Background: Marginal Zone Lymphoma (MZL) is a group of B-cell malignancies. Orelabrutinib (ORE), the first approved BTKi in China for patients after at least one treatment. This phase II trial evaluates the efficacy and safety of orelabrutinib combined with obinutuzumab (OG) in treatment-naïve MZL.

Method: This prospective single-arm phase II trial (NCT06513234) enrolled systemic treatment-naïve patients with MZL, including those who previously received local therapy and/or antimicrobial therapy, and subsequently progressed or relapsed, or are unsuitable for local therapy. Treatment consisted of: Induction phase (6 cycles, 28 days/cycle): Orelabrutinib (150mg/day orally), Obinutuzumab (1000mg IV, C1: D1/D8/D15; C2-6: D1). Maintenance phase (≤18 cycles): Orelabrutinib monotherapy (150mg/day). Primary endpoint: 12-month complete response rate (CRR); Secondary endpoints: ORR, PFS, OS, and safety. A Bayesian optimal phase II design was employed (allowing for ~15% dropout).

Result: As of Jul 2025, 33 patients were enrolled (MALT 12.1%, NMZL 21.2%, SMZL 66.7%), baseline characteristics: median age 60 years (range 29–80 years), staging: stage IVA 63.6% (21/33), stage IVB 27.3% (9/33); 81.8% (27/33) with bone marrow involvement, 75.8% (25/33) with splenomegaly. MZL-IPI ≥ 2 points 63.7% (21/33). Among 27 efficacy-evaluable patients:25 patients completed interim assessment (3/4 cycles): ORR 96.0% (95%CI 79.6-99.9), CR rate 72.0% (50.6-87.9); 10 patients completed 6 cycles assessment: ORR 100% (69.2-100), CR rate 70.0% (34.8-93.3). Best response: CR rate 74.1% (53.7-88.9), ORR 96.3% (81.0-99.9). By Subtype (Best Response):17 pts of SMZL: CR rate 82.4% (14/17), ORR 94.1% (16/17). 7 pts of NMZL: CR rate 42.9% (3/7), ORR 100% (7/7); 3 pts of MALT all achieved CR. With a median follow-up of 4.6 months (range 0–10.7), one patient (SMZL) experienced disease progression (PD). Median PFS and OS were not reached. Common adverse events are grade 1-2 hematological toxicity, and no unexpected adverse events have occurred.

Conclusion: The OG regimen demonstrated promising antitumor activity in treatment-naïve MZL with no severe toxicities observed. These early results support OG as a potential chemotherapy-free first-line option for MZL. Longer follow-up is needed to assess durability of response and survival outcomes.

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2025
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