Siontis Brittany L, Rice John D, Schuetze Scott M, Rottmann Douglas, Angeles Christina V, Fox Amanda K, Zyczynski Laurie E, Hayek Salim, Robinson Steven I, Okuno Scott H, Ho Thanh P, Chugh Rashmi
Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
Clin Cancer Res. 2025 Jul 15;31(14):2919-2925. doi: 10.1158/1078-0432.CCR-25-0298.
Soft-tissue sarcomas are rare malignancies with poor prognosis and limited systemic treatment options. We conducted a phase II study to assess the efficacy and safety of trabectedin and olaparib in patients with advanced disease.
Patients with soft-tissue sarcoma who received ≥1 prior therapy were recruited into two cohorts. Cohort 1 included leiomyosarcoma and liposarcoma; cohort 2 included other histologies. All patients received trabectedin (1.1 mg/m2 24-hour infusion every 21 days) and olaparib (150 mg twice daily continuously). The study was conducted using a Simon minimax two-stage design with a primary endpoint of objective response (OR) rate per RECIST 1.1.
Twenty-nine (cohort 1, 16; cohort 2, 13) patients enrolled; one patient in cohort 2 was not evaluable. There were no confirmed ORs in cohort 1; the best response was stable disease in 12 (75%) patients and progressive disease in four (25%). Two partial responses were observed in cohort 2 (n = 12). The most common adverse events were fatigue (75%), neutropenia (75%), anemia (68%), and thrombocytopenia (68%). The median progression-free survival and overall survival for all patients were 3.5 (95% confidence interval, 3.3-8.2) and 13.2 months (95% confidence interval, 10.3-20.9), respectively. Next-generation sequencing of 17 tumors revealed multiple abnormalities, most commonly in TP53, RB1, and ATRX.
Trabectedin plus olaparib conferred high rates of toxicity and failed to demonstrate ORs in leiomyosarcoma and liposarcoma. Preliminary evidence of clinical benefit in two patients in cohort 2 suggests potential value of either or both drugs in other sarcomas.
软组织肉瘤是一种罕见的恶性肿瘤，预后较差，全身治疗选择有限。我们开展了一项II期研究，以评估曲贝替定和奥拉帕利对晚期疾病患者的疗效和安全性。
接受过≥1次既往治疗的软组织肉瘤患者被纳入两个队列。队列1包括平滑肌肉瘤和脂肪肉瘤；队列2包括其他组织学类型。所有患者接受曲贝替定（1.1mg/m²，每21天进行1次24小时静脉输注）和奥拉帕利（150mg，每日2次，持续给药）。该研究采用Simon最小最大两阶段设计，主要终点为根据RECIST 1.1标准评估的客观缓解（OR）率。
29例患者入组（队列1，16例；队列2，13例）；队列2中有1例患者无法评估。队列1中未观察到确认的OR；最佳疗效为12例（75%）患者病情稳定，4例（25%）患者疾病进展。队列2中观察到2例部分缓解（n = 12）。最常见的不良事件为疲劳（75%）、中性粒细胞减少（75%）、贫血（68%）和血小板减少（68%）。所有患者的中位无进展生存期和总生存期分别为3.5个月（95%置信区间，3.3 - 8.2）和13.2个月（95%置信区间，10.3 - 20.9）。对17个肿瘤进行的二代测序显示存在多种异常，最常见于TP53、RB1和ATRX。
曲贝替定联合奥拉帕利毒性发生率高，在平滑肌肉瘤和脂肪肉瘤中未显示出OR。队列2中2例患者有临床获益的初步证据表明这两种药物中的一种或两种在其他肉瘤中可能具有潜在价值。
