Milademetan in Advanced Solid Tumors with <i>MDM2</i> Amplification and Wild-type <i>TP53</i>: Preclinical and Phase II Clinical Trial Results
Ecaterina E. Dumbrava, Thomas E. Stinchcombe, Mrinal M. Gounder, Gregory M. Coté, Glenn J. Hanna, Bradley Sumrall, Trisha M. Wise‐Draper, Mohammed Kanaan, Steven M. Duffy, Christopher Sumey, Patrick Cobb, Andre Neil Forbes, Aviva G. Beckmann, Eric E. Schadt, Nora Ku, Vijaya G. Tirunagaru, Kanchan Singh, Xinyu Pei, Feng Xu, Robert C. Doebele, Christopher T. Chen
Abstract
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.