Inhibition of ROR1 signaling with zilovertamab plus ibrutinib in chronic lymphocytic leukemia: safety, mechanistic insights, and an exploratory signal in del(17p) disease.

The receptor tyrosine kinase‑like orphan receptor (ROR1) is aberrantly expressed on chronic lymphocytic leukemia (CLL) cells and promotes survival signaling through NF‑κB, ERK1/2, and mTORC1. Zilovertamab is a humanized monoclonal antibody targeting ROR1. We conducted a multicenter phase 1b/2 study of zilovertamab plus ibrutinib (Z + I) in relapsed/refractory CLL. Phase 1b/2a (N = 34) established a recommended zilovertamab dose based on safety, pharmacokinetics, and ROR1 occupancy. In phase 2b, patients were randomized to zilovertamab plus ibrutinib (N = 18) or ibrutinib alone (I; N = 10); the primary endpoint was complete response (CR) per iwCLL, with progression‑free survival (PFS) and safety as secondary endpoints. Z + I was well tolerated, with no dose‑limiting toxicities and safety profile consistent with BTK inhibition. CR rates, overall response, and PFS were similar between randomized arms. In a post hoc subset of 10 patients with del(17p), Z + I was associated with prolonged disease control relative to historical BTK inhibitor experience; this hypothesis-generating observation requires prospective confirmation. Zilovertamab achieved ROR1 occupancy and attenuated NF‑κB, ERK1/2, and mTORC1 signaling in CLL cells, supporting further exploration of ROR1‑targeted strategies in biologically high‑risk CLL. The study was registered at ClinicalTrials.gov (NCT03088878).