**14.2 Immune checkpoint therapy and CDK4/6 (CDK4/6) inhibitors in combination therapy**

In patients with ER-positive, HER2-negative metastatic breast cancers, pharmacological inhibitors of CDK4/6 have demonstrated remarkable activity [91–93]. Inhibitors of CDK4/6 have been demonstrated to improve anti-tumor immune response in preclinical models by manipulating two main immune evasion mechanisms in tumors [94–96]. First, CDK4/6 inhibitors elevate intracellular levels of double-stranded RNA by activating tumor cell expression of endogenous retroviral components. As a result, type III interferon synthesis is stimulated, which in turn improves tumor antigen presentation. Secondly, CDK4/6 inhibitors significantly reduce regulatory T-cell proliferation. Finally, these events facilitate tumor cell clearance by cytotoxic T cells, which can be intensified even further by the introduction of an immune checkpoint inhibitor. Abemaciclib in conjunction with pembrolizumab was studied in patients with HER2-, HR+, MBC in a phase I trial (JPBJ, NCT02079636). The main objective of the study was to determine the combination therapy's safety profile. A total of 28 patients were enrolled in the study. At the end of 24 weeks, four patients (14%) showed an analytical response. At the appropriate early time intervals in the MONARCH 1 analysis, this response was greater than the response shown by patients treated with abemaciclib monotherapy [97].
