Abstract 4181: CDK4/6 inhibition with Abemaciclib improves intracranial and extracranial response to checkpoint blockade in pre-clinical models of brain metastasis

Abstract While immune checkpoint inhibitors (ICI) have revolutionized treatment of advanced cancers, few of the 30% of cancer patients who develop brain metastases benefit from immunotherapy. Inhibition of CDK4/6 pathway - altered in >50% of brain metastatic patients - can reportedly increase tumor inflammation and sensitize extracranial tumors to ICI. To determine whether intracranial tumors can be similarly sensitized, we studied efficacy of combination CDK4/6 inhibitor Abemaciclib and ICI in immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial murine tumors that are ICI-resistant. 8-week-old female C57BL/6 mice received subcutaneous injections of 2x105 YUMM1.7 or B16-F10 melanoma cells 3 days prior to intracranial injections of 1x104 YUMM1.7-FmC (firefly luciferase-tagged) cells or 5x103 B16-F10 cells respectively. 8-week-old female BALB/C mice similarly received 2x105 4T1 mammary carcinoma cells in mammary fat pad 3 days prior to intracranial injections with 2x104 4T1-FmC cells. Mice were randomized into 4 treatment groups (n=5-7/group): Abemaciclib monotherapy (administered daily), anti-PD-1 monotherapy (every 3 days), Abemaciclib and anti-PD-1 (combination therapy), and treatment with vehicle and isotype-matched antibody as control. In all 3 tumor models, extracranial tumor growth was significantly reduced compared to control mice following combination therapy (P<0.05 for all), while Abemaciclib monotherapy only reduced growth of subcutaneous YUMM1.7 tumors (P<0.05). Intracranial tumor growth, calculated using bioluminescence imaging early-in-treatment and post-treatment, was significantly reduced compared to control-treated tumors following combination therapy in both YUMM1.7-FmC and 4T1-FmC models (P<0.05 for both). In mice bearing B16-F10 tumors, where overall survival was used as an indirect measure of intracranial tumor growth, combination therapy improved survival (p<0.05) compared to both control and Abemaciclib monotherapy arms. These results indicate CDK4/6 inhibition with Abemaciclib can improve both extracranial and intracranial responses to ICI and sensitize brain metastases to immunotherapy. Our pre-clinical findings warrant further investigation to determine whether this combination approach can improve patient outcomes. Citation Format: Naema Nayyar, Mohini Singh, Magali de Sauvage, Nazanin Ijad, Ashish Dahal, Jane Chuprin, Michael Brehm, Priscilla Brastianos. CDK4/6 inhibition with Abemaciclib improves intracranial and extracranial response to checkpoint blockade in pre-clinical models of brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4181.