Abstract Background: CDK4/6 inhibitors (CDK4/6i) have changed the treatment landscape for patients with metastatic hormone receptor positive (HR+)/HER2- breast cancer. Multiple studies have evaluated the role of neoadjuvant CDK4/6 inhibitors. NEOPAL was a phase II study, which compared neoadjuvant chemotherapy to neoadjuvant endocrine therapy (NET) and CDK4/6i, which showed similar clinical response and breast conserving surgery rates but with more favorable toxicity profile with the combination NET and CDK4/6i. There is increasing pre-clinical data showing synergism between CDK 4/6i and radiation therapy (RT) secondary to radiosensitizing estrogen receptor (ER) positive cells leading to decrease in the surviving fraction of cells. Retrospective studies that have looked at the combination of CDK4/6i with RT in patients with metastatic breast cancer have shown that the combination is well tolerated. The advantages of preoperative RT include accurate tumor site identification, better target volume delineation and tumor downstaging with increased rates of breast conserving surgery. Preoperative RT can overcome treatment planning challenges seen in patients who have had reconstructive surgery such as tissue expander, implant and flap irradiation issues. It is relevant to understand the benefit of concurrent radiation and CDK4/6i in the pre-operative setting in select patient population. RADIANT study is a single-arm, phase 1b study that will evaluate the concurrent use of abemaciclib and letrozole with pre-operative RT in HR+/HER2 negative early-stage breast cancer. METHODS: The study will recruit 15 patients diagnosed with HR+/HER2- breast cancer to evaluate combination of endocrine therapy, CDK4/6i (abemaciclib) and preoperative radiation. (Clinicaltrials.gov Identifier: NCT06139107) The study hypothesize that the combination will be safe and tolerable. The primary objective of the study is to evaluate safety and tolerability of the combination of abemaciclib and radiation as assessed by adverse events (AEs). Secondary objective is to determine the clinical efficacy of the study treatment regimen as determined by Residual Cancer Burden (RCB). Patients with cT1c-T2N0 HR+/HER2- tumors with low-risk or intermediate risk Oncotype DX Breast Recurrence score (≤25) will be eligible for the study. The study is divided into 4 parts- PART A (pre-radiation), PART B (Radiation), PART C (post-radiation) and PART D (breast surgery). All cycles will be based on abemaciclib and will be 28 days. PART A: Patient will take letrozole 2.5mg daily and Abemaciclib 150mg twice a day for 3 cycles . Towards the end of PART A, patients will have on-treatment biopsy. PART B: Patients will then receive breast radiation concurrently with abemaciclib and letrozole. While getting concurrent radiation (Part B), we will use a streamlined Bayesian Optimal Interval (BOIN) design. Enrollment will be in cohorts of 3 patients to 2 dose levels of abemaciclib --- 100mg BID and 50mg BID. Fifteen patients will be enrolled to part B of this trial based on streamlined BOIN design. The BOIN procedure targets a toxicity rate of 0.33, and we will enroll patients in cohorts of 3 patients. We will use a posterior probability for overdose control of 0.85.A dose limiting toxicity (DLT) is defined as any grade 4 skin, hematologic (white blood cells only) or grade 2 or greater pneumonitis/Interstitial lung disease resulting from Part B of the study. If no DLTs occur in at 100mg dose during PART B, the study will not enroll to 50mg dose. PART C: After the completion of radiation, patients will continue on to PART C for 2 cycles of abemaciclib and letrozole. PART D: Patients will have breast surgery in Part D along with sentinel lymph node biopsy following completion of systemic therapy. The study is currently enrolling patients at Rutgers Cancer Institute. Citation Format: M. George, S. Jabbour, N. Ohri, C. Omene, M. Kowzun, S. Kumar, D. Toppmeyer, B. Haffty. Radiant study: Phase 1b study of pre-op radiation with abemaciclib and letrozole in early-stage hormone-receptor positive breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-29.
George et al. (2026) studied this question.