Orelabrutinib Combined with Bendamustine-Rituximab or Obinutuzumab Followed By Orelabrutinib Maintenance Therapy for Untreated Marginal Zone Lymphoma (MZL): A Prospective ,Multicenter, Clinical Study（Optimize Study）
Authors: Zhang Xuewu , Zhu Yanan , Zhang Xiang , Ye Xingnong , Xu Gaixiang , Ma Liya , Ren Yanling , Mao Liping , Yang Min , Yang Chunmei , Wei Juying , Lou Yinjun , Mai Wenyuan , Xie Wanzhuo , Meng Haitao , Tong Hongyan , Jin Jie , Yu Wenjuan 
Published: December 2024

Background:
There is no standard front-line therapy for MZL patients requiring systemic treatment. Exploring more effective, low-toxicity treatment regimens for MZL patients is a scientifically valuable and clinically significant attempt. Reducing chemotherapy cycles or chemo-free therapy for untreated MZL is a growing trend. BTK inhibitors have shown durable responses with a favorable benefit-risk profile for all MZL subtypes in the relapsed setting. Orelabrutinib, a novel highly selective BTK inhibitor, has been approved by the NMPA for the treatment of MZL in patients who have received at least one prior treatment. Orelabrutinib has demonstrated an overall response rate (ORR) of 58.9%, 24-month progression free survival (PFS) rate of 75.8%, and acceptable safety for previously treated pts with MZL (Deng et al. Am J Hematol. 2023). The ongoing Optimize prospective trial is exploring efficacy and safety of orelabrutinib plus bendamustine-rituximab or obinutuzumab in untreated MZL.
Methods:
Optimize study (NCT06504940) is a phase 2, prospective, multicenter study of orelabrutinib plus bendamustine-rituximab or obinutuzumab in pts with untreated MZL. This study included two groups of group A and group B. Group A: for pts with age &lt; 70 years and good fitness, pts will receive 3 cycles of orelabrutinib plus bendamustine-rituximab (BR:B70mg/m2 d1-2; R375mg/m2 d0). Pts who achieved PR or better entered the maintenance phase of orelabrutinib monotherapy (up to 21 cycles, 28 days per cycle). Orelabrutinib was administered at a dose of 150mg QD throughout the study. Group B: for pts with age ≥ 70 years or with age &lt; 70 years and poor fitness, pts will receive 6 cycles of orelabrutinib plus obinutuzumab (G 1000mg iv D1, D8,D15/C1,D1 /C2-C6). Pts who achieved PR or better entered the maintenance phase of orelabrutinib monotherapy (up to 18 cycles, 28 days per cycle). Key inclusion criteria: aged ≥18 years; histologically confirmed MZL (nodal, splenic, or extra nodal); evaluate for indications for treatment; ECOG PS 0-3（if the score is 3 points, the physician needs to evaluate the deterioration of physical condition mainly due to the tumor）; and adequate organ function. Pts with central nervous system (CNS) lymphoma, history of or current relevant CNS pathology, histological evidence of transformation to high-grade or diffuse large B-cell lymphoma, and currently or previously have other malignant tumors are excluded. The primary endpoints of group A are the incidence of grade 3-5 adverse events (AEs) and 12-month complete response rate (CRR). The primary endpoint for group B is 2-year progression-free survival (PFS) rate. Key secondary endpoints are overall response rate (ORR), duration of response (DOR), time to response(TTR), overall survival and safety. The trial is currently recruiting and is expected to enroll approximately 37 pts in group A and 36 pts in group B.