Milademetan in advanced solid tumors with MDM2 amplification and wild-type TP53: pre-clinical and phase 2 clinical trial results.

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 pre-clinical and clinical activity of milademetan, a potent and selective oral small molecule inhibitor of the MDM2-p53 interaction, in MDM2amp, TP53-wildtype (wt) solid tumors. 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 objective response rate (ORR), and key secondary endpoints included progression-free survival (PFS) and adverse events. Milademetan showed potent activity against MDM2amp, TP53-wt laboratory models. In the phase II trial, 40 patients received milademetan, of whom 31 had centrally confirmed molecular testing. The best overall response was 19.4% (6/31) with 1 confirmed response (3.2%) and 5 unconfirmed partial responses, including a patient with endometrial stromal sarcoma who achieved 100% target lesion reduction. The median PFS was 3.5 months (95% CI:1.8, 3.7). Grade 3 or 4 adverse events observed included thrombocytopenia, neutropenia, anemia, leukopenia, and diarrhea. 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 MDM2 inhibitor efforts should focus on combination strategies or treatment in earlier lines of therapy to achieve more durable clinical benefit.