BLU-222, an investigational, oral, potent, and highly selective CDK2 inhibitor (CDK2i), as monotherapy in patients (pts) with advanced solid tumors and in combination with ribociclib (RIBO) and fulvestrant (FUL) in HR+/HER2− breast cancer (BC).

1056 Background: CDK2 is implicated in CDK4/6 inhibitor (CDK4/6i) resistance in hormone receptor-positive/human epidermal growth factor receptor-2–negative (HR+/HER2−) BC. In addition, amplification and overexpression of cyclin E1 gene ( CCNE1), which leads to hyperactivation of cyclin E/CDK2 and CDK2 dependence, is associated with shorter survival in multiple aggressive cancers. CDK2 inhibition is thus an attractive novel anticancer approach. BLU-222 is an investigational, oral, potent, selective CDK2i in clinical development showing promise as a monotherapy and combination therapy. Methods: VELA (NCT05252416) is an international, open-label, phase 1/2 study evaluating BLU-222 safety and efficacy through dose escalation following a Bayesian Optimal Interval design. BLU-222 BID was administered in continuous 28-day cycles as monotherapy or in combination with RIBO + FUL. In monotherapy cohorts, pts with advanced relapsed/recurrent cancer were enrolled regardless of CCNE1 status. A combination cohort enrolled pts with HR+/ HER2− BC whose disease had progressed after treatment with a CDK4/6i. Results: As of January 22, 2024, 64 pts were included in the safety population: 53 in monotherapy cohorts (50-800 mg BID), 11 in the combination cohort (100-200 mg BID + 400 mg RIBO + 500 mg FUL). Median age was 63 y (range, 21-85); 88% were female. Most frequent cancer types in monotherapy cohorts were BC (32%, 17/53), ovarian (21%, 11/53), endometrial (8%, 4/53), and uterine (8%, 4/53). Pts had a median of 5 prior lines of therapy (LoT). Maximum tolerated dose had not been reached as of the data cutoff. With monotherapy, the most common treatment-emergent adverse events (TEAEs; ≥15%) included gastrointestinal events (nausea, diarrhea, vomiting), fatigue, anemia, photophobia, and hypokalemia. Dose-limiting toxicities occurred in 2 pts, 1 with grade 3 nausea at 800 mg BID and 1 with grade 3 blurred vision/photophobia at 600 mg BID; both improved after dose reduction. Increasing doses of BLU-222 monotherapy were associated with decreased TK1 activity and pRb. Eleven HR+/HER2− BC pts with a median of 5 prior LoT received BLU-222 with RIBO + FUL but have limited follow-up. The initial cohort of BLU-222 with RIBO + FUL was well tolerated. Updated combination data will be presented at the meeting. Conclusions: BLU-222 monotherapy was generally well tolerated in unselected heavily pretreated pts. In addition to encouraging safety, markers of cell cycle modulation and antitumor activity were seen. The initial cohort of BLU-222 with RIBO + FUL exhibited no additional safety concerns. Together, these data demonstrate the clinical potential of BLU-222 in CDK2-vulnerable tumors. Enrollment is ongoing for dose escalation and optimization. Clinical trial information: NCT05252416 .