Tibremciclib or Placebo Plus Fulvestrant in Hormone Receptor-Positive and ERBB2-Negative Advanced Breast Cancer After Endocrine Therapy: A Randomized Clinical Trial.

Tibremciclib (BPI-16350), a novel CDK4/6 inhibitor, has demonstrated favorable tolerability and promising antitumor activity as a monotherapy or combined with fulvestrant among patients with HR+/ERBB2- ABC in a phase 1 trial. Further investigations are necessary to assess the efficacy and safety of tibremciclib.

Tibremciclib（BPI-16350），一种新型CDK4/6抑制剂，在一项1期试验中，作为单药治疗或与fulvestrant联合使用，在HR+/ERBB2- ABC患者中显示出良好的耐受性和有希望的抗肿瘤活性。进一步的研究是必要的，以评估tibremciclib的有效性和安全性。

Background

To compare tibremciclib plus fulvestrant and placebo plus fulvestrant in terms of efficacy and safety among patients with HR+/ERBB2- ABC who exhibited disease progression after ET.

比较tibremciclib联合fulvestrant与安慰剂联合fulvestrant在HR+/ERBB2- ABC患者中的疗效和安全性，这些患者在内分泌治疗后疾病进展。

DESIGN, SETTING, AND PARTICIPANTS: The TIFFANY trial was a double-blind, placebo-controlled, phase 3 randomized clinical trial of patients with HR+/ERBB2- ABC who had experienced progression while receiving prior ET and had received no more than 1 line of chemotherapy.

TIFFANY试验是一项双盲、安慰剂对照的III期随机临床试验，研究对象为HR+/ERBB2- ABC患者，这些患者在之前接受内分泌治疗后疾病进展，并且接受的化疗不超过1线。

This trial was conducted at 69 Chinese centers between May 25, 2022, and April 25, 2023.

本试验在中国的69个中心进行，时间跨度为2022年5月25日至2023年4月25日。

The data cutoff date for this analysis was March 31, 2024.

本次分析的数据截止日期为2024年3月31日。

Methods

Patients were randomly assigned to receive tibremciclib (400 mg, orally, once daily) plus fulvestrant or placebo plus fulvestrant at a 2:1 ratio until disease progression, death, or treatment discontinuation for various reasons.

患者被随机分配接受口服每日一次的tibremciclib（400毫克）加fulvestrant或安慰剂加fulvestrant，比例为2:1，直至疾病进展、死亡或因各种原因停药。

main_outcomes_and_measures

The primary end point was investigator-assessed progression-free survival(PFS), and the secondary end points included the objective response rate, overall survival, and safety.

主要终点是研究者评估的无进展生存期（PFS），次要终点包括客观缓解率、总生存和安全性。

Results

A total of 274 female patients (median [IQR] age, 53.0 [46.0-60.0] years) were randomly assigned to receive tibremciclib plus fulvestrant (184 [67.2%]) or placebo plus fulvestrant (90 [32.8%]).

共有274名女性患者（中位年龄53.0岁，四分位数间距[46.0-60.0]岁）被随机分配接受tibremciclib加fulvestrant治疗（184名，占67.2%）或安慰剂加fulvestrant治疗（90名，占32.8%）。

Among these patients, 144 PFS events occurred (80 in the tibremciclib arm and 64 in the placebo arm), with a median follow-up of 12.9 months for both arms.

在这些患者中，共有144起无进展生存（PFS）事件发生（tibremciclib组80起，安慰剂组64起），两组的中位随访时间均为12.9个月。

Tibremciclib plus fulvestrant significantly improved PFS compared with placebo plus fulvestrant (median, 16.5 months [95% CI, 12.8-16.6] vs 5.6 months [95% CI, 4.5-9.2]; hazard ratio, 0.37; 95% CI, 0.27-0.52; P < .001).

Tibremciclib联合fulvestrant显著改善了与安慰剂联合fulvestrant相比的无进展生存期（PFS），中位数为16.5个月[95%置信区间（CI），12.8-16.6]对比5.6个月[95% CI，4.5-9.2]；风险比为0.37；95% CI，0.27-0.52；P < .001。

In patients with measurable disease, tibremciclib plus fulvestrant achieved an objective response rateof 45.6% (95% CI, 37.6%-53.7%) compared with 12.9% (95% CI, 6.1%-23.0%) in the placebo arm (P < .001).

在有可测量疾病的患者中，Tibremciclib联合fulvestrant实现了45.6%的客观缓解率（95% CI，37.6%-53.7%），与安慰剂组的12.9%（95% CI，6.1%-23.0%）相比（P < .001）。

The most common grade 3 or higher treatment-emergent adverse events in the tibremciclib vs placebo arm were neutropenia (15.2% vs 5.6%, respectively), anemia (12.0% vs 4.4%, respectively), and hypokalemia (12.0% vs 0%, respectively).

tibremciclib 与安慰剂组中，最常见的3级或更高级别的治疗相关不良事件分别是中性粒细胞减少症（分别占15.2%和5.6%）、贫血（分别占12.0%和4.4%）以及低钾血症（分别占12.0%和0%）。

No drug-related deaths occurred in the tibremciclib arm, and 1 death occurred in the placebo arm.

在tibremciclib组中没有发生与药物相关的死亡事件，而安慰剂组中发生了1例死亡。

conclusions_and_relevance

The results of this randomized clinical trial suggest that tibremciclib plus fulvestrant was associated with statistically significant and clinically meaningful improvements in PFS compared with placebo plus fulvestrant.

这项随机临床试验的结果表明，与安慰剂加氟维司群相比，tibremciclib加氟维司群与无进展生存期（PFS）的统计学显著性和临床意义上的改善相关。

Furthermore, tibremciclib plus fulvestrant demonstrated a manageable safety profile in patients with HR+/ERBB2- ABC who experienced progression while receiving prior ET.

此外，对于接受过先前内分泌治疗（ET）后疾病进展的HR+/ERBB2-晚期乳腺癌（ABC）患者，tibremciclib加氟维司群显示出可控的安全性特征。

trial_registration

ClinicalTrials.gov Identifier: NCT05433480.

临床试验注册号：NCT05433480。