背景：Dalpiciclib（SHR6390）是一種新型 CDK4/6 抑製劑，已在既往接受過治療的 HR +/HER2-晚期乳腺癌（ABC）患者中證實了其作為單藥治療的耐受性和初步抗腫瘤活性。在此，我們在ABC 患者中將 dalpiciclib 與氟維司群進行評價。

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：在這項隨機、雙盲、3 期試驗中，入組了既往內分泌治療後複發或進展的 HR +/HER2-局部晚期或轉移性乳腺癌患者。符合條件的患者按 2：1 隨機接受 dalpiciclib（dalp；150 mg po qd，d1-21，q4w）或安慰劑（PBO）聯合氟維司群（fulv；500 mg im，第 1 周期 d1、d15，然後 d1 q4w）。主要終點為研究者（INV）評估的 PFS。截至 2020 年 11 月 15 日，發生了 162 起（占預計總數的 71.4%）疾病進展或死亡事件，並進行了預先計劃的期中分析。相應的優效性邊界為單側 P =0.0080（Lan-DeMets[O’Brien-Fleming]邊界）。

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).

結果：總體而言，361 例患者隨機接受 dalp-fulv（n = 241）或 PBO-fulv（n = 120）。中位隨訪 10.5 個月，與 PBO-fulv 相比，dalp-fulv 顯著改善 INV 評估的 PFS（中位數，15.7[95%CI 11.1-NR]vs 7.2[95%CI 5.6-9.2]個月；HR，0.42[95%CI 0.31-0.58]；P < 0.0001）。IRC 評估的 PFS 與 INV 評估一致（表）。基於至首次後續化療的時間，dalpiciclib 的獲益延長至初始研究治療後（TFSCT；HR，0.47[95%CI 0.32-0.69]；P < 0.0001）。OS 數據尚不成熟，共記錄了 25 例死亡。dalp-fulv組 dalpiciclib 和氟維司群的中位暴露持續時間分別為 9.4（IQR，4.3-11.4）個月和 9.9（4.7-11.9）個月，PBO-fulv 組中氟維司群的中位暴露持續時間為 6.1（3.7-11.0）個月。Dalp-fulv 組最常見（發生率≥3%）的 3 級或 4 級 AE 為中性粒細胞減少症（84.2%；PBO-fulv 組為 0%）和白細胞減少症（62.1%；vs 0%）。dalp-fulv 組 2.5%的患者和 PBO-fulv 組 3.3%的患者報告了因 AE 導致的治療中止。dalp-fulv 組 SAE 的發生率為 5.8%，PBO-fulv 組為 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

結論：本研究達到其主要終點，表明與安慰劑 + 氟維司群相比，dalpiciclib + 氟維司群顯著改善 PFS，且安全性可管理。我們的研究結果支持 dalpiciclib 聯合氟維司群作為內分泌治療後複發或進展的 HR +/HER2-ABC 患者的新治療選擇。

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.