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

Abstract

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.

Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma

“…conducted a phase Ib proof-of-concept trial in which patients with advanced WDLPS and DDLPS received concomitant siremadlin, a selective MDM2 inhibitor, with ribociclib, a selective CDK4/6 inhibitor. In this study, no patients achieved complete response and three patients achieved partial response ( 202 ). The overall disease control rate remained poor at 27% among the cohort, and one patient died of treatment related hematotoxicity.…”

New targeted treatments for advanced sarcomas

“…Despite the initial hype about the role of MDM2 inhibitor in well differentiated and DDLPS, the development of MDM2 inhibitors was hampered by the difficulty to reach an optimal dosing regimen to mitigate the bone marrow suppression side effects of MDM2 inhibitors [16]. Continuous dosing, pulsed dosing or interrupted dosing have all been tested, but it seemed that each different drug has its own optimal way of dosing [12,17,18 ▪ ]. At present, there are two MDM2 inhibitors in the process of late-stage development for liposarcoma.…”

“…Inhibition of MDM2 and CDK4 simultaneously is a rationale strategy for liposarcoma patients. However, the development of combination of siremadlin, an MDM2 inhibitor, with ribociclib, a CDK4/6 inhibitor was again slowed by the need to test multiple dosing regimens to mitigate the side effects of bone marrow suppression [18 ▪ ]. Eventually, an optimal dosing regimen was reached, and among 74 well differentiated and DDLPS patients, there were three and 38 patients with PR and stable disease (SD), respectively, to the combination treatment [18 ▪ ].…”

Deciphering the Prognostic and Therapeutic Significance of Cell Cycle Regulator CENPF: A Potential Biomarker of Prognosis and Immune Microenvironment for Patients with Liposarcoma

“…Although these treatments provide good controls of the local lesions, remote recurrence occurs in 40% to 50% of patients indicating that the disease is progressing [ 6 ]. In addition to traditional treatment methods, targeted therapy is gradually applied in clinical practice [ 7 ]. However, bridging the gap in terms of therapeutic needs, even though several potential biomarkers have been proposed to monitor LPS progression, such as miR-145 , miR-451 [ 8 ], MDM2 [ 9 ] and CDK4 [ 10 ], is still required.…”