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)

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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish
Pages (from-to)4177-4185
Number of pages9
JournalClinical Cancer Research
Volume27
Issue number15
DOIs
StatePublished - Aug 1 2021

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