Background: This study further evaluated the safety and efficacy of the combination of alisertib and sapanisertib in an expansion cohort of patients, including a subset of patients with refractory pancreatic adenocarcinoma, with further evaluation of the pharmacodynamic characteristics of combination therapy. Methods: Twenty patients with refractory solid tumors and 11 patients with pancreatic adenocarcinoma were treated at the recommended phase 2 dose of alisertib and sapanisertib. Adverse events and disease response were assessed. Patients in the expansion cohort were treated with a 7-day lead-in of either alisertib or sapanisertib prior to combination therapy, with tumor tissue biopsy and serial functional imaging performed for correlative analysis. Results: Toxicity across treatment groups was overall similar to prior studies. One partial response to treatment was observed in a patient with ER positive breast cancer, and a patient with pancreatic cancer experienced prolonged stable disease. In an additional cohort of pancreatic cancer patients, treatment response was modest. Correlative analysis revealed variability in markers of apoptosis and immune cell infiltrate according to lead-in therapy and response. Conclusions: Dual targeting of Aurora A kinase and mTOR resulted in marginal clinical benefit in a population of patients with refractory solid tumors, including pancreatic adenocarcinoma, though individual patients experienced significant response to therapy. Correlatives indicate apoptotic response and tumor immune cell infiltrate may affect clinical outcomes.
背景：本研究在扩展队列患者中进一步评估了阿利塞替与沙帕尼塞替联合用药的安全性和有效性，包括难治性胰腺腺癌患者亚组，并对联合治疗的药效学特征进行了深入评估。方法：20例难治性实体瘤患者和11例胰腺腺癌患者接受阿利塞替与沙帕尼塞替的推荐二期剂量治疗。对不良事件和疾病反应进行评估。扩展队列患者在联合治疗前接受为期7天的阿利塞替或沙帕尼塞替导入治疗，并进行肿瘤组织活检和系列功能成像以进行相关性分析。结果：各治疗组的毒性特征与既往研究总体相似。1例ER阳性乳腺癌患者观察到部分缓解，1例胰腺癌患者实现长期疾病稳定。在另一组胰腺癌患者中，治疗反应较为有限。相关性分析显示，根据导入治疗方案和治疗反应，凋亡标志物和免疫细胞浸润存在差异性。结论：在难治性实体瘤（包括胰腺腺癌）患者群体中，奥罗拉A激酶和mTOR的双重靶向治疗仅产生有限的临床获益，但个别患者对治疗表现出显著反应。相关性分析表明，凋亡反应和肿瘤免疫细胞浸润可能影响临床结局。
肿瘤(癌症)患者之家