Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results from a Proof-of-Concept, Phase Ib Study

Purpose: Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53-MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy.

Patients and methods: In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A [4-week cycle: siremadlin once daily (QD) and ribociclib QD (2 weeks on, 2 weeks off)], Regimen B [3-week cycle: siremadlin once every 3 weeks; ribociclib QD (2 weeks on, 1 week off)], and Regimen C [4-week cycle: siremadlin once every 4 weeks; ribociclib QD (2 weeks on, 2 weeks off)]. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens.

Results: As of October 16, 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1-174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity.

Conclusions: Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.

 

Comments:

The purpose of the study you described was to investigate the combination of siremadlin, a p53-MDM2 inhibitor, and ribociclib, a CDK4/6 inhibitor, in patients with locally advanced or metastatic well-differentiated liposarcoma (WDLPS) or dedifferentiated liposarcoma (DDLPS). These types of liposarcoma are characterized by the co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes.

The study was a phase Ib dose-escalation trial, aiming to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in different treatment regimens. The regimens evaluated were:

- Regimen A: 4-week cycle with siremadlin administered once daily and ribociclib administered once daily for 2 weeks followed by a 2-week break.
- Regimen B: 3-week cycle with siremadlin administered once every 3 weeks and ribociclib administered once daily for 2 weeks followed by a 1-week break.
- Regimen C: 4-week cycle with siremadlin administered once every 4 weeks and ribociclib administered once daily for 2 weeks followed by a 2-week break.

A total of 74 patients were enrolled in the study, and the median duration of exposure to the combination therapy was 13 weeks, ranging from 1 to 174 weeks. Dose-limiting toxicities were observed in 10 patients, primarily consisting of Grade 3 or 4 hematologic events (related to the blood system). The recommended dose for expansion (RDE) was determined to be siremadlin 120 mg administered once every 3 weeks plus ribociclib 200 mg once daily (Regimen B).

In terms of efficacy, three patients achieved a partial response to the treatment, indicating a reduction in tumor size, while 38 patients achieved stable disease, indicating that the tumors did not progress further. Unfortunately, one patient in Regimen C died as a result of treatment-related hematotoxicity (toxicity affecting the blood system).

Overall, the combination of siremadlin and ribociclib demonstrated manageable toxicity and showed early signs of antitumor activity in patients with advanced WDLPS or DDLPS. However, it's important to note that these results were based on a phase Ib study, and further research is necessary to validate the findings and establish the safety and efficacy of this combination therapy.

Related Products

Cat.No.	Product Name	Information
S8606	Siremadlin (HDM201)	Siremadlin (HDM201) is a novel, highly potent and selective inhibitor of the p53-Mdm2 interaction with affinity constant for Mdm2 in the picomolar range and a selectivity ratio greater than 10000-fold vs Mdm4.

Related Targets

MDM2/MDMX