Phase I/II Trial of Exemestane, Ribociclib, and Everolimus in Women with HR+/HER2- Advanced Breast Cancer after Progression on CDK4/6 Inhibitors (TRINITI-1)

Clin Cancer Res. 2021 Aug 1;27(15):4177-4185. doi: 10.1158/1078-0432.CCR-20-2114. Epub 2021 Mar 15.


Purpose: Standard-of-care treatment for metastatic hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2- advanced breast cancer (ABC) after progression on a CDK4/6i.

Patients and methods: This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2- breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis.

Results: Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1-28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1-51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported.

Conclusions: Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2- ABC after progression on a CDK4/6i.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aminopyridines / therapeutic use*
  • Androstadienes / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Disease Progression
  • Everolimus / therapeutic use*
  • Female
  • Humans
  • Middle Aged
  • Purines / therapeutic use*
  • Receptor, ErbB-2 / analysis


  • Aminopyridines
  • Androstadienes
  • Purines
  • Everolimus
  • Receptor, ErbB-2
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • exemestane
  • ribociclib