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.

Figure 1.

TRINITI-1 study design. ^a The MTD was defined as the highest combination drug dose not causing DLTs in > 33% of treated patients in the first treatment cycle. ABC, advanced breast cancer; CBR, clinical benefit rate; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; DLT, dose-limiting toxicity; DOR, duration of response; ET, endocrine therapy; EVE, everolimus; EXE, exemestane; HER2−, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; MTD, maximum tolerated dose; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; QD, once daily; RIB, ribociclib; RP2D; recommended phase II dose.

Figure 2.

Progression-free survival among n = 95 efficacy-evaluable patients. PFS, progression-free survival.

Figure 3.

Progression-free survival by baseline mutation of (A) PIK3CA, (B) ESR1, and (C) PIK3CA and/or ESR1. MUT, mutated; PFS, progression-free survival; WT, wild type.