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Abstract Background: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a validated therapeutic target in haematologic malignancies, including chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL), where it is selectively expressed on tumour cells but absent from most normal adult tissues. Over 200 patients have been treated with ROR1-directed therapies—including monoclonal antibodies, CAR-T cells, and ADCs—without evidence of on-target, off-tumour toxicity. Importantly, ROR1 is also expressed at low levels on quiescent cancer-initiating stem cells (CISCs), which evade conventional therapies and contribute to disease persistence and relapse. Targeting this compartment may offer a path to deeper and more durable remission. NVG-111 is a novel, humanised, first-in-class bispecific T-cell engager (TCE) that binds ROR1 and CD3. Similar in size to blinatumomab, NVG-111 is designed to redirect cytotoxic T cells to eliminate ROR1-expressing tumour cells, including CISCs. Here we report final safety and efficacy data, with all eligible participants completing 2-year follow-up after time-limited exposure to NVG-111 and data lock in February 2025. Methods: This open-label, dose-escalation study (NCT04763083) evaluated the safety, pharmacokinetics, and efficacy of NVG-111, administered as continuous intravenous infusion across 6 dose levels (0.3–45 µg/day). Fourteen ROR1-positive participants (CLL, n=11; MCL, n=3) received NVG-111 either as monotherapy (n=5) or with ibrutinib (n=9). Median age was 60 years (range 52–83); median prior lines of therapy: 2 (range 2–6), including chemoimmunotherapy and BTKi. Step-up dosing was used in later cohorts. Primary endpoints were safety and tolerability; secondary endpoints included ORR, CR, DoR, and PFS per iwCLL or Lugano criteria. Results: Between May 2021 and April 2023, 14 patients were enrolled (11 CLL, 3 MCL). Per protocol, 13 were evaluable for safety and 12 for efficacy. Among the 11 CLL patients, 9 (82%) had high-risk molecular features, including TP53 aberrations (22%), ATM mutations (44%), and NOTCH1 mutations (11%). All received time-limited NVG-111 therapy, with a median of 3 treatment cycles (range 1–6), per protocol. Treatment-emergent adverse events (TEAEs) occurred in all safety-evaluable participants, mostly during the first week and all fully reversible. Common TEAEs were Grade 1–2 nausea, headache, and fatigue. Cytokine release syndrome (CRS) was observed in 57% (all Grade 1–2) and ICANS in 14% (Grade 2–3). Three DLTs occurred, all reversible. Haematotoxicity was limited to one case of Grade 4 neutropenia, resolved within 48 hours with G-CSF. Mild, transient neutrophilia was seen in all others. Pharmacodynamic analyses showed robust CD8+ T cell activation on-treatment without signs of exhaustion across dose levels. Normal mature B cells were preserved, reducing risk of immunoparesis. Among efficacy-evaluable patients, 67% (8/12) had objective responses, including 33% (4/12) complete responses. Deeper responses were seen with additional cycles. Responders entered a 2-year follow-up without further NVG-111 exposure. With all participants completing follow-up, median PFS was 26.9 months. More than half remained in ongoing response, with restricted mean DoR estimated at 18.3 months. Conclusion: NVG-111, a first-generation ROR1-targeting bispecific TCE, shows encouraging and durable anti-tumour activity in relapsed/refractory CLL and MCL, with a safety profile consistent with its mechanism. Despite limited treatment, outcomes compare favourably with those of continuously administered next-generation BTK inhibitors in R/R CLL. These long-term follow-up data support clinical proof of concept for selective ROR1 targeting via bispecific TCEs. This differentiated approach warrants further evaluation in B-cell malignancies and other ROR1-expressing tumours.