Blueprint Medicines Corporation announced updated data from the ongoing Phase 1 dose escalation portion of the VELA clinical trial of BLU-222, an investigational, highly selective and potent CDK2 inhibitor, in combination with ribociclib and fulvestrant in patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The data, which mark the first promising clinical results for a CDK2 inhibitor in combination with an approved CDK4/6 inhibitor, will be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting on June 2, 2024. Updated Phase 1/2 VELA Trial Results: Based on previously reported positive BLU-222 monotherapy clinical data, a combination dose escalation arm was initiated in the VELA trial to assess the safety and clinical activity of BLU-222 in combination with ribociclib, a CDK4/6 inhibitor approved by the U.S. Food and Drug Administration for advanced or metastatic HR+/HER2- breast cancer, and fulvestrant, a commonly used estrogen receptor antagonist.

As of the data cutoff date, 19 patients with HR+/HER2- breast cancer who had progressed on prior CDK4/6 inhibitors were treated with 100 mg to 400 mg twice daily (BID) of BLU-222 plus 400 mg once daily (QD) of ribociclib and combined with fulvestrant. The combination of BLU-222, ribociclib, and fulvestrant was well-tolerated at all BLU-222 dose levels tested. No dose-limiting toxicities, treatment-related severe adverse events (SAEs), or BLU-222-related treatment discontinuations were reported.

Treatment-related hematologic and gastrointestinal AEs were generally mild. The maximum tolerated combination dose has not been identified, and combination dose escalation is ongoing. Pharmacokinetic data showed dose-proportional exposures of BLU-222, with sustained coverage above the predicted efficacious concentration at the 400 mg BID dose level.

In addition, the combination of BLU-222 with ribociclib and fulvestrant had no clinically meaningful impact on individual drug exposures. Preliminary clinical activity showed compelling reductions in thymidine kinase 1 (TK1) and circulating tumor DNA (ctDNA), biomarkers that have been shown to be predictive of clinical benefit. TK1, a biomarker of tumor proliferation, had the deepest reduction among patients treated with BLU-222 400 mg BID, ribociclib 400 mg QD, and combined with fulvestrant, and was statistically significantly correlated with BLU-222 exposure.

All patients with evaluable ctDNA, a biomarker of tumor burden, treated with the BLU-222 400 mg BID combination dose regimen showed ctDNA reductions. Early evidence of clinical benefit includes an unconfirmed partial response in a patient who had previously progressed following six lines of therapy in the metastatic setting, including prior palbociclib and trastuzumab deruxtecan. These data highlight the impact of CDK2 inhibition when BLU-222 is combined with other therapies.