TPS771 Background: Over the last few years there has been a rapid increase in the clinically relevant agents available to treat metastatic renal cell carcinoma (mRCC). We note, however, that the vast majority of new agents available for mRCC do not exploit new clinical targets or pathways. We believe that the identification of new, clinically relevant targets in RCC will propel the field even further forward, expand treatment options, and lead to improved survival for mRCC patients. SGI-1776, a selective PIM1 kinase inhibitor, has previously been shown to induce reduction in tumor size as monotherapy and in combination with sunitinib in mouse pre-clinical studies of RCC. In our tissue microarray studies a subset of ~26% of RCC showed high staining for PIM1 kinase while only 1% of normal adjacent tissue showed similar high staining. Wildtype PIM1 is constitutively active, thus these data suggest that PIM1 activity is increased in a subset of RCC. Abemaciclib is a potent CDK4/6 inhibitor with an IC50 of 2 and 10 nM, respectively. It is also a potent PIM1 inhibitor with an IC50 of 50 nM. We have shown that abemaciclib decreases cell viability and increases apoptosis in RCC cell lines, and does so at greatest effect in combination with sunitinib. We have also shown that abemaciclib induces regression of RCC tumors in a mouse model of RCC, with the most rapid responses observed when abemaciclib is combined with sunitinib. Based on these data we have opened a phase Ib dose escalation study to determine the safety and tolerability of abemaciclib in combination with sunitinib in patients with mRCC. The study includes an expansion cohort at the recommended phase II dose to evaluate for a signal for efficacy. Pattern and intensity of PIM1 staining in tumor tissue will be evaluated as a potential biomarker of response. We are also collecting blood and urine to evaluate additional potential biomarkers of response. Methods: Clinical trial information: NCT03905889 .[Table: see text]
Review: Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions
