The preliminary results of MRG001-C002: A phase II Study of MRG001 combined with Orelabrutinib in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL)

Abstract Background: Patients (pts) with R/R DLBCL who failed with multi-agent therapy have a poor prognosis. MRG001 is a CD20-directed antibody drug conjugate (ADC) composed of a chimeric anti-CD20 monoclonal antibody (mAb) conjugated to the monomethyl auristatin E (MMAE) via a valine citrulline linker. MRG001 had shown clinical efficacy in the previous R/R DLBCL study [Yuqin Song, Blood, 2021]. To further enhance the efficacy, we explored the combination therapy. Orelabrutinib, a new-generation bruton's tyrosine kinase (BTK) inhibitor, has no off-target impact on interleukin-2 (IL-2)-inducible T cell kinase pathway. It can preserve NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC) induced by anti-CD20 mAb and enhanced the apoptosis of tumor cells, which may have compelling mechanistic synergy with MRG001. Preclinical study had shown the addition of orelabrutinib to anti-CD20 mAb had produced promising anti-tumor effects in B-cell lymphomas [Yu H, Mol Ther Oncolytics, 2012]. To validate the synergistic potential of combining these two agents, we conducted the multicenter Phase II study, aimed to evaluate the safety and efficacy of MRG001 in combination with Orelabrutinib in R/R DLBCL. Here we reported the preliminary results. Methods: Pts aged ≥18 years with ECOG PS 0-2, histologically diagnosed R/R DLBCL who had failed at least 1 prior therapy were enrolled. All pts received MRG001 1.8 mg/kg intravenously once every 3 weeks, Orelabrutinib 150 mg orally once daily, from day 2 to day 21 in 21-day cycles, until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was overall response rate (ORR) assessed by investigators according to the Lugano response criteria, secondary endpoints were progression free survival (PFS), duration of response (DoR) and safety. Results: As of the data cutoff date (Jun 20, 2025), 22 pts were enrolled and received ≥1 dose of MRG001 and orelabrutinib. Of these pts, 2pts withdrew early and 4 pts had not yet reached their first tumor evaluation, resulting in 16 efficacy-evaluable pts with ≥1 post-baseline tumor assessment. The median follow-up was 3.8 months (range: 1.8–5.5). Baseline characteristics of the enrolled cohort (n=22) reflected a heavily pretreated population: the median age was 58 years (32-74); 11 (50.0%) pts were male; 14 (68.6%) pts had an ECOG PS 1 and 3 (13.6%) pts had an ECOG PS 2; the median prior therapy lines was 3 (1-10), with 11 (50.0%) pts having received ≥3 prior lines; and 8 (36.4%) presenting with bulky disease (≥7.5cm). Among the 16 efficacy-evaluable pts, ORR was 75.0% (95% CI: 47.6, 92.7), comprising 4 (25.0%) complete responses (CR) pts and 8 (50.0%) partial responses (PR) pts. An additional 3 pts (18.8%) achieved stable disease, yielding a disease control rate (DCR) of 93.8% (95% CI: 69.8, 99.8). Median progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were not yet mature at the time of analysis. Notably, high activity was observed in key high-risk subgroups. Among the 4 pts previously exposed to anti-CD3/CD20 bispecific antibodies, 3 pts achieved PR and 1 pt achieved CR (ORR 100%). In the 8 evaluable pts with ≥3 prior lines, ORR was 87.5% and DCR was 100.0%. For the 4 evaluable pts with bulky disease, ORR was 50.0% and DCR was 100.0%. Treatment related adverse events (TRAEs) occurred in 21 of 22 (95.5%) pts. The most commonly reported TRAEs were neutrophil count decreased (72.7%), white blood cell count decreased (63.6%), anemia (50.0%), and platelet count decreased (50.0%). Grade 3/4 TRAEs were observed in 14 (63.6%) pts, predominantly neutrophil count decreased (54.5%), and white blood cell count decreased (36.4%). No treatment-related tumor lysis syndrome occurred, and no TRAEs led to discontinuation or death. Conclusion: Phase II results show that MRG001 combined with Orelabrutinib had clinically encouraging antitumor activity in pts with R/R DLBCL. Additionally, the safety profile was manageable, and pts tolerated treatment well. The trial is still ongoing.