CDK2 is implicated in CDK4/6 inhibitor (CDK4/6i) resistance in HR+/HER2− breast cancer. Furthermore, amplification and overexpression of the cyclin E1 gene (CCNE1), which results in hyperactivation of cyclin E/CDK2 and CDK2 dependency, has been linked to lower survival in a variety of aggressive cancer types. CDK2 inhibition is thus a promising new anticancer strategy. BLU-222 is an investigational, oral, potent, selective CDK2i in clinical development showing promise as a monotherapy and combination therapy.

Blueprint Medicines' BLU-222 is gaining traction in oncology as a promising CDK2 inhibitor, particularly in HR+/HER2- breast cancer and other malignancies where CDK2 dysregulation is a major factor. The lifting of the partial clinical hold by the US FDA is a big step forward, suggesting that the safety concerns about BLU-222 have been appropriately addressed. The decision to pursue a partnership for BLU-222 in HR+/HER2- breast cancer exemplifies Blueprint Medicines' strategic approach of leveraging external expertise and resources to enhance the potential of its therapeutic concepts. However, the competitive landscape in the CDK2 inhibitor space presents a challenge, as several other companies are also advancing their candidates targeting this pathway.  According to DelveInsight, the total number of incident cases of HR+/HER2– breast cancer in the United States was 208,000 in the US. The results presented at ASCO 2024 were as follows:

Safety Result: 

As of April 10, 2024, 75 patients were included in the safety population. 56 in monotherapy cohorts and the combination cohort (BLU-222 + ribociclib + fulvestrant)

• BLU-222 with ribociclib and fulvestrant combination therapy was well tolerated in patients with HR+/HER2- breast cancer, with no BLU-222-related dose discontinuations, only low-grade GI toxicity and low-frequency hematologic toxicity

• BLU-222 in combination with ribociclib and fulvestrant resulted in compelling reductions in TK1 and ctDNA, with a statistically significant correlation of TK1 reduction with BLU-222 exposure level

KOL insights

“Updated Phase I dose escalation data from ongoing Phase I/II study of BLU-222 as a monotherapy in heavily pretreated, advanced cancers in combination with ribociclib and fulvestrant in HR+/HER2- breast cancer after progression on CDK4/6i was well tolerated.” –Expert Opinion.

“BLU-222 is an investigational, oral, potent, and highly selective CDK2 inhibitor (CDK2) with demonstrated activity as monotherapy and combination treatment in preclinical models of HR+/HER2-breast cancers and CCNE1-amplified solid cancers.”–Expert Opinion.

Conclusion- 

CDK2 is implicated in CDK4/6 inhibitor (CDK4/6) resistance in HR+/HER2− breast cancer. Dependency on CDK2 is also linked to a variety of other aggressive cancers. CDK2 dependency has also been connected to a number of other aggressive malignancies. CDK2 inhibition combined with CDK4/6 and endocrine therapy is a promising therapeutic strategy for treating or preventing CDK4/6 resistance in HR+/HER2-breast tumors. BLU-222 monotherapy was generally well tolerated in unselected heavily pretreated patients. In addition to encouraging safety, signs of cell cycle regulation and anticancer activity were detected. The initial cohort of BLU-222 with ribociclib + fulvestrant revealed no new safety concerns. These findings highlight BLU-222's therapeutic promise in CDK2-vulnerable malignancies. Enrollment is ongoing for dose escalation and optimization of BLU-222 in combination with 400 mg and 600 mg dose levels of ribociclib with fulvestrant. Dose confirmation cohorts for the combination with ribociclib and letrozole are planned.