Abstract：
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 clinical benefit in this patient population. We conducted a phase Ib/II study in patients with MDM2-amplified, wild-type TP53 intimal sarcoma as a substudy of a large nationwide registry for rare cancers in Japan. Milademetan (260 mg) was administered orally once daily for 3 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. Antitumor 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.
Strategies to optimize outcomes could include the use of new biomarkers (TWIST1 amplification and CDKN2A loss) to select patients with MDM2-amplified intimal sarcoma who might benefit from milademetan and combination with other targeted treatments. Sequential liquid biopsy of TP53 can be used to evaluate disease status during treatment with milademetan. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749.
Strategies to optimize outcomes could include the use of new biomarkers (TWIST1 amplification and CDKN2A loss) to select patients with MDM2-amplified intimal sarcoma who might benefit from milademetan and combination with other targeted treatments. Sequential liquid biopsy of TP53 can be used to evaluate disease status during treatment with milademetan. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749.
摘要：
内膜肉瘤是一种极其罕见的危及生命的恶性肿瘤。在>70%的内膜肉瘤中观察到鼠双2分钟(MDM2)扩增。Milademetan,MDM2抑制剂，可能在该患者群体中提供临床益处。我们在MDM2扩增的野生型TP53内膜肉瘤患者中进行了1b/2期研究，作为日本全国罕见癌症大型注册的子研究。Milademetan（260mg）每天口服一次，每14天连续三天，在28天周期内两次。在11名患者中，10个被包括在功效分析中。两名患者(20%)表现出>15个月的持久反应。抗肿瘤活性与TWIST1扩增相关(P=0.028),与CDKN2A丢失负相关(P=0.071)。在连续的液体活检中检测到获得的TP53突变，这是对milademetan的一种新的探索性抗性机制。这些结果表明，milademetan可能是内膜肉瘤的潜在治疗策略。
