Clinical activity and exploratory resistance mechanism of milademetan, an MDM2 inhibitor, in intimal sarcoma with MDM2 amplification: an open-label phase 1b/2 study.

Intimal sarcoma is an extremely rare life-threatening malignant neoplasm. Murine double minute 2 (MDM2) amplification is observed in > 70% of intimal sarcomas. Milademetan, an MDM2 inhibitor, may provide a clinical benefit in this patient population. We conducted a phase 1b/2 study in patients with MDM2-amplified wild-type TP53 intimal sarcoma as a sub-study of a large nationwide registry for rare cancers in Japan. Milademetan (260 mg) was administered orally once daily for three days every 14 days, twice in a 28-day cycle. Of 11 patients enrolled, 10 were included in the efficacy analysis. Two patients (20%) showed durable responses for >15 months. Anti-tumor activity correlated with TWIST1 amplification (P = 0.028) and negatively with CDKN2A loss (P = 0.071). Acquired TP53 mutations were detected in sequential liquid biopsies as a novel exploratory resistance mechanism to milademetan. These results suggest that milademetan could be a potential therapeutic strategy for intimal sarcoma.