Abstract IA13: Preliminary results of a multicentric, prospective randomized trial testing focal radiotherapy and immunotherapy in HR+ breast cancer patients
Authors: Silvia C. Formenti
Journal: Clinical Cancer Research (2025)

Abstract Radiation (RT) is a potent immune modulator, since it harnesses both the innate and adaptive components of the immune system (reviewed in Galluzzi et al NRCO, 2023:20:543-557). The promising immunological impacts of RT inspired a clinical trial in HR+ BC conducted as part of a level 3 breakthrough award (BC180595), partnering P.I.s Drs. S. Formenti and S. Demaria.The trial was designed to evaluate the therapeutic impact of RT in combination with immunotherapies (PD1 and FLT-3 Ligand), applied preoperatively, during neoadjuvant aromatase inhibition. The trial tested the role of increasing cross-presentation by using FLT-3 Ligand and overcoming immune resistance by targeting the PD1 pathway. All patients received focal radiothepy to the imaged primary tumor (8Gyx3, total dose 24 Gy) while receiving letrozole (as standard endocrine therapy), preoperatively. Patients were randomly assigned to 4 arms : ARM1 - Letrozole (2.5 mgm PO qDay) and Radiation to the tumor (8Gy x 3); ARM 2 - Letrozole and Radiation to the tumor followed by Pembrolizumab, started after radiation, q3 weeks for a total of 5 doses; ARM 3 - Letrozole and Radiation to the tumor preceded by Flt3 ligand (75 microgram/kg/ day, s.c. for 5 consecutive days), and ARM 4 Letrozole and Radiation to the tumor preceded by Flt3 ligand and followed by Pembrolizumab (doses as above). The endpoint for the trial is pathological response defined by residual cancer burden (RCB score), a pathological assessment method predictive of survival outcomes (https://doi.org/10.1186/s12885-023-11719-z). For this trial "responders" were considered patients with tumor achieving RCB response of 0 or 1. Because of the randomized design with a control arm of patients receiveng letrazole and focal RT only, the study enables to learn how the additional immunotherapies affect pathological response of RT + letrozole . Pathological response from the 17/27 accrued patients that had surgery are: for arm 1 = 33% (1/3), for arm 2 = 100% (3/3), for arm 3 = 12% (2/6) and for arm 4 = 20% (1/5). The trial utilizes a 3-stage design, by analyzing data when 6 patients with RCB response are available in each arm, before increasing accruals to that arm, with a Bayesian optimal phase II design (BOP2) ( Zhou, H., et al , 2017,Statistics in Medicine, 36: 3302-3314). This design has a power of 82% with a type I error rate controlled at 0.1. The trial continues accrual, with parallel immunomonitoring analysis of circulating biomarkers of response as well as spatial transcriptomics analysis on pretreatment biopsies, post RT and surgical tissues for each patient, to generate fundamental data on mechanisms of immune response in HR+ breast cancer treated with the different combinations tested. Preliminary information on the translational studies will be presented. Citation Format: Silvia C. Formenti. Preliminary results of a multicentric, prospective randomized trial testing focal radiotherapy and immunotherapy in HR+ breast cancer patients. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA13