Abstract P3-10-17: Phase I/II study of the novel radioligand therapy [177Lu]Lu-NeoB plus capecitabine in patients w/ ER+/HER2- advanced breast cancer (ABC) w/GRPR expression after progression on prior endocrine therapy (ET) plus a CDK4/6 inhibitor (C

Abstract Background: A CDK4/6i in combination with ET has become standard of care in first-line ER+/HER2− ABC, but despite significant improvements in survival, these patients will eventually experience disease progression. The optimal treatment sequence following progression on a CDK4/6i + ET has not yet been established and is dependent on various factors. Thus, new targeted treatments are needed for patients with ET-resistant ABC. [177Lu]Lu-NeoB (177Lu-NeoB) is a first-in-class radioligand therapy that binds selectively to GRPR, which is expressed in ER+ breast cancer, including in primary lesions, lymph nodes, and distant metastases. NeoRay is a first-in-human trial testing 177Lu-NeoB in advanced solid tumors. We describe the CAAA603D12101 study (NeoB D1), a phase I/II, open-label, multicenter study evaluating 177Lu-NeoB in combination with capecitabine, a known radiosensitizer, in patients with ER+/HER2− ABC with GRPR expression after progression on prior ET plus a CDK4/6i. Methods: The NeoB D1 study includes dose-escalation and dose-optimization parts for 177Lu-NeoB. Eligible patients include adult men and pre/peri/postmenopausal women with histologically or cytologically confirmed ER+/HER2− ABC and measurable disease per RECIST v1.1. Pre/perimenopausal women are only included in the phase II part of the trial and will require, along with men, the addition of a gonadotropin-releasing hormone analogue. Patients can have received one to three prior lines of ET in the ABC setting, one of which is required to have included a CDK4/6i. If the participant has progressive disease while on or within 12 months of adjuvant treatment, this is considered a line of therapy. For patients with a confirmed deleterious or suspected deleterious germline BRCA1/2 mutation, prior treatment with a PARP inhibitor is allowed. For patients with HER2-low disease, prior treatment with trastuzumab deruxtecan is allowed. All patients are required to have diagnostic screening with a target lesion showing uptake of [68Ga]Ga-NeoB. In the phase I part of the study, patients will receive 177Lu-NeoB at 150 millicurie (mCi) Q6W plus capecitabine (1000 mg/m2 BID for 14 days, followed by 7 days off). If dose escalation is supported, then patients will be randomized to the two higher dose levels (200 mCi Q6W or 100 mCi Q3W); if dose escalation is not supported, then lower dose levels will be explored. The phase II part will randomize patients to two dose levels of 177Lu-NeoB plus capecitabine based on multiple different scenarios. Treatment duration of 177Lu-NeoB is planned to be six administrations for the Q6W regimen and 12 administrations for the Q3W regimen. The primary objectives of the dose-escalation part are the incidence and severity of dose-limiting toxicities and adverse events and dose modifications of 177Lu-NeoB plus capecitabine. The dose-optimization primary objectives are objective response rate, clinical benefit rate, time to response, duration of response, progression-free survival, and overall survival. Secondary objectives include pharmacokinetic and biodistribution (dosimetry) data. Planned enrollment is approximately 58 patients across both phases. Patient enrollment is currently open. ClinicalTrials.gov ID: NCT06247995. Citation Format: Mario Campone, Louise Emmett, Dejan Juric, Debasish Tripathy, Sonia Pernas, Monica Zuradelli, Kevin Perraud, Aleix Prat. Phase I/II study of the novel radioligand therapy [177Lu]Lu-NeoB plus capecitabine in patients w/ ER+/HER2- advanced breast cancer (ABC) w/GRPR expression after progression on prior endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK4/6i) for ABC [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-10-17.