FiREBOLT: A phase 1 study evaluating radioligand therapy with LY4337713 in adults with select FAP+ solid tumors (Trial in progress)

Background: Fibroblast activation protein (FAP) is a transmembrane glycoprotein highly expressed on cancer-associated fibroblasts in tumor stroma but minimally expressed in normal adult tissues 1 . FAP-targeted imaging radioligands have shown high rates of positivity across a wide range of cancers. However, first-generation FAP-targeting therapeutic radioligands have been limited by rapid tumor washout, resulting in low absorbed doses and limited efficacy. LY4337713 is a next-generation FAP-targeting radioligand therapy labeled with Lu-177 that demonstrated high tumor retention, for at least up to 144 hours 2 , while maintaining rapid normal organ clearance in preclinical studies and in a clinical imaging study. Methods: FiREBOLT is a phase 1a/1b, open-label, multicenter study of LY4337713 in participants (pts) with select FAP+ advanced/metastatic solid tumors (NCT07213791), specifically breast cancer (HR+/HER2-, HER2+, triple-negative [TNBC]), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), cholangiocarcinoma (CCC), ovarian, gastric, or esophageal cancers. Eligible pts must have RECIST measurable disease and FAP uptake confirmed by imaging. Prior lines of therapy allowed are outlined in the Table. Phase 1a dose escalation will assess safety and tolerability of LY4337713 monotherapy. The dose-limiting toxicity (DLT) monitoring period will be 28 days and the modified toxicity probability interval-2 (mTPI-2) statistical model will guide dose decisions to determine the maximum tolerated dose (MTD) or the highest tested dose deemed safe. Previously cleared dose levels with therapeutically relevant exposures or direct evidence of clinical activity will permit backfills. In dose optimization, pts will be randomized 1:1 between 2-3 dose regimens of LY4337713 to determine the optimal dose level and schedule. Phase 1b dose expansion will assess antitumor efficacy per RECIST 1.1 in tumor-specific cohorts. Additional secondary and exploratory objectives in the study include assessing PK, biodistribution, and radiation dosimetry of LY4337713. Table 1 Fitzgerald A, et al. Cancer Metastasis Rev . 2020, 39(3):783-803 2 Kaoma C, et al. JNM. 2025 , 66(1):251266 Table Phase Tumor Type Prior Therapy Dose Escalation • HR+/HER2- Breast Cancer (BC) • ≤5 prior lines, including CDK4/6 a inhibitor • HER2+ BC • ≥2 HER2 targeted lines, including ≥1 ADC b (if available) • TNBC • ≥2 prior lines for metastatic disease • PDAC • Progressed after 1-2 prior regimens • Ovarian Cancer (platinum resistant or refractory) • ≥1 platinum-based therapy • Other solid tumors (CRC, CCC, gastric, esophageal) • ≥1 prior systemic line (including prior line(s) in combo with immunotherapy or VEGF c inhibitor) Dose Expansion • Advanced or metastatic solid tumors • ≥1 prior line of therapy a CDK 4/6, cyclin-dependent kinase 4/6; b ADC, antibody drug conjugate; c VEGF, vascular endothelial growth factor