背景：Dalpiciclib（SHR6390）是一种新型 CDK4/6 抑制剂，已在既往接受过治疗的 HR +/HER2-晚期乳腺癌（ABC）患者中证实了其作为单药治疗的耐受性和初步抗肿瘤活性。在此，我们在ABC 患者中将 dalpiciclib 与氟维司群进行评价。

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.

方法：在这项随机、双盲、3 期试验中，入组了既往内分泌治疗后复发或进展的 HR +/HER2-局部晚期或转移性乳腺癌患者。符合条件的患者按 2：1 随机接受 dalpiciclib（dalp；150 mg po qd，d1-21，q4w）或安慰剂（PBO）联合氟维司群（fulv；500 mg im，第 1 周期 d1、d15，然后 d1 q4w）。主要终点为研究者（INV）评估的 PFS。截至 2020 年 11 月 15 日，发生了 162 起（占预计总数的 71.4%）疾病进展或死亡事件，并进行了预先计划的期中分析。相应的优效性边界为单侧 P =0.0080（Lan-DeMets[O’Brien-Fleming]边界）。

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).

结果：总体而言，361 例患者随机接受 dalp-fulv（n = 241）或 PBO-fulv（n = 120）。中位随访 10.5 个月，与 PBO-fulv 相比，dalp-fulv 显著改善 INV 评估的 PFS（中位数，15.7[95%CI 11.1-NR]vs 7.2[95%CI 5.6-9.2]个月；HR，0.42[95%CI 0.31-0.58]；P < 0.0001）。IRC 评估的 PFS 与 INV 评估一致（表）。基于至首次后续化疗的时间，dalpiciclib 的获益延长至初始研究治疗后（TFSCT；HR，0.47[95%CI 0.32-0.69]；P < 0.0001）。OS 数据尚不成熟，共记录了 25 例死亡。dalp-fulv组 dalpiciclib 和氟维司群的中位暴露持续时间分别为 9.4（IQR，4.3-11.4）个月和 9.9（4.7-11.9）个月，PBO-fulv 组中氟维司群的中位暴露持续时间为 6.1（3.7-11.0）个月。Dalp-fulv 组最常见（发生率≥3%）的 3 级或 4 级 AE 为中性粒细胞减少症（84.2%；PBO-fulv 组为 0%）和白细胞减少症（62.1%；vs 0%）。dalp-fulv 组 2.5%的患者和 PBO-fulv 组 3.3%的患者报告了因 AE 导致的治疗中止。dalp-fulv 组 SAE 的发生率为 5.8%，PBO-fulv 组为 6.7%。

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.

*1-sided stratified

结论：本研究达到其主要终点，表明与安慰剂 + 氟维司群相比，dalpiciclib + 氟维司群显著改善 PFS，且安全性可管理。我们的研究结果支持 dalpiciclib 联合氟维司群作为内分泌治疗后复发或进展的 HR +/HER2-ABC 患者的新治疗选择。

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.