domatinostat (4SC-202) / 4SC - LARVOL DELTA

Recent knowledge on squamous cell carcinoma of the oral cavity: Contributing factors, underlying molecular pathways, and current attitudes in the therapeutic approaches. (PubMed, Int J Mol Cell Med) - "Innovative treatments are being explored, including combination therapies such as metformin with 4SC-202, which show promise in reducing tumor cell migration and enhancing chemotherapy sensitivity. Additionally, nanoengineered formulations of cisplatin aim to improve drug delivery specificity and minimize systemic toxicity, offering a more patient-friendly approach...Addressing these areas is crucial for advancing prevention, enabling early diagnosis, and improving survival and quality of life for patients with OCSCC. This work supports ongoing progress in oral cancer research and clinical care."

Journal • Review • Epstein-Barr Virus Infections • Head and Neck Cancer • Infectious Disease • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR

Targeting HDAC3 dynamics: Allosteric role of Phe200 in inhibitor binding and breast cancer therapy. (PubMed, J Mol Graph Model) - "Among the compounds, domatinostat and entinostat exhibited the strongest affinities (ΔGbind ≈ -70 kcal/mol), in reasonable agreement with experimental data (r = 0.60). This supports an allosteric inhibition mechanism in which ligands lock HDAC3 into inactive conformations. Collectively, these findings offer mechanistic insights into HDAC3 regulation and highlight structural hot spots for the rational design of selective inhibitors with potential applications in targeted breast cancer therapy."

Journal • Breast Cancer • Oncology • Solid Tumor • HDAC3

Long-term outcome of adding the histone deacetylase inhibitor (HDACi) domatinostat (DOM) to neoadjuvant (neoadj) nivolumab (NIVO) +/- ipilimumab (IPI) in interferon-gamma signature (IFNγ) high/low stage III melanoma patients (pts) (ESMO 2025) - P1/2 | "All pts had surgery in w6 followed by adjuvant NIVO or dabrafenib + trametinib. DOM bid increased IFNγ in 9/10 pts combined with NIVO (in 6/10 from IFNγ low to high) and in 3/3 pts combined with IPI+NIVO (in 2/3 from IFNγ low to high). Table: 1614P Estimated 4-year event-free survival (%) Estimated 4-year overall survival (%) All 73% (95%CI 61%-87%) 84% (95%CI 74%-96%) IFNγ high 2x NIVO mono q3w ( n =10) 90% (95%CI 73%-100%) 100% 2x NIVO q3w + 6 weeks of DOM twice daily ( n =10) 80% (95%CI 59%-100%) 100% IFNγ low 2x NIVO + IPI q3w + 6 weeks of DOM once daily ( n =10) 50% (95%CI 27%-93%) 50% (95%CI 27%-93%) 2x NIVO q3w + 6 weeks of DOM twice daily ( n =10) 70% (95%CI 47%-100%) 80% (95%CI 59%-100%) 2x NIVO + IPI q3w + 6 weeks of DOM twice daily ( n =4) 75% (95%CI 43%-100%) 100% Conclusions Addition of HDACi to neoadj CPI might improve the long-term outcomes of IFNγ low pts and warrants further investigation using alternative dosing schemes or novel HDACi to improve..."

Clinical • Epigenetic controller • Melanoma • Oncology • Solid Tumor • IFNG

Efficient Inhibition of FOXM1 Expression and Viability of High-grade Meningioma Cells by Domatinostat-mediated Dual Targeting of HDAC1 and HDAC2. (PubMed, Anticancer Res) - "Simultaneous inhibition of the class I HDACs, HDAC1 and HDAC2, reduced FOXM1 expression and suppressed cell proliferation in high-grade meningiomas. Furthermore, the class I HDAC inhibitor domatinostat inhibited FOXM1 expression and cell proliferation in high-grade meningioma cells within a concentration range that was not toxic to normal cell lines. These results suggest the potential of domatinostat as a therapeutic option for the treatment of high-grade meningiomas, which are often difficult to manage clinically."

Journal • Brain Cancer • Meningioma • Oncology • Solid Tumor • FOXM1 • HDAC1 • HDAC2

HDAC Class I Inhibitor Domatinostat Induces Apoptosis Preferentially in Glioma Stem Cells Through p53-Dependent and -Independent Activation of BAX Expression. (PubMed, Int J Mol Sci) - "Together, the results suggest that the unique ability of domatinostat to activate the p53-dependent and -independent programs of BAX expression selectively in GSCs could account for its preferential cytotoxicity against GSCs. Our findings may also help guide the selection of patients with glioblastoma, and possibly those with other types of cancer, who are most likely to benefit from domatinostat treatment and optimize the treatment strategy for such patients."

Journal • Brain Cancer • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Glioblastoma • Glioma • Oncology • Solid Tumor • BAX • TP53

PCNA and histone deacetylase targeted inhibitors in cutaneous T-cell lymphoma (AACR 2025) - "Inspired by phosphoproteomic analyses of AOH1996-treated cells, we investigated its potential in combination therapy with the histone deacetylase inhibitors (HDACi) vorinostat and belinostat. Enhanced growth inhibition was also observed when AOH1996 was combined with other HDACi, such as domatinostat and panobinostat. These findings highlight the therapeutic potential of AOH1996 in combination with HDACi, particularly for CTCL, and pave the way for further exploration of this approach in cancer treatment."

Epigenetic controller • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • PCNA

DONIMI: Multicenter Phase 1b Trial Testing the Neoadjuvant Combination of Domatinostat, Nivolumab and Ipilimumab in IFN-gamma Signature-low and IFN-gamma Signature-high RECIST 1.1-measurable Stage III Cutaneous or Unknown Primary Melanoma (clinicaltrials.gov) - P1/2 | N=44 | Completed | Sponsor: The Netherlands Cancer Institute | Active, not recruiting ➔ Completed

Trial completion • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • IFNG

Discovery of Novel 5-Cyano-3-phenylindole-Based LSD1/HDAC Dual Inhibitors for Colorectal Cancer Treatment. (PubMed, J Med Chem) - "Compound 20c effectively modulated the expression of biomarkers associated with LSD1 and HDAC inhibition and demonstrated superior antiproliferative activity compared to SAHA and 4SC-202 across multiple colorectal cancer cell lines...It demonstrated significantly enhanced antitumor efficacy compared to SAHA, without causing observable toxicity. These findings highlight the potential of LSD1/HDAC dual inhibitors for the treatment of malignant cancers."

Journal • Colorectal Cancer • Oncology • Solid Tumor • HDAC1

SYNERGISTIC ANTIPROLIFERATIVE AND PRO-APOPTOTIC EFFECTS OF EPIGENETIC DRUGS GUADECITABINE AND DOMATINOSTAT IN PLEURAL MESOTHELIOMA CELLS (CHEST 2024) - "In conclusion, the combination treatment of gDAC and domatinostat at low and clinically well tolerated doses exhibited a synergistic activity in inducing anti-proliferative and pro-apoptotic effects in PM cell line MPP89. Further research is needed to validate our in vitro findings in vivo and explore the mechanisms underlying the synergistic effects of domatinostat and gDAC in PM cells. CLINICAL IMPLICATIONS: This study contributes to addressing the urgent need for novel therapeutic approaches in PM and suggests the potential clinical utility of gDAC and domatinostat combination treatment in PM patients."

Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Sarcoma • Solid Tumor

Low dose dual epigenetic therapy utilizing hypomethylating agents and HDAC inhibitors prolong survival in an orthotopic PDAC model and alter the tumor microenvironment. (AACRPanCa 2024) - "Background: We have previously studied the effect of hypomethylating agent Decitabine (5- aza-dC; DAC) on pancreatic cancer using the KPC model (KrasG12D/+; Trp53R172H/+; Pdx1- Cre) and observed increased CD4+/CD8+ TILs, greater PD1 expression and slowed tumor growth with increased tumor necrosis...Three HDAC inhibitors were chosen for in vivo testing, Domatinostat, Pracinostat and Entinostat... Our results show that the combination of hypomethylating agent plus HDAC inhibitor has several beneficial effects on the tumor immune response in PDAC. HDAC inhibitors specifically reduce the suppressive myeloid cell population we previously identified after DAC therapy. The combination of dual low dose epigenetic therapy using a hypomethylating agent plus HDAC inhibitor followed by αPD1 results in significant survival benefit in the orthotopic KPC model."

Biomarker • IO biomarker • Tumor microenvironment • Gastrointestinal Cancer • Gene Therapies • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • KRAS • PDX1

High concurrent interferon gamma signature expression in the primary tumor and lymph node metastasis is associated with superior outcome upon neoadjuvant ipilimumab + nivolumab in stage III melanoma (ESMO 2024) - P1/2, P2 | "To address the question of whether the IFNg can be analyzed using primary tumor material (P-IFNg) instead of LN-IFNg or, in the case of incongruencies, has a higher predictive value when combined with LN-IFNg, we analyzed the IFNg signature in paired samples (P and LN) from stage III melanoma pts. Paraffin primary tumor tissue from pts with stage III melanoma, treated in the OpACIN-neo, PRADO and DONIMI trials (neoadjuvant anti-PD1 +/- anti-CTLA4 +/- domatinostat), was retrospectively analyzed with the nanostring nCounter PanCancer immune profiling panel and compared to fresh frozen LN biopsies. Our results suggest that pts with concurrently high IFNg-signature expressions (high IFNg in P and LN) have a better outcome than LN-IFNg high pts only. If confirmed, these findings could inform treatment selection and prognosis."

Clinical • IO biomarker • Melanoma • Oncology • Solid Tumor • BRAF • IFNG

AGM highlights – Positive progress in 2023/2024 leaves company well positioned for resminostat commercialisation (4SC Press Release) - "Yakult Honsha – our partner for resminostat in Japan – is preparing its filing with the Japanese PMDA and is currently waiting on data from the rollover arm of RESMAIN and longer-term overall survival outcomes, which will be available in Q4 2024....Domatinostat was successfully partnered with Vuja De, a US biotech company focused on evaluating domatinostat plus Rapamycin, a low-dose FDA-approved oral mTOR inhibitor, in cancers, such as recurrent metastatic osteosarcoma and refractory sarcomas. Vuja De expects to begin the first clinical studies in late 2024."

Licensing / partnership • New trial • P2 data • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma

LOW DOSE DOUBLE EPIGENETIC THERAPY IMPROVES IMMUNOTHERAPY RESPONSE AND PROLONGS SURVIVAL IN PANCREATIC CANCER. (DDW 2024) - "We previously showed, using the KPC (Kras LSL G12D/+; p53 r172H/+; Pdx1-Cre) mouse model of pancreatic cancer (PDAC), that sequential treatment with the DNA hypomethylating agent (HMA) decitabine (DAC) followed by aPD-1 initially enhanced anti-tumor effects, yet tumors developed resistance linked to a unique M2-polarized Chil3+ myeloid subtype...We then evaluated four different HDAC inhibitors with reported immunomodulatory effects and non-overlapping HDAC isoform specificities: Romidepsin (RM), Domatinostat (DM), Pracinostat (PR) and Entinostat (EN)...Our findings identify a functionally immune suppressive HMA specific myeloid effect. The addition of a second epigenetic agent enhances the therapeutic efficacy resulting in prolonged survival and reverses the suppressive myeloid cell related effects of DAC + aPD1."

IO biomarker • Gastrointestinal Cancer • Gene Therapies • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • KRAS • PDX1

MERKLIN 2: Domatinostat in Combination With Avelumab in Patients With Advanced Merkel Cell Carcinoma Progressing on Anti-PD-(L)1 (clinicaltrials.gov) - P2 | N=19 | Completed | Sponsor: 4SC AG | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Feb 2024

Combination therapy • Metastases • Trial completion • Trial completion date • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE. (PubMed, ESMO Open) - P2 | "Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2."

Combination therapy • Journal • Metastases • Mismatch repair • P2 data • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy. (PubMed, J Med Chem) - "Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577)...LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents."

Combination therapy • Journal • Review • Oncology

DONIMI: Multicenter Phase 1b Trial Testing the Neoadjuvant Combination of Domatinostat, Nivolumab and Ipilimumab in IFN-gamma Signature-low and IFN-gamma Signature-high RECIST 1.1-measurable Stage III Cutaneous or Unknown Primary Melanoma (clinicaltrials.gov) - P1/2 | N=44 | Active, not recruiting | Sponsor: The Netherlands Cancer Institute

Trial completion date • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • IFNG

DONIMI: Multicenter Phase 1b Trial Testing the Neoadjuvant Combination of Domatinostat, Nivolumab and Ipilimumab in IFN-gamma Signature-low and IFN-gamma Signature-high RECIST 1.1-measurable Stage III Cutaneous or Unknown Primary Melanoma (clinicaltrials.gov) - P1/2 | N=44 | Active, not recruiting | Sponsor: The Netherlands Cancer Institute | Phase classification: P1b ➔ P1/2

Phase classification • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • IFNG

INVESTIGATING THE ROLE OF HDACS IN THE PROGRESSION OF METASTATIC UNDIFFERENTIATED PLEOMORPHIC SARCOMA (CTOS 2023) - "Preliminary drug screening data suggests that HDAC inhibitors, such as Domatinostat, have the potential to specifically target the MCs in order to inhibit metastasis in UPS... HDACs have been identified as potential therapeutic targets for metastatic UPS. Previous data has shown that a single subpopulation of cells is responsible for the formation of these distant lesions. Ongoing studies aim to identify which HDACs are important for metastasis in addition to elucidating their mechanism of disease progression and further analysis of the effect of pharmacological inhibition."

Metastases • Oncology • Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma • KRAS

Domatinostat Targets the FOXM1-Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents. (PubMed, Int J Mol Sci) - "Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1-survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer."

Combination therapy • Journal • Gene Therapies • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • BIRC5 • FOXM1

MERKLIN 2: Domatinostat in Combination With Avelumab in Patients With Advanced Merkel Cell Carcinoma Progressing on Anti-PD-(L)1 (clinicaltrials.gov) - P2 | N=19 | Active, not recruiting | Sponsor: 4SC AG | Trial completion date: Jul 2023 ➔ Dec 2024 | Trial primary completion date: Jul 2022 ➔ Feb 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

Domatinostat-induced cutaneous toxicities in neoadjuvant treatment for stage III melanoma (EADO 2023) - "Supplemental domatinostat (a class I histone deacetylase inhibitor) to neoadjuvant nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) was hypothesized to lead to an increased anti-tumor immune response due to its beneficial immune-modulating effects including IFN-γ signature expression increase. New ICI treatment strategies with supplemental drugs, targeting other immunosuppressive pathways such as domatinostat, may lead to unexpected dermatologic toxicities with thus far unknown mechanisms and different clinical presentations than ICI-associated dermatitis or classic drug reaction with eosinophilia and systematic symptoms (DRESS)."

Clinical • IO biomarker • Melanoma • Oncology • Solid Tumor • IFNG

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression. (PubMed, J Cancer Res Clin Oncol) - "Our results demonstrate that the direct anti-tumor effect of HDACi domatinostat on MCC cells is at least in part mediated via decreased HES1 expression allowing the induction of IFNα, which in turn causes apoptosis."

Journal • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • CASP3 • CASP7 • HES1 • IFNA1

HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction. (PubMed, Int J Mol Sci) - "Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2 breast cancer patients."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PHLDA1 • PLEK

IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma. (PubMed, J Exp Med) - "Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • IFNG