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Milademetan in Advanced Solid Tumors with MDM2 Amplification and Wild-type TP53: Preclinical and Phase II Clinical
Ecaterina E Dumbrava1, Thomas E Stinchcombe2, Mrinal Gounder3
1University of Texas MD Anderson Cancer Center, Houston, Texas.
Purpose:
Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that degrades the tumor suppressor p53. In cancers, MDM2 amplification (MDM2amp) leads to overexpression of MDM2, inducing p53 degradation and a p53-null phenotype even in the absence of TP53 mutations. We report here the preclinical and clinical activities of milademetan, a potent and selective oral small-molecule inhibitor of the MDM2-p53 interaction, in MDM2amp, TP53 wild-type (WT) solid tumors.
Patients And Methods:
Milademetan was tested against a variety of cell line and xenograft tumor models. This supported a phase II basket study (MANTRA-2) in patients with advanced MDM2amp, TP53-WT solid tumors. The primary endpoint was the objective response rate, and key secondary endpoints included progression-free survival and adverse events.
Results:
Milademetan showed potent activity against MDM2amp, TP53-WT laboratory models. In the phase II trial, 40 patients received milademetan, 31 of whom had centrally confirmed molecular testing. The best overall response was 19.4% (6/31) with one confirmed response (3.2%) and five unconfirmed partial responses, including a patient with endometrial stromal sarcoma who achieved a 100% target lesion reduction. The median progression-free survival was 3.5 months (95% confidence interval, 1.8-3.7). Grade 3 or 4 adverse events observed included thrombocytopenia, neutropenia, anemia, leukopenia, and diarrhea.
Conclusion:
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 efforts should focus on combination strategies, further biomarker refinement, or novel MDM2 targeting approaches to achieve more durable clinical benefit.
Insights
Milademetan showed activity in MDM2-amplified, TP53-wildtype solid tumors, but responses were short-lived. Future research should explore combination therapies or earlier treatment for sustained clinical benefit.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- MDM2 amplifies in cancers, degrading the tumor suppressor p53, leading to a p53-null phenotype.
- This occurs even without TP53 mutations, highlighting MDM2 as a therapeutic target.
Purpose of the Study:
- To evaluate the pre-clinical and clinical activity of milademetan, an oral MDM2-p53 inhibitor.
- To assess milademetan's efficacy in MDM2-amplified, TP53-wildtype solid tumors.
Main Methods:
- Milademetan was tested in laboratory models and a Phase II basket study (MANTRA-2) of patients with advanced MDM2amp, TP53-wt solid tumors.
- Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and adverse events.
Main Results:
- Milademetan demonstrated potent activity in preclinical models.
- In the Phase II trial (n=40), the ORR was 19.4% (6/31), with one confirmed partial response and five unconfirmed partial responses.
- Median PFS was 3.5 months, and common Grade 3/4 adverse events included thrombocytopenia and neutropenia.
Conclusions:
- Milademetan exhibited a manageable safety profile and induced responses in refractory MDM2amp, TP53-wt solid tumors.
- Observed tumor reductions were transient, suggesting a need for combination strategies or earlier intervention for durable benefit.
