Background: BPI-16350 is a highly potent CDK4/6 inhibitor, and has a similar structure to abemaciclib but with less inhibition of CDK9 in pre-clinical experiments. This is an open-label, dose-escalation and -expansion phase I study to evaluate the safety, pharmacokinetics, and preliminary antitumor activity of BPI-16350 as monotherapy (Part A) and combined treatment with fulvestrant (FUL) in pts with HR+/HER2- MBC (Part B). Methods: In Part A, patients (pts) who had failed standard therapies were eligible to receive BPI-16350 in a standard 3+3 pattern at doses ranging from 50−500 mg QD. In Part B, BPI-16350 (300 mg or 400 mg QD) plus intramuscular FUL was administered in pts who had experienced secondary endocrine resistance. Pts in this part should have received no more than one line of chemotherapy for metastatic disease and no prior therapies with other CDK4/6 inhibitors, FUL or everolimus. Results: As of 13 November 2022, 24 pts were enrolled in Part A (50 mg, n=4; 100 mg, n=4; 200 mg, n=3; 300 mg, n=3; 400 mg, n=4; 500 mg, n=6), including 23 pts with MBC and one pt with abdominal liposarcoma. 66.7% (16/24) of pts had received ≥ 2 lines of chemotherapies and 70.8% (17/24) had received ≥ 2 lines of endocrine therapies. Only one dose-limiting toxicity event (i.e. Grade 3 blood creatinine increased) was observed at 500 mg dose, and the maximum tolerated dose was not reached. Grade ≥ 3 AEs occurred in 45.8% (11/24) of pts, with the most common being diarrhea (4/24), anemia (3/24), and neutropenia (2/24). The median time to peak concentration for BPI-16350 was 2.0-17.0 hours, and the mean half-life was 35.6-51.0 hours, supporting once-daily dosing. After a single oral dose of 50–500 mg of BPI-16350, the drug exposure was dose-proportional. With a QD dosing regimen, accumulation was 2.1–3.3 fold. The disease control rate (DCR) was 70.8% (17/24, 95% CI: 48.9%-87.4%). One pt (4.2%) achieved a partial response at 500 mg dose. In Part B, 46 pts with HR+/HER2- MBC were enrolled (300 mg, n=9; 400 mg, n=37), and 63.0% (29/46) of pts were still on treatment. Grade ≥ 3 AEs occurred in 42.5% (20/46) of pts, with the most common being anemia (8/46), leukopenia (6/46), hypokalemia (6/46), and neutropenia (5/46). Among the 46 pts, 43 pts were evaluable for efficacy. The DCR was 97.7% (42/43, 95% CI: 87.7%-99.9%). The confirmed overall response rate was as high as 60.5% (26/43, 95% CI: 44.4%-75%). The median progression-free survival has not been reached (95% CI: 11.1 months–not reached). Conclusions: To our knowledge, BPI-16350 plus FUL demonstrated numerically highest antitumor activity compared with the already approved CDK4/6 inhibitors and less Grade ≥ 3 diarrhea than abemaciclib. A phase III study (NCT05433480) comparing BPI-16350 plus FUL versus placebo plus FUL in pts with MBC is ongoing. Clinical trial information: NCT03791112.