Abstract CT219: Neoadjuvant letrozole and palbociclib in stage II-IIIB HR[+]/HER2[-] breast cancer with Oncotype DX Recurrence Score® (RS) 18-25 or 26-100. Analysis of RS changes at surgery (DxCARTES trial)

BACKGROUND: The combination of a CDK4/6 inhibitor (palbociclib, abemaciclib, or ribociclib) with an aromatase inhibitor (AI) significantly reduces Ki67 compared to single-agent AI in the neoadjuvant setting, but the rates of pathological complete response (pCR) or residual cancer burden (RCB) 0-I remain modest. Despite this inadequate pathological downstaging, to date, there is no data about the efficacy of this treatment in terms of molecular downstaging detected by a more refined genomic signature than Ki67, such as the Oncotype DX Breast Recurrence Score® (RS) test. The aim of this trial is to validate the ability of neoadjuvant palbociclib plus letrozole to modify two initial intermediate or high RS tumor cohorts. TRIAL DESIGN: This is an international, multicenter, open-label, non-comparative, phase II trial. Main selection criteria include: (1) Pre- or post-menopausal women with treatment-naïve, centrally assessed, HR-positive/HER2-negative, Ki67 ≥ 20%, and stage II-IIIB breast cancer; (2) Pre-treatment RS result ≥ 18; (3) Patients agree to collect tissue samples at screening, at Cycle 1 Day 14 of treatment, and at surgery. Patients will be allocated, according to the pre-treatment RS result, either to Cohort A (RS 18-25) or Cohort B (RS 26-100) and will receive treatment with palbociclib (125 mg QD, 3/1 schedule) in combination with letrozole (2.5 mg QD, every 28-day cycle), ± LHRH analogs if pre-menopausal status, for 24 weeks. Definitive breast surgery will be performed within 7 days after completion of 6 treatment cycles. The primary objective of the study is to explore the ability of palbociclib in combination with letrozole to induce global molecular changes, measured by either the post-treatment RS result at surgery, or pCR. Secondary objectives include: (1) Concordance rate among post-treatment RS result and RCB, Ki67, and preoperative endocrine prognostic index (PEPI) score; (2) Overall response rate; (3) Safety-related outcome as per Common Terminology Criteria for Adverse Events v. 5.0. Patients will be accrued in a Simon’s two-stage design trial: optimal design in Cohort A and minimax design in Cohort B. With a unilateral type one error (alpha) set at 0.025 and a 0.8 power (type two error beta = 0.2), the required number of evaluable patients are 28. Considering a drop-out rate no lower than 10%, a sample size of 33 patients in each cohort will be needed. First Patient First Visit: Expected on April 2019. Citation Format: Antonio Llombart Cussac, José Pérez-García, Ángel Guerrero, Begoña Bermejo, Miguel Gil, Vicente Carañana, Serafín Morales, Juan de la Haba, María Fernández, Emilio Alba, Ander Urruticoechea, Lourdes Calvo, Mireia Margeli, Antonio Antón, Manuel Ruíz Borrego, Joan Albanell, Pedro Sánchez Rovira, Meritxell Bellet, Sofia Braga, Passos Coelho, Miguel Abreu, Javier Cortés. Neoadjuvant letrozole and palbociclib in stage II-IIIB HR[+]/HER2[-] breast cancer with Oncotype DX Recurrence Score® (RS) 18-25 or 26-100. Analysis of RS changes at surgery (DxCARTES trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT219.