milademetan (RAIN-32) / Daiichi Sankyo, Rigel Pharmaceuticals, Pathos - LARVOL DELTA

A druggable genome screen identifies b-catenin transcription targets as desmoid cell vulnerabilities (AACR 2026) - "Inhibition of exportin-1 with selinexor or shRNA directed at XPO1 inhibited proliferation (by 51%, p<0.05), but failed to affect β-catenin subcellular localization as in other systems...Inhibition of MDM2 with milademetan or shRNA similarly increased p53 and p21 and reduced proliferation (by 60%, p<0.05)...BRD4 inhibition via shRNA or treatment with birabresib reduced proliferation (85%, p<0.01) but did not affect p53/p21 signaling... BRD4, MDM2 and XPO1 were identified as potential therapeutic targets in DT with gene products modulating p53/p21 or β-catenin activity. Both BRD4 and MDM2 represent direct transcriptional targets of β-catenin though negative regulation of MDM2 in the context of DT cell dependency on its protein product suggest secondary genetic events or environmental signaling may be necessary to counteract this potential tumor suppressive effect of β-catenin."

IO biomarker • Oncology • Sarcoma • Solid Tumor • BRD4 • CDKN1A • MDM2 • TERT • TGFBI • TP53 • XPO1

A Phase I study of Milademetan (DS3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis. (PubMed, Blood Cancer J) - P1/2 | "The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response."

Combination therapy • Journal • P1 data • Acute Myelogenous Leukemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • MCL1 • MDM2 • YTHDF2

A phase 2 study of the MDM2 inhibitor milademetan in patients with TP53-wild type and MDM2-amplified advanced or metastatic solid tumors (MANTRA-2) (AACR 2022) - P2 | "Enrollment of 65 patients is planned to ensure that 57 patients have centrally confirmed TP53 WT and MDM2 copy number ≥12. The trial opened in November 2021 and is actively enrolling patients."

Clinical • P2 data • Brain Cancer • CNS Tumor • Glioblastoma • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2

MANTRA: A randomized, multicenter, phase 3 study of the MDM2 inhibitor milademetan versus trabectedin in patients with de-differentiated liposarcomas (AACR 2022) - P3 | "Exploratory endpoints: molecular markers in peripheral blood and/or tumor tissue; milademetan pharmacokinetics. To demonstrate a 3-month increase in PFS (from 3 to 6 months) corresponding to a hazard ratio of 0.5, approximately 160 patients will be required to observe 105 events with 93.9% power and 2-sided significance level of 5%."

Clinical • P3 data • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2

Efficacy and safety findings from MANTRA: A global, randomized, multicenter, phase III study of the MDM2 inhibitor milademetan vs trabectedin in patients with dedifferentiated liposarcomas (ESMO Asia 2023) - P3 | "TEAEs were consistent with previous reports and manageable by dose interruptions/modifications. Further evaluation of milademetan is warranted in populations that may benefit from MDM2 inhibition."

Clinical • P3 data • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2

Milademetan in advanced solid tumors with MDM2 amplification and wild-type TP53: pre-clinical and phase 2 clinical trial results. (PubMed, Clin Cancer Res) - "Milademetan had a manageable safety profile and achieved responses against a variety of refractory MDM2amp, TP53 -wt solid tumors, but tumor reductions were short-lived. Subsequent MDM2 inhibitor efforts should focus on combination strategies or treatment in earlier lines of therapy to achieve more durable clinical benefit."

Journal • P2 data • Preclinical • Hematological Disorders • Leukopenia • Neutropenia • Oncology • Sarcoma • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • Uterine Cancer • MDM2 • TP53

Clinical MDM2 inhibitors Idasanutlin and Milademetan as a new approach to targeted apoptos induction in the p53-mutated triple-negative breast cancer (TNBC) (DGS 2025) - "Since P53 is mutated in the TNBC cell lines used, other mechanisms, such as a P73-MDM2 inhibition, allegedly explain the observed antitumer effect. MDM2 inhibitors could therefore also have a therapeutic potential in P53-mutated TNBC cells and form a promising basis for the further development of targeted therapy options of the TNBC."

Clinical • P53mut • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • TP53

Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition With Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild Type Acute Myeloid Leukemias. (PubMed, Clin Cancer Res) - P1 | "Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3 targeting strategies for FLT3-mutant AML."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD34 • FLT3 • TP53 • YTHDF2

Pharmacological Inhibition of MDM2 Induces Apoptosis in p53-Mutated Triple-Negative Breast Cancer. (PubMed, Int J Mol Sci) - "We here selected the clinical-stage MDM2 inhibitors Idasanutlin and Milademetan and investigated their anti-tumoral effects in TNBC. This effect was observed despite an inactivating p53 mutation and was apparently independent of p53 expression. Our data suggest that MDM2 is a promising target in TNBC and clinical-stage MDM2 inhibitors should be further evaluated for their potential therapeutic application."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CASP7

TARGETING PRIMARY AND SECONDARY ONCOGENIC DRIVERS IN RETROPERITONEAL DEDIFFERENTIATED LIPOSARCOMAS (CTOS 2024) - "Cabazitaxel and ifosfamide resulted in the highest maximum tumor volume inhibition (mTVI%), which was 94-100% and 83-98%, respectively. MDM2 inhibition with milademetan resulted in different effects in the two analyzed models, which were higher in LS-MP (mTVI% 83%) compared to LS-NV (mTVI%35%). Conversely, the AURKA inhibitor alisertib resulted in a higher mTVI% in the LS-NV (93%) compared to the LS-MP (50%) model. We identified and validated therapeutic targets for DDLPS beyond the oncogenic drivers of this disease. These findings have significant implications for developing combination treatments, which will be tested in new in vivo experiments to prioritize innovative treatment strategies for clinical trials."

Liposarcoma • Oncology • Sarcoma • Solid Tumor • CDK4 • CHEK1 • HMGA2 • MDM2

The MDM2 degraders KTX-049 and KT-253 are highly active in wild-type TP53 (WT p53) Merkel cell carcinoma (MCC) (EORTC-NCI-AACR 2024) - "Here, we analyze the in vitro and in vivo efficacy of MDM2 degraders in MCC tumor models and compare their efficacy to an MDM2 small molecule inhibitor, DS-3032.Materials and Established MCCP cell lines with WT or mutant (MUT) p53 and two MCCP patient derived cell lines (PDCLs) with WT p53 were treated with KTX-049, a tool MDM2 degrader, or DS-3032. Selective and potent MDM2 degraders including clinical stage KT-253 show promising efficacy in WT p53 MCC preclinical models. These results support exploration of KT-253 clinical activity in WT p53 MCC where degradation of MDM2 is one of the key mechanisms for impeding tumor growth."

Tumor mutational burden • Endocrine Cancer • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • ANXA5 • CASP3 • CASP7 • EP400 • MYCL • TMB • TP53

Effects of Mdm2 Inhibitors on Cellular Viability of Breast Cancer Cell Lines HP100, MCF7. (PubMed, Bratisl Lek Listy) - "Our research concluded that Nutlin 3 has a superior effect over Yh239-EE and Miladometan in treating Breast cancer; moreover, the combination group has shown to be more effective than treatment with Doxorubicin or MDM2 inhibitors alone. Interesting information is that Doxorubicin also causes an increase in P53 levels. This result provided us with a promising therapeutic strategy for the treatment of breast cancer. However, more research is required to be conducted on more types of cell lines and in human or animal models (Tab. 4, Fig. 8, Ref. 33). Text in PDF www.elis.sk Keywords: breast cancer, Miladometan, cell viability, proliferation, therapeutic strategy."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • MDM2

Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers and MDM2 Amplification. (PubMed, JCO Precis Oncol) - "These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MDM2 • RET • TP53

Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies. (PubMed, Cancer Med) - "Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal."

Combination therapy • Journal • Monotherapy • P1 data • Acute Myelogenous Leukemia • Fatigue • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • TP53

Analysis of correlation between high expression of nucleoporin 85 (NUP85) and immune cell infiltration in hepatocellular carcinoma (PubMed, Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi) - "The expression of NUP85 was significantly correlated with multiple drugs, such as Milademetan (PD0325901), a structural analog of Vemurafenib (PLX4720), and Regorafenib (PD0325901). These factors significantly and unfavorably affected the OS of HCC patients, and the areas under the ROC curve (AUC) for the 1-year, 3-year, and 5-year OS prognostic diagnosis of HCC patients were all greater than 0.7. Conclusion The high expression of NUP85 in HCC is correlated with a poor prognosis and is related to various immune cells and drugs, making it a potential biomarker for di-agnosis, treatment, and prognosis in HCC."

Immune cell • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Twist1 forms a trimeric complex with p53 and MDM2 and attenuates the efficacy of MDM2 inhibitors (EACR 2024) - "The interaction is direct, as demonstrated by GST pull downs, and occurs under para-physiological conditions, as shown by TurboID proximity-dependent biotinylation experiments.Modulation of Twist1 expression in p53 wild type/MDM2 overexpressing sarcoma cell models affects p53 and the response to MDM2i (Nutlin-3a, Milademetan/DS-3032, Idasanutlin/RG7388, SAR405838). Conversely, ectopic Twist1 expression attenuates MDM2i efficacy. This effect depends on Twist1 binding to p53 and MDM2, as a Twist1 mutant defective for this binding loses the inhibitory capacity.Conclusion Twist forms a p53:Twist:MDM2 trimeric complex and, by enhancing MDM2-mediated degradation of p53, attenuates the efficacy of MDM2i"

Clinical • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • MDM2 • TWIST1

DEMETER: Milademetan and Fulvestrant in GATA3-mutant, ER+HER- Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1 | Terminated | Sponsor: Institut Curie | N=48 ➔ 1 | Trial completion date: Dec 2026 ➔ Nov 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2025 ➔ Nov 2023; Financial partner providing study drug could no longer support the trial

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • ER • GATA3 • HER-2

DEMETER: A phase 2 multicenter trial of milademetan and fulvestrant in patients with ER+, HER2- advanced breast cancer (SABCS 2023) - No abstract available

Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • ER • HER-2

DEMETER: Milademetan and Fulvestrant in GATA3-mutant, ER+HER- Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=48 | Active, not recruiting | Sponsor: Institut Curie | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • ER • GATA3 • HER-2

MILADEMETAN VS. TRABECTEDIN IN PATIENTS WITH DEDIFFERENTIATED LIPOSARCOMA: RESULTS FROM THE PHASE 3 MANTRA STUDY (CTOS 2023) - No abstract available

Clinical • P3 data • Liposarcoma • Oncology • Sarcoma • Solid Tumor

Efficacy and safety findings from MANTRA: A global, randomized, multicenter, phase III study of the MDM2 inhibitor milademetan vs trabectedin in patients with dedifferentiated liposarcomas (ESMO 2023) - P3 | "Further evaluation of milademetan is warranted in populations that may benefit from MDM2 inhibition. Table: LBA89 Study findings Efficacy population Milademetan (n=86) Trabectedin (n=89) Median PFS by BICR, m 3.6 2.2 HR=0.89 (95% CI 0.61–1.29; p=0.53) Median PFS by investigator, m 3.7 2.1 HR=0.80 (95% CI 0.55–1.15; p=0.22) Median OSa, m 9.5 10.2 HR=1.27 (95% CI 0.80–2.04; p=0.31) ORR, n (%) 4 (4.7) 3 (3.4) p=0.67 DCR, n (%) 29 (33.7) 24 (27.0) p=0.33 Safety population n=86 n=79 Most common milademetan TEAEs, %NauseaThrombocytopeniaAnemiaVomiting 70.961.644.244.2 58.225.336.719.0 Most common grade 3/4 milademetan TEAEs, %ThrombocytopeniaNeutropeniaAnemia 39.525.618.6 13.926.619.0 TEAEs – fatal/grade 5, % 0 6.3 TEAEs leading to dose reductions, % 44.2 29.1 TEAEs leading to discontinuations, % 11.6 19.0"

Clinical • Late-breaking abstract • P3 data • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2

An Updated Review of the Biomarkers of Response to Immune Checkpoint Inhibitors in Merkel Cell Carcinoma: Merkel Cell Carcinoma and Immunotherapy. (PubMed, Cancers (Basel)) - "Avelumab therapy has shown promising results in Merkel cell polyomavirus (MCPyV)-negative MCC patients with TMB-H, while pembrolizumab therapy has shown better response in patients with low TMB. A study evaluating neoadjuvant nivolumab therapy found no significant difference in treatment response between the tumor etiologies and TMB levels. In addition to ICI therapy, other treatments that induce apoptosis, such as milademetan, have demonstrated positive responses in MCPyV-positive MCC, with few somatic mutations and wild-type TP53. This review summarizes current knowledge and discusses emerging and potentially predictive biomarkers for MCC therapy with ICI."

Biomarker • Checkpoint inhibition • IO biomarker • Journal • Review • Tumor mutational burden • Merkel Cell Carcinoma • Microsatellite Instability • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • MSI • PD-L1 • TMB • TP53

MANTRA: Treatment of Milademetan Versus Trabectedin in Patient With Dedifferentiated Liposarcoma (clinicaltrials.gov) - P3 | N=175 | Terminated | Sponsor: Rain Oncology Inc | Trial completion date: Jul 2025 ➔ Oct 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jul 2025 ➔ Oct 2023; Sponsor Decision

Trial completion date • Trial primary completion date • Trial termination • Liposarcoma • Oncology • Sarcoma • Solid Tumor

An Updated Review of the Biomarkers of Response to Immune Checkpoint Inhibitors in Merkel Cell Carcinoma: Merkel Cell Carcinoma and Immunotherapy (Multidisciplinary Digital Publishing Institute) - "Avelumab therapy has shown promising results in Merkel cell polyomavirus (MCPyV)-negative MCC patients with TMB-H, while pembrolizumab therapy has shown better response in patients with low TMB. A study evaluating neoadjuvant nivolumab therapy found no significant difference in treatment response between the tumor etiologies and TMB levels. In addition to ICI therapy, other treatments that induce apoptosis, such as milademetan, have demonstrated positive responses in MCPyV-positive MCC, with few somatic mutations and wild-type TP53."

Review • Merkel Cell Carcinoma

MANTRA-2: Milademetan in Advanced/Metastatic Solid Tumors (clinicaltrials.gov) - P2 | N=40 | Terminated | Sponsor: Rain Oncology Inc | N=65 ➔ 40 | Trial completion date: Aug 2024 ➔ Oct 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2024 ➔ Oct 2023; Sponsor Decision

Enrollment change • Metastases • Pan tumor • Trial completion date • Trial primary completion date • Trial termination • Adrenal Cortex Carcinoma • Biliary Cancer • Bladder Cancer • Breast Cancer • Cervical Cancer • Cholangiocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Germ Cell Tumors • Head and Neck Cancer • Hepatology • Lung Adenocarcinoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Sarcoma • Solid Tumor • Testicular Cancer • Urothelial Cancer • MDM2 • TP53