Background: Dalpiciclib (Dalp; SHR6390) is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary clinical activity as monotherapy for pretreated advanced breast cancer (ABC). Here we conducted a multicenter, phase 1b trial to further assess the safety, pharmacokinetics and efficacy of Dalp in combination with endocrine therapy (ET) in HR+/HER2- ABC. Methods: 5 cohorts of patients with HR+/HER2- locally recurrent or metastatic BC and any menopausal status were enrolled (~15 patients/combination regimen). Patients without prior treatment for ABC (cohort1/2) were given Dalp (125 or 150 mg po qd, d1-21, q4w) plus letrozole (LTZ; 2.5 mg po qd) or anastrozole (ATZ; 1 mg po qd); patients who progressed after ET (cohort 3-5) were given Dalp (125, 150, or 175 mg po qd, d1-21, q4w) plus fulvestrant (Fulv; 500 mg im, cycle 1 d1, d15, then d1 q4w). The primary endpoint was safety. The data cutoff date was Sep. 20, 2021. Results: 58 patients received Dalp plus LTZ/ATZ and 46 received Dalp plus Fulv. No maximum tolerated dose of Dalp was reached with LTZ/ATZ or Fulv. Across all cohorts, 75.0%-93.8% of patients had a grade ≥3 treatment-related adverse event (TRAE), with the most common being neutropenia (grade 3, 40.0%-87.5%; grade 4, 4.2%-46.7%) and leukopenia (grade 3, 33.3%-80.0%; grade 4, 0%; Table). Treatment-related serious AEs occurred in 2 (3.4%) patients with Dalp plus LTZ/ATZ and none with Dalp plus Fulv. At the tested dose levels, steady-state areas under the concentration curve and peak concentration of Dalp increased with dose in combination with LTZ/ATZ or Fulv. Dalp 150 mg was associated with a numerically higher objective response rate in both ET-untreated (67.6%, 95% CI 49.5-82.6) and ET-pretreated (53.3%, 95% CI 26.6-78.7) patients per investigator. The median progression-free survival with Dalp 150 mg was 20.3 mo (95% CI 16.9-not reached [NR]) and 16.7 mo (95% CI 1.9-24.1) in ET-untreated and ET-pretreated patients respectively. Conclusions: Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile, with hematological toxicities as the most common TRAEs. The recommended phase 3 dose of dalpiciclib was 150 mg. Together with the promising anti-tumor activity observed with the combination therapy in HR+/HER2- ABC, further trials are warranted. Clinical trial information: NCT03481998.

Data are n (%).