CFI-402257 + fulvestrant

CFI-402257 + fulvestrant is a combination therapy being investigated for the treatment of advanced solid tumors, particularly estrogen receptor-positive (ER+), HER2-negative advanced breast cancer. This combination consists of CFI-402257, a potent and selective TTK (also known as Mps1) inhibitor, and fulvestrant, an established estrogen receptor antagonist. ## Mechanism of Action CFI-402257 is a potent TTK/Mps1 (Monopolar spindle 1) kinase inhibitor with a Ki value of 0.09 nM and cellular IC50 of 6.5 nM[9]. TTK is a dual-specificity serine-threonine kinase critical for the spindle assembly checkpoint (SAC), which is a genome-surveillance mechanism that ensures proper chromosome alignment and error correction during mitosis[9]. Inhibition of TTK causes premature mitotic exit with unattached chromosomes, resulting in chromosomal missegregation, aneuploidy, and ultimately cell death[9]. When combined with fulvestrant (an estrogen receptor antagonist), this therapy targets both cell cycle regulation and estrogen receptor signaling pathways in ER+/HER2- breast cancer cells. ## Clinical Development The FDA granted fast track designation to CFI-402257 both as a single agent and in combination with fulvestrant for patients with ER+/HER2- advanced breast cancer who have progressed on previous CDK4/6 inhibitors and endocrine therapy[3][5]. This designation was granted in January 2023, highlighting the unmet medical need in this patient population[2][3]. A Phase 1 clinical trial (NCT05251714) is evaluating CFI-402257 as a single agent in advanced solid tumors and in combination with fulvestrant in patients with ER+/HER2- advanced breast cancer[5]. The study is expected to be completed by August 2025[5]. ## Clinical Results In clinical studies, CFI-402257 has demonstrated a tolerable safety profile at the recommended Phase 2 dose of 168 mg once daily, with manageable dose-dependent neutropenia being the primary toxicity[8]. In a heavily pre-treated population (N=86), the overall response rate was 6% for monotherapy patients (4/66) and 10% for ER+/HER2- breast cancer patients treated in combination with fulvestrant (2/20)[8]. The most frequent grade 3 or higher treatment-emergent adverse effects in the single-agent and combination arms included anemia, neutropenia, and febrile neutropenia[3]. The combination has shown early signs of durable activity with a manageable safety profile in ER+/HER2- breast cancer patients who have failed CDK4/6 inhibitors[2][3][5]. ## Development Status This combination therapy represents a promising approach for patients with ER+/HER2- advanced breast cancer, particularly those who have progressed on prior CDK4/6 inhibitors and endocrine therapy, where there remains a significant unmet medical need.