Binghe Xu, Qingyuan Zhang, Pin Zhang, Xichun Hu, Wei Li, Zhongsheng Tong, Tao Sun, Yuee Teng, Xinhong Wu, Quchang Ouyang, Xi Yan, Jing Cheng, Qiang Liu, Jifeng Feng, Xiaojia Wang, Xiaoyu Zhu, Fei Wu, Xiao Zhang, Jianjun Zou

Background: Dalpiciclib (SHR6390), a novel CDK4/6 inhibitor, as monotherapy has demonstrated tolerability and preliminary antitumor activity in pretreated HR+/HER2 -advanced breast cancer (ABC). Here we evaluated dalpiciclib with fulvestrant in ABC.

Methods: In this randomized, double-blind, phase 3 trial, patients (pts) with HR+/ HER2- Locally advanced or metastatic breast cancer who had relapsed or progressed on previous endocrine therapy were enrolled. Eligible pts were randomized 2:1 to receive dalpiciclib (dalp; 150 mg po qd, d1-21, q4w) or placebo (PBO) with fulvestrant (fulv; 500 mg im, cycle 1 d1, d15, then d1 q4w). The primary endpoint was investigator (INV)-assessed PFS. As of Nov. 15, 2020, 162 (71.4% of total projected) events of disease progression or death had occurred and a preplanned interim analysis was done. The corresponding superiority boundary was 1-sided P = 0.0080 (Lan-DeMets [O’Brien-Fleming] boundary).

Results: Overall, 361 pts were randomized to receive dalp-fulv (n = 241) or PBO-fulv (n = 120). With a median follow-up of 10.5 mo, dalp-fulv significantly improved INV-assessed PFS versus PBO-fulv (median, 15.7 [95% CI 11.1-NR] vs 7.2 [95% CI 5.6-9.2] mo; HR, 0.42 [95% CI 0.31-0.58]; P < 0.0001). PFS per IRC were consistent with INV assessment (Table). The benefit of dalpiciclib extended beyond initial study treatment based on time to first subsequent chemotherapy (TFSCT; HR, 0.47 [95% CI 0.32-0.69]; P < 0.0001). OS data were not mature with a total of 25 deaths documented. Median duration of exposure was 9.4 (IQR, 4.3-11.4) mo with dalpiciclib and 9.9 (4.7-11.9) mo with fulvestrant in the dalp-fulv group and was 6.1 (3.7-11.0) mo with fulvestrant in the PBO-fulv group. The most common (incidence $3%) grade 3 or 4 AEs with dalp-fulv were neutropenia (84.2%; vs 0% with PBO-fulv) and leukopenia (62.1%; vs 0%). Treatment discontinuation due to AE was reported for 2.5% of pts with dalp-fulv vs 3.3% with PBO-fulv. The incidence of SAE was 5.8% with dalp-fulv vs 6.7% with PBO-fulv

Conclusions: The study met its primary endpoint, demonstrating that dalpiciclib plus fulvestrant significantly improved PFS versus placebo plus fulvestrant, with a manageable safety profile. Our findings support dalpiciclib plus fulvestrant as a new treatment option in pts with HR+/HER2- ABC who relapsed or progressed on endocrine therapy.

Clinical trial information: NCT03927456. Research Sponsor: Jiangsu Hengrui Medicine Co., Ltd.