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Novel CDK2/4/6 inhibitor culmerciclib (TQB3616) plus fulvestrant in previously treated, HR-positive, HER2-negative

Yongmei Yin1, Qingyuan Zhang2, Tao Sun3

  • 1Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China. ym.yin@hotmail.com.

Signal Transduction and Targeted Therapy
|December 18, 2025
PubMed

Insights

Culmerciclib combined with fulvestrant significantly improves progression-free survival in advanced breast cancer (ABC) patients resistant to CDK4/6 inhibitors. This combination therapy offers a new treatment option for HR-positive, HER2-negative ABC.

Area of Science:

  • Oncology
  • Clinical Pharmacology
  • Medical Therapeutics

Background:

  • Cyclin-dependent kinase 2 (CDK2) is a key mediator of resistance to CDK4/6 inhibitors in advanced breast cancer (ABC).
  • Targeting both CDK2 and CDK4/6 simultaneously may overcome resistance and improve treatment outcomes in HR-positive, HER2-negative ABC.

Purpose of the Study:

  • To evaluate the efficacy and safety of culmerciclib, a novel CDK2/4/6 inhibitor, in combination with fulvestrant for patients with HR-positive, HER2-negative advanced breast cancer.
  • To assess the impact of concurrent CDK2/4/6 blockade on progression-free survival (PFS) in pretreated patients.

Main Methods:

  • A randomized, double-blind, parallel-controlled, phase 3 trial (NCT05375461) involving 293 pretreated patients with HR-positive, HER2-negative locally recurrent or metastatic breast cancer.
  • Patients were randomized (2:1) to receive either culmerciclib plus fulvestrant or a placebo plus fulvestrant.
  • The primary endpoint was investigator-assessed progression-free survival (PFS).

Main Results:

  • Culmerciclib plus fulvestrant significantly extended median PFS compared to placebo plus fulvestrant (16.6 months vs. 7.5 months; hazard ratio 0.36, P < 0.001).
  • Consistent efficacy was observed across various patient subgroups.
  • The objective response rate was significantly higher with culmerciclib plus fulvestrant (40.2%) versus placebo (12.1%; P < 0.001).

Conclusions:

  • The combination of culmerciclib and fulvestrant demonstrated a significant improvement in PFS, meeting the primary endpoint of the trial.
  • The regimen was generally well-tolerated, with diarrhea and neutropenia being the most common adverse events.
  • Culmerciclib plus fulvestrant represents a promising therapeutic strategy for pretreated HR-positive, HER2-negative advanced breast cancer patients.

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