A Phase Ib Expansion Cohort Evaluating Aurora A Kinase Inhibitor Alisertib and Dual TORC1/2 Inhibitor Sapanisertib in Patients with Advanced Solid Tumors

Simple Summary Drugs that target Aurora A kinase as a treatment for cancer can lead to activation of the PI3K/AKT/mTOR pathway and ultimately resistance to treatment. We evaluated the preliminary efficacy of the addition of an inhibitor of this pathway (TORC1/2 inhibitor sapanisertib) to Aurora A kinase inhibitor alisertib in patients with advanced solid cancers, including a group with pancreatic adenocarcinoma. Select patients experienced prolonged stabilization of their cancers when treated with this combination therapy, including two with pancreatic cancer. To explore potential differences in response to this therapy, changes in the tumor tissues and immune system were evaluated, as were changes in imaging that can evaluate tumor activity. The genetic make-up of the tumor as well as spread of cancer to the liver may contribute in this setting.Abstract 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.