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

Importance: Cyclin-dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapy (ET) are now considered the standard treatment regimen for hormone receptor-positive (HR+) and ERBB2 (formerly HER2)-negative (ERBB2-) advanced breast cancer (ABC). 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.

Objective: 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.

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. This trial was conducted at 69 Chinese centers between May 25, 2022, and April 25, 2023. The data cutoff date for this analysis was March 31, 2024.

Interventions: 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.

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.

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%]). 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. 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). In patients with measurable disease, tibremciclib plus fulvestrant achieved an objective response rate of 45.6% (95% CI, 37.6%-53.7%) compared with 12.9% (95% CI, 6.1%-23.0%) in the placebo arm (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). No drug-related deaths occurred in the tibremciclib arm, and 1 death occurred in the placebo arm.

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

Trial Registration: ClinicalTrials.gov Identifier: NCT05433480.