158TiP Neoadjuvant abemaciclib and giredestrant trial in patients with ER-positive, HER2-negative early breast cancer (GIM31-Neo-AGILE trial)

Giredestrant (G) is a potent new-generation oral selective estrogen receptor degrader and a full antagonist of estrogen receptor (ER). Preliminary results showed promising clinical activity and benefit rates of G in both metastatic (m) and neo-adjuvant (NA) breast cancer (BC) settings. In the preoperative setting, G showed superiority over anastrazole in achieving a complete cell cycle arrest (CCCA). The first data on the combination of G and abemaciclib (A) showed a good safety profile with a 40% clinical benefit rate in heavily pre-treated patients (pts) with ER+ HER2- mBCs. In the NA setting, the addition of CDK4/6 inhibitors, such as A, to the standard endocrine therapy (ET) enhanced CC control with a significant increase in CCCA rates in the association arm compared with the ET arm. The Neo-Agile trial is a multicentric phase II, window-of-opportunity (WOO)/neoadjuvant study that will evaluate the safety and pharmacodynamics of G in combination with A in ER+ early BC (EBC). The study will also serve to better understand the clinical potential of the A-G combination to move forward with new trials to consolidate this combination in the NA/adjuvant setting of ER+ and HER2- BC. Eligible patients (pts) (post-menopausal women) have a confirmed diagnosis of untreated ER+/HER2- EBC (cT1c–4a–c; cN0-N2a). Pts (#51) will receive A 150 mg twice daily and G once daily for a total of 24 weeks (W) (2 W of WOO phase and 22 W of NA phase) before surgery. After the WOO phase pts will undergo a core biopsy to centrally assess the CCCA. The primary endpoint, CCCA (central Ki67<2.7%) at W2, will be assessed by a blinded independent central review. Secondary outcomes include percent change in Ki67 expression from baseline to W2, ROR score reduction (from baseline to W2 and surgery), clinical and radiologic (magnetic resonance imaging) objective responses, safety, and quality of life assessments. Exploratory endpoints are mechanisms of response and resistance to therapy, the correlation between gut/loco regional microbiome and response to treatment, the correlation between Ki-67% reduction and 18-Fluorothymidine (FLT) uptake reduction and pathological complete response rate (ypT0/is, ypN0) of G plus A. EudraCT 2023-510153-42-00. The authors. Acknowledgement: OncotechFoundation and CRT (Clinical Research Technology – Salerno) Funding and drug supply: Roche S.p.A e (Funding and drug supply), Eli Lilly Italia S.p.A. (drug supply).