Abstract OT2-19-01: Presurgical treatment with ribociclib and letrozole in patients with locally advanced breast cancer: The NEOLETRIB study
Authors: Tekpli Xavier , Goel Shom , Holm Barbro , Fallang Lars-Egil , Reitsma Laurens Cornelus , Geisler Stephanie Beate , Presterud Ødegård Hilde , Fosskaug Cathrine Bergquist , Lindem Ida Caroline , Seyedzadeh Manouchehr , Geitung Jonn Terje , Reis Joana , Gjesdal Kjell Inge , Buvarp Unn-Cathrin , Loeng Marie , Sahlberg Kristine Kleivi , Porojnicu Alina Carmen , Skjerven Helle Kristine , Tahiri Andliena , Jabeen Shakila , Lüders Torben , Bemanian Vahid , Jahnsen Jørgen , Lyngra Marianne , Hurtado Antoni , Carroll Jason , Chen Shiuan , Kristensen Vessela , Geisler Jürgen 
Published: March 2022

Abstract
Background: The introduction of CDK4/6 inhibitors has been one of the most pivotal breakthroughs in breast cancer therapy in recent decades. A growing body of evidence now suggests that novel targeting inhibitors of CDK4/6, as well as MAPK and PI3K inhibitors, might have anti-tumor effects beyond tumour cell cytostasis, including immunomodulation. Specifically, studies have demonstrated that CDK4/6 inhibitors can have immunogenic effects, through the induction of a senescent-like phenotype in tumor cells, changes in tumor cell metabolism, and direction modulation of T cell function. Trial design: NEOLETRIB is a multicenter, single-arm, open-label, neoadjuvant, phase II trial. Eligibility criteria: Patients suffering from locally advanced breast cancer defined as either large T2 (&gt; 3 cm), or T3/T4, and/or N2-3 are suitable for inclusion. Both, luminal-A and luminal-B tumors are allowed. HER-2 positive and triple-negative patients are excluded from this trial, as are patients with patients with evidence of distant metastasis. Treatment: All patients receive neoadjuvant therapy for at least 6 months with ribociclib (600 mg daily, 21 days on/7 days off) and letrozole (2.5 mg daily). Premenopausal women will also receive goserelin (3.6 mg s.c. every 28 days) according to clinical practice. Specific aims: The primary objective is to evaluate the intra-tumor immunological effects in individual patients treated with letrozole and ribociclib in the neoadjuvant setting. Secondary objectives include evaluation of clinical and pathological response to the treatment combination, identification of early and late molecular mechanisms of treatment adaptation and resistance, and investigation of the effects of the treatment on the gut microbiota and vice versa. As an exploratory objective, we aim to study the relationship between cancer treatment effects, the immune competent cells in the blood and the gut microbiota. Long-term follow-up will continue after the primary analysis for up to 10 years or until death, withdrawal of consent, loss to follow-up, or trial closure. To allow for the planned laboratory sub-studies, tumor tissue biopsies, blood and stool samples will be collected at baseline, day 21 and at time of surgery, with additional blood and stool samples collected at day 90. The samples will be analyzed to evaluate and measure numerous parameters including levels of cytokines and metabolites, cell free DNA-fragments, and intra-tumor gene expression/regulation using state of the art laboratory methods together with international collaborators. Advanced MRI-techniques are used at baseline and following 3 and 6 months on treatment for clinical efficacy measurements in the breast. Statistical methods: Due to the nature of this single-arm study with longitudinal sampling from individual patients, the statistics will be descriptive in nature, focusing on intra-patient comparisons over time. The inclusion goal of 100 patients is based on the response rate of neoadjuvant trials with ribociclib to allow for a minimum of 30 patients in the responder & non-responder arms, which is sufficient for hypothesis generating results. Present accrual and target accrual: Following 8 weeks after initiation of this trial, the first 10 patients have been enrolled. The target accrual is 100 patients with complete study procedures.
Citation Format: Xavier Tekpli, Shom Goel, Barbro Holm, Lars-Egil Fallang, Laurens Cornelus Reitsma, Stephanie Beate Geisler, Hilde Presterud Ødegård, Cathrine Bergquist Fosskaug, Ida Caroline Lindem, Manouchehr Seyedzadeh, Jonn Terje Geitung, Joana Reis, Kjell Inge Gjesdal, Unn-Cathrin Buvarp, Marie Loeng, Kristine Kleivi Sahlberg, Alina Carmen Porojnicu, Helle Kristine Skjerven, Andliena Tahiri, Shakila Jabeen, Torben Lüders, Vahid Bemanian, Jørgen Jahnsen, Marianne Lyngra, Antoni Hurtado, Jason Carroll, Shiuan Chen, Vessela Kristensen, Jürgen Geisler. Presurgical treatment with ribociclib and letrozole in patients with locally advanced breast cancer: The NEOLETRIB study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-01.