Milademetan in Advanced Solid Tumors with MDM2 Amplification and Wild-type TP53: Preclinical and Phase II Clinical Trial Results

Purpose: Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that degrades the tumor suppressor p53. In cancers, MDM2 amplification (MDM2^amp) 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 MDM2^amp, 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 MDM2^amp, 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 MDM2^amp, 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 progressionfree 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 MDM2^amp, 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.