Abstract PS5-07-11: A phase 1 study of LY4257496, a novel GRPR-targeted radioligand therapy, in patients with GRPR-positive metastatic ER+ breast cancer and other advanced solid tumors - OMNIRAY (Trial in Progress)

Abstract Background: Gastrin-releasing peptide receptor (GRPR) is a G protein-coupled receptor overexpressed in estrogen receptor-positive (ER+) breast cancers (BC) and other solid tumors.1 LY4257496 is a novel GRPR antagonist with improved in vivo stability, radiolabeled with lutetium-177, enabling targeted delivery of beta-radiation to GRPR-overexpressing cancer cells leading to DNA damage and cell death. The OMNIRAY phase 1 trial is evaluating LY4257496 as monotherapy in patients (pts) with GRPR-positive advanced solid tumors and in combination with endocrine therapy (ET), CDK4/6 inhibitor (CDK4/6i) therapy, or cytotoxic chemotherapy in pts with GRPR positive, ER+, HER2- metastatic breast cancer (MBC). Trial Design: This is a global, first-in-human phase 1a/b trial of LY4257496 in pts with selected GRPR-positive advanced solid tumors, including dose escalation of LY4257496 monotherapy followed by dose expansion of LY4257496 alone and in combination with other anti-cancer therapies. Dose escalation will enroll pts with ER+ MBC (HER2- or HER2+), colorectal cancer (CRC), metastatic castration-resistant prostate cancer (mCRPC), and endometrial cancer in cohort A1 and pts with ER+, HER2- MBC in the randomized dose optimization cohort A2. Dose expansion will enroll pts with ER+, HER2- MBC treated with LY4257496 monotherapy (cohort B1) and in combination with ET (cohort B2), capecitabine (cohort B3), or ET + abemaciclib (cohort B4). Additional monotherapy cohorts will include CRC (cohort C) and other GRPR-positive solid tumors (cohort D). Monotherapy dose escalation will be evaluated using a modified toxicity probability interval-2 (mTPI-2) design. In dose expansion, each combination cohort will include a safety lead-in of 3-6 pts. LY4257496 will be administered intravenously on an every 4 to 6 weeks treatment cycle for up to 6 cycles. Split dosing (treating on D1 and D8 of each cycle) will also be explored. Eligibility criteria: Eligible pts must have a locally advanced, unresectable, or metastatic solid tumor that is GRPR-positive on screening nuclear medicine GRPR imaging (SPECT/CT or PET/CT) as assessed by the treating investigator based on imaging interpretation manual. In dose escalation, pts with ER+ MBC may have received up to 5 prior systemic treatment regimens. In dose expansion, prior therapy requirements are outlined in the Table below. Key exclusions include prior radiopharmaceutical (except 177Lu-PSMA-617 for mCRPC), recent pancreatitis, and untreated central nervous system metastases. Key study objectives: Evaluate safety, antitumor activity, optimal dose, PK, and biodistribution and dosimetry of LY4257496. Citation Format: K. Jhaveri, L. Bodei, P. Bedard, K. Jerzak, D. Juric, J. O'Shaughnessy, E. Mayer, N. Harbeck, H. Rugo, A. Bardia, P. Veit-Haibach, P. Heidari, V. Prasad, K. Herrmann, C. Trieu, F. Almaguel. A phase 1 study of LY4257496, a novel GRPR-targeted radioligand therapy, in patients with GRPR-positive metastatic ER+ breast cancer and other advanced solid tumors - OMNIRAY (Trial in Progress) 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 PS5-07-11.