumor DNA identifies patients in high risk of recurrence in early stages melanoma
Presenter: Filip Janku
Session: Poster Display session 3
Resources:
Abstract
4295 - Identification of the founder BRCA1 mutation c.4117G>T (p.Glu1373*) recurring in Abruzzo and Lazio regions of Central Italy and predisposing to breast/ovarian and BRCA1-related cancers
Presenter: Daniela Di Giacomo
Session: Poster Display session 3
Resources:
Abstract
2214 - Enzalutamide (ENZA) and Apalutamide (APA) In vitro chemical reactivity studies and Activity in a Mouse Drug Allergy Model (MDAM)
Presenter: Mausumee Guha
Session: Poster Display session 3
Resources:
Abstract
5044 - Influence of genetic variation in COMT on cisplatin-induced nephrotoxicity in cancer patients.
Presenter: Bram Agema
Session: Poster Display session 3
Resources:
Abstract
3293 - Cardioprotective and anti-inflammatory effects of Empagliflozin during treatment with Doxorubicin: a cellular and preclinical study
Presenter: Vincenzo Quagliariello
Session: Poster Display session 3
Resources:
Abstract
3324 - Breast Cancer Organoids Model Treatment Response of HER2 Targeted Therapy in HER2-mutant Breast Cancer
Presenter: Xuelu Li
Session: Poster Display session 3
Resources:
Abstract