milademetan (RAIN-32)

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.

Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3 targeting strategies for FLT3-mutant AML.

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.

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.

These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.

Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.

P2, N=1, Terminated, 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

P2, N=48, Active, not recruiting, Institut Curie | Recruiting --> Active, not recruiting

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.

P2, N=40, Terminated, 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

P2, N=48, Recruiting, Institut Curie | Not yet recruiting --> Recruiting