Background: FCN-437c is an oral potent and highly selective CDK4/6 inhibitor without the inhibition of CDK1, CDK2, or CDK5. In the phase 1a dose-escalation part of this study (NCT04488107), the safety profile of FCN-437c was acceptable in patients with ABC, and the maximum tolerated dose was determined to be 300 mg QD when used as monotherapy (presented at AACR 2021). Phase 1b aimed to explore the RP2D and to evaluate the tolerability and antitumor activity of FCN-437c combined with letrozole in patients with previously untreated HR+/HER2– ABC. Methods: Adult, post-menopausal female patients diagnosed with treatment-naive ER+/HER2– ABC were eligible for this expansion stage. Patients received FCN-437c once daily at 200 mg or 300 mg on a 21-day-on and 7-day-off schedule in combination with letrozole 2.5 mg once daily in 28-day cycles. The primary endpoints were safety and RP2D. Results: As of November 26, 2021, 29 patients were enrolled and had a median follow-up of 10.4 months. Of these patients, 25 (86.2%) were endocrine-sensitive and 4 (13.8%) were endocrine-resistant. Visceral disease was present in 21 patients (72.4%), and 1 (3.4%) patient had bone-only disease. DLTs of grade 4 neutropenia occurred in 2 patients (40.0%) in 300 mg dose group; they were considered intolerable. One out of the first 6 patients experienced DLTs in 200 mg dose group (grade 4 neutropenia, leukopenia, and thrombocytopenia); these were also considered to be FCN-437c-related SAEs. FCN-437c-related grade ≥3 TEAEs were observed in 26 (89.7%) patients, with neutropenia (n=24, 82.8%) and leukopenia (n=14, 48.3%) being most common. Among the 28 measurable patients, 16 patients had a PR, the ORR was 57.1% (95% CI 37.2–75.5); the CBR was 82.1% (95% CI 63.1–93.9) (Table). Median PFS, DOR, and OS were not reached. At 6 and 12 months, PFS rates were 92.3% and 83.5%, and DOR rates were 100% and 90%, respectively. A RP2D of 200 mg was suggested per safety considerations and preliminary antitumor activity. Conclusions: FCN-437c plus letrozole was well tolerated and demonstrated antitumor activity in patients with previously untreated HR+/HER2– ABC. FCN-437c in combination with NSAI as the first-line treatment for HR+/HER2– ABC will be further investigated in a phase 3 trial. Clinical trial information: NCT04488107.