Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer

Nature. 2024 Dec;636(8042):474-480. doi: 10.1038/s41586-024-08035-2. Epub 2024 Nov 27.

Abstract

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy improve the outcomes of patients with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer and can be used early as first-line treatment or deferred to second-line treatment1-7. Randomized data comparing the use of CDK4/6i in the first- and second-line setting are lacking. The phase 3 SONIA trial (NCT03425838) randomized 1,050 patients who had not received previous therapy for advanced breast cancer to receive CDK4/6i in the first- or second-line setting8. All of the patients received the same endocrine therapy, consisting of an aromatase inhibitor for first-line treatment and fulvestrant for second-line treatment. The primary end point was defined as the time from randomization to disease progression after second-line treatment (progression-free survival 2 (PFS2)). We observed no statistically significant benefit for the use of CDK4/6i as a first-line compared with second-line treatment (median, 31.0 versus 26.8 months, respectively; hazard ratio = 0.87; 95% confidence interval = 0.74-1.03; P = 0.10). The health-related quality of life was similar in both groups. First-line CDK4/6i use was associated with a longer CDK4/6i treatment duration compared with second-line use (median CDK4/6i treatment duration of 24.6 versus 8.1 months, respectively) and more grade ≥3 adverse events (2,763 versus 1,591, respectively). These data challenge the need for first-line use of a CDK4/6i in all patients.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase III
  • Comparative Study

MeSH terms

  • Aged
  • Antineoplastic Agents* / administration & dosage
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Antineoplastic Agents, Hormonal / administration & dosage
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Aromatase Inhibitors / administration & dosage
  • Aromatase Inhibitors / pharmacology
  • Aromatase Inhibitors / therapeutic use
  • Breast Neoplasms* / classification
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Cyclin-Dependent Kinase 4* / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4* / metabolism
  • Cyclin-Dependent Kinase 6* / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6* / metabolism
  • Disease Progression
  • Estrogen Receptor Antagonists / administration & dosage
  • Estrogen Receptor Antagonists / pharmacology
  • Estrogen Receptor Antagonists / therapeutic use
  • Female
  • Fulvestrant / administration & dosage
  • Fulvestrant / therapeutic use
  • Humans
  • Middle Aged
  • Neoplasm Staging
  • Progression-Free Survival
  • Protein Kinase Inhibitors* / administration & dosage
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Quality of Life
  • Time-to-Treatment*

Substances

  • Antineoplastic Agents
  • Antineoplastic Agents, Hormonal
  • Aromatase Inhibitors
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Estrogen Receptor Antagonists
  • Fulvestrant
  • Protein Kinase Inhibitors