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)

• Published in: Clinical cancer research 2021-08, Vol.27 (15), p.4177-4185
• Main Authors: Bardia, Aditya, Hurvitz, Sara A, DeMichele, Angela, Clark, Amy S, Zelnak, Amelia, Yardley, Denise A, Karuturi, Meghan, Sanft, Tara, Blau, Sibel, Hart, Lowell, Ma, Cynthia, Rugo, Hope S, Purkayastha, Das, Moulder, Stacy
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-2114

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. 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. 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. 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.