An evaluation of abemaciclib activity in combination with sunitinib in renal cell carcinoma.

Abstract

452 Background: The majority of therapeutic agents used in renal cell carcinoma (RCC) target the vascular endothelial growth factor and mammalian target of rapamycin pathway. Exceptions include the immunotherapy agents interleukin-2 and nivolumab. To change the natural history of RCC and improve upon current treatment regimens we believe new therapeutic targets are necessary. CDK4/6 and PIM1 kinase have both been identified as possible therapeutic targets in RCC. Abemaciclib is a potent inhibitor of both CDK4/6 and PIM1 kinases. We have demonstrated that abemaciclib causes increased apoptosis and decreased cellular viability in RCC cell lines and tumor responses in mice (submitted). Here we report the results of an additional pre-clinical study of the effects of abemaciclib alone and in combination with sunitinib. Methods: Tumors were established in nude mice by subcutaneous flank injection of 786-O cells. Tumors were allowed to establish and grow to about 1 cm. Mice were treated by oral gavage with vehicle, sunitinib, abemaciclib, or combination. Tumors were measured with calipers to determine response. Mice that received sunitinib were subsequently treated with combination therapy and response determined by caliper measurement. At the conclusion of the course of treatment mice were euthanized and the tumors removed, weighed, fixed, and embedded in paraffin. Results: Mice treated with vehicle had continued tumor growth during the course of therapy. Mice treated with sunitinib showed mostly disease stabilization, paralleling the response seen in clinic. Mice in the abemaciclib cohort showed gradual decline in tumor size over the course of treatment. Mice in the combination therapy cohort exhibited a rapid reduction in tumor size with sustained response. Interestingly mice in the sunitinib cohort experiencing stable disease or growing tumor had rapid decrease in tumor size with the initiation of combination therapy. Conclusions: Abemaciclib is active in a mouse model of RCC. The combination of abemaciclib/sunitinib causes rapid reduction in tumor size in treatment naïve and sunitinib pre-treated mice. These data support the use of combination abemaciclib/sunitinib therapy in a human clinical trial.