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

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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).