MO01.33 CRESTONE – Clinical Study of REsponse to Seribantumab in Tumors with NEuregulin-1 (NRG1) Fusions – A Phase 2 Study of the anti-HER3 mAb for Advanced or Metastatic Solid Tumors (NCT04383210)

NRG1 (Neuregulin-1) gene fusions are rare oncogenic drivers found in 0.2% of solid tumors, including lung, pancreatic, gallbladder, breast, ovarian, colorectal, neuroendocrine, and sarcomas. is the predominant ligand HER3 to a lesser extent HER4. fusion proteins retaining an active EGF-like domain drive tumorigenesis proliferation through aberrant activation. Importantly, often mutually exclusive with other known driver alterations. have been correlated worse overall disease-free survival poor response treatment standard therapies chemotherapy, PD-(L)1 checkpoint inhibitors combinations these agents. Inhibition its dimerization partners represents rational novel therapeutic approach for tumors harboring supported by case studies clinical responses anti-HER3 antibodies or pan-ERBB (tyrosine kinase inhibitors) TKIs like afatinib. Seribantumab fully human IgG2 mAb against uniquely able inhibit NRG1-dependent activation HER3, HER3-HER2 dimerization, downstream signaling PI3K/AKT MAPK pathways. The safety profile seribantumab has well characterized prior monotherapy combination over 800 patients. CRESTONE open label, multicenter Phase 2 basket trial adult patients fusion-positive locally advanced metastatic who progressed on nonresponsive available therapies. will enroll at least 75 previously treated across three cohorts. Cohort 1 (N=55) include not received any ERBB targeted therapy. (up N=10) after which includes 3 without binding domain. status enrollment be determined local CLIA similarly accredited molecular assay. centrally confirmed using RNA-based NGS This study evaluate dosing regimen weekly induction, biweekly consolidation, Q3W maintenance designed rapidly achieve steady state levels, optimize exposure, deliver maximal inhibition. primary endpoint ORR per RECIST v1.1 independent radiologic review. Secondary endpoints duration (DoR), safety, PFS, OS, benefit rate. An interim analysis planned following 20 1. accruing United States. Clinical information: NCT04383210.