Sarcoma Oncology Research Center, Santa Monica, CA, U.S.A.
Anticancer Res. 2023 May;43(5):1993-2002. doi: 10.21873/anticanres.16360.
BACKGROUND/AIM: Advanced sarcoma has a poor prognosis. Dysregulation of the mammalian target of rapamycin (mTOR) occurs in various types of cancer. We aimed to determine the safety and efficacy of mTOR inhibitor nab-sirolimus when combined with the immune checkpoint inhibitor nivolumab.
Previously treated patients ≥18 years with confirmed diagnosis of advanced sarcoma or tumor with mutations in the mTOR pathway were treated with 3 mg/kg nivolumab intravenously every 3 weeks; escalating doses of nab-sirolimus at 56, 75 or 100 mg/m were administered intravenously on days 8 and 15 beginning in cycle 2. The primary aim was to determine the maximum-tolerated dose; we also determined disease control, objective response, progression-free survival, overall survival, and correlation between response using Immune-related Response Evaluation Criteria for Solid Tumors (irRECIST) versus RECIST v1.1.
The maximum-tolerated dose was 100 mg/m There were two patients with partial response, 12 with stable disease and 11 with progressive disease. Median progression-free and overall survival were 12 and 47 weeks, respectively. The best responders (partial responses) were patients with undifferentiated pleomorphic sarcoma with loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), tuberous sclerosis complex 2 (TSC2) mutation and estrogen receptor-positive leiomyosarcoma. Treatment-related adverse events of grade 3 or more included thrombocytopenia, oral mucositis, rash, hyperlipidemia and increased serum alanine aminotransferase.
The data indicate that (i) treatment with nivolumab plus nab-sirolimus is safe with no unexpected adverse events; (ii) treatment outcome parameters were not improved by combining nivolumab with nab-sirolimus; and (iii) best responders were patients with undifferentiated pleomorphic sarcoma with PTEN loss and TSC2 mutation and estrogen receptor-positive leiomyosarcoma. Future direction in sarcoma research with nab-sirolimus will be biomarker-based (TSC1/2/mTOR, tumor mutational burden/mismatch repair deficiency etc.).
背景/目的：晚期肉瘤预后较差。哺乳动物雷帕霉素靶蛋白（mTOR）在各种类型的癌症中失调。我们旨在确定 mTOR 抑制剂依维莫司与免疫检查点抑制剂纳武单抗联合使用的安全性和疗效。
以前接受过治疗的年龄≥18 岁的晚期肉瘤或 mTOR 通路基因突变的肿瘤患者，每 3 周静脉注射 3mg/kg 纳武单抗；从第 2 周期开始，在第 8 天和第 15 天静脉注射递增剂量的依维莫司，分别为 56、75 或 100mg/m。主要目的是确定最大耐受剂量；我们还确定了疾病控制、客观反应、无进展生存期、总生存期，以及使用实体瘤免疫相关反应评估标准（irRECIST）与 RECIST v1.1 相比的反应相关性。
最大耐受剂量为 100mg/m。有 2 例患者部分缓解，12 例患者疾病稳定，11 例患者疾病进展。中位无进展生存期和总生存期分别为 12 周和 47 周。最佳反应者（部分缓解）为去磷酸化酶和张力蛋白同源物缺失于染色体 10（PTEN）缺失、结节性硬化症复合物 2（TSC2）突变和雌激素受体阳性平滑肌肉瘤的未分化多形性肉瘤患者。3 级或以上的治疗相关不良事件包括血小板减少症、口腔黏膜炎、皮疹、高脂血症和血清丙氨酸氨基转移酶升高。
数据表明：（i）纳武单抗联合依维莫司治疗安全，无意外不良事件；（ii）联合纳武单抗和依维莫司治疗并未改善治疗结局参数；（iii）最佳反应者为去磷酸化酶和张力蛋白同源物缺失于染色体 10（PTEN）缺失、结节性硬化症复合物 2（TSC2）突变和雌激素受体阳性平滑肌肉瘤的未分化多形性肉瘤患者。未来以依维莫司为基础的肉瘤研究方向将是基于生物标志物（TSC1/2/mTOR、肿瘤突变负担/错配修复缺陷等）。
