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).

Abstract

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.

• Authors: Aditya Bardia, Sara A Hurvitz, Angela DeMichele, Amy S Clark, Amelia Zelnak, Denise A Yardley, Meghan Karuturi, Tara Sanft, Sibel Blau, Lowell Hart, Cynthia Ma, Hope S Rugo, Das Purkayastha, Stacy Moulder
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 15 Pg. 4177-4185 (08 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33722897 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

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

Topics

• Adult
• Aged
• Aged, 80 and over
• Aminopyridines (therapeutic use)
• Androstadienes (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Breast Neoplasms (chemistry, drug therapy, 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)