Orelabrutinib combined with bendamustine-rituximab or obinutuzumab followed by orelabrutinib maintenance in untreated marginal zone lymphoma (Optimize): A multicenter, single-arm, phase II study

Abstract

Abstract Background: The absence of a standard first-line treatment for marginal zone lymphoma (MZL) and the toxicities of existing systemic therapies have inspired the exploration of novel regimens. In recent years, Bruton's tyrosine kinase inhibitors (BTKis) have demonstrated durable responses with a favorable benefit-risk profile across all MZL subtypes in the relapsed/refractory setting. Orelabrutinib is a novel BTK inhibitor with higher selectivity and fewer off-target than other BTK inhibitors. The National Medical Products Administration has approved it for the treatment of patients (pts) with MZL who have received at least one prior treatment. Aims:To evaluate the efficacy and safety of orelabrutinib plus bendamustine-rituximab or obinutuzumab followed by orelabrutinib maintenance in untreated MZL. Methods Optimize was a multicenter, open-label, single-arm, phase II study (NCT06504940) that recruited treatment-naïve pts with MZL from 7 centers in China. Fit pts aged 18-70 years (group A) received 3 cycles of induction treatment with orelabrutinib (150 mg/day) plus bendamustine (70 mg/m2 on days 1-2) and rituximab (375 mg/m2 on day 0), while pts aged ≥70 years or unfit pts aged <70 years (group B) received 6 cycles of orelabrutinib (150 mg/day) plus obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2-6) every 4 weeks. Subsequently, pts without disease progression in both groups continued orelabrutinib maintenance at the same dose and scheduled for up to 21 (group A) or 18 (group B) cycles. The primary endpoint was complete response rate (CRR) at the end of induction treatment for both groups. Key secondary endpoints in both groups were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results As of Jul 2025, a total of pts were enrolled (group A, n=19; group B, n=6). The median age of overall population was 60.0 years (group A, 59.0 years; group B, 70.5 years), and 48% of pts were male (group A, 57.9%; group B, 16.7%). The majority of pts presented with MALT lymphoma (overall, 64.0%; group A, 63.2%25; group B, 66.7%) and had Ann Arbor stage II-IV disease (overall, 80%; group A, 84.2%; group B, 66.7%). International Prognostic Index (IPI) score of 2/3 and Ki-67 expression of >20% were reported in 48.0% (group A, 47.3%; group B, 50%) and 24.0% (group A, 21.1%; group B, 33.3%) of pts, respectively. At the end of induction treatment, efficacy evaluation was conducted in 12 pts in group A and 3 pts in group B. The CRR was 75% (9/12) in group A and 66.7% (2/3) in group B. The ORR was 93.3% and the CRR was 93.3% in the overall population. At the data cutoff, the median PFS and OS remained immature. Grade 3-4 adverse events (AEs) were occurred in 43.7% of pts overall (group A, 46.2%; group B, 33.3%).The primary toxicities were hematologic, including neutropenia, thrombocytopenia, and leukopenia. No BTKi-related AEs, such as atrial fibrillation or bleeding, were observed. Conclusion:Orelabrutinib combined with bendamustine-rituximab or obinutuzumab followed by orelabrutinib maintenance was effective and well-tolerated in untreated pts with MZL. The study is ongoing, with updated efficacy and safety data to be released in the future.