BLU-222 + fulvestrant

**BLU-222 + fulvestrant** is a combination therapy under investigation primarily for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. BLU-222 is a highly selective and potent cyclin-dependent kinase 2 (CDK2) inhibitor developed by Blueprint Medicines, designed to overcome resistance to CDK4/6 inhibitors, which is common in HR+/HER2- breast cancer. Fulvestrant is a selective estrogen receptor degrader (SERD) that antagonizes and degrades the estrogen receptor. Preclinical and emerging clinical evidence indicate that combining BLU-222 with endocrine therapy such as fulvestrant has synergistic antitumor activity, especially in tumors resistant to standard CDK4/6 inhibitor therapy. BLU-222 works by inhibiting aberrant CDK2 activity (often driven by CCNE1 amplification), thus restoring control of the cell cycle and reducing tumor proliferation. Early clinical investigations are ongoing, often in combination with both fulvestrant and a CDK4/6 inhibitor (such as ribociclib), and suggest the combination is generally well tolerated with signals of antitumor activity[1][3][5].