Efficacy and Safety of Orelabrutinib in Relapsed/Refractory Waldenstrom's Macroglobulinemia Patients
Authors: Zhou Daobin , Jin Jie , Fu Zheng-zheng , Yi Shuhua , Zhao Wei Li , Sun Zimin , Yang Wei , Li Dengju , Cui Guohui , Hu Jianda , Liu Ting , Song Yongping , Xu Bing , Zhu Zunmin , Xu Wei , Zhang Mingzhi , Tian Yamin , Zhu Huaqiang , Zhang Bin , Zhao Renbin , Zhang Xiang-Yang 
Published: November 2021

Abstract
Background
Waldenstrom's Macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with immunoglobulin M (IgM) monoclonal gammopathy. Bruton's tyrosine kinase (BTK) plays a key role in signaling pathways for the survival of WM clone, particular in patients harboring MYD88 L265P mutations. However, due to target selectivity issue, Clinical uses of early BTK inhibitors are still compromised with off-target activities to many other kinases besides BTK. Orelabrutinib is a novel, highly potent small molecule inhibitor of BTK with superior selectivity for B-cell malignancies and autoimmune diseases. Preliminary efficacy and safety data of ICP-CL-00105 in relapsed/refractory WM patients are presented here.
Methods
ICP-CL-00105 is a single arm, multiple centers, open label, phase 2 study in clinical and histopathological confirmed patients with R/R WM requiring treatment per IWWM-7. MYD88 and CXCR4 mutations were assessed in bone marrow samples at baseline. Orelabrutinib at a daily dose of 150mg was administered orally until disease progression or unacceptable toxicity. Blood samples for IgM were assessed at baseline and every cycle for 6 cycles and every 3 cycles thereafter by central lab. Responses were assessed in accordance with IWWM-6 and NCCN guidelines. The primary endpoint was major response rate (MRR) as assessed by IRC. Key secondary endpoints were MRR as assessed by investigator, overall response rate (ORR), duration of major response (DOMR), progression-free survival (PFS), OS, changes in IgM levels from baseline, improvement on hemoglobin levels and safety. Treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) were assessed according to NCI CTCAE v4.03.
Results
As of June 1, 2021, for the 47 patients the median follow-up duration was 10.5 months. The median age was 63 years (range, 56-68 years), 40 patients (85.1%) were male. 87.2% of patients were at intermediate or high risk according to the Prognostic Scores (IPSS). The proportion of patients with MYD88 L265PCXCR4 wildtype was 83% at baseline. With a median duration of treatment of 9.2 months, MRR was 74.5% as assessed by investigator. ORR was 87.2% with 97.9% patients achieved disease control. The estimated 12-month DOMR were 89.5%. The estimated 12-month PFS and OS were 88.0% and 92.3%, respectively. The median PFS and median OS have not been reached. The MRR was higher in patients with MYD88 L265PCXCR4 wildtype (79.5%). The median IgM level was 30.3g/L at baseline. The decline in the serum IgM levels from baseline were observed with a median reduction by 79.0% (IQR: -89.4, -57.2). The median hemoglobin level at baseline was 102g/L. Durable improvement in hemoglobin levels was found in 83% of patients with a median maximal improvement of 40g/L (IQR: 24.0, 62.0).
Safety data were summarized by the cutoff date of June 1, 2021. The most commonly reported AEs were thrombocytopenia (27.7%)，neutropenia (14.9%), leukopenia (10.6%), upper respiratory infection (14.9%)，weight increased (14.9%), influenza-like disease (12.8%) and rash (10.6%). Most reported AEs (89.5%) were grade 1-2. 16 patients (34.0%) reported grade ≥ 3 TEAE while 9 patients (19.1%) reported grade ≥ 3 TRAE. There was no reported grade ≥3 atrial fibrillation and/or atrial flutter, or grade ≥3 diarrhea. Only One TRAE (2.1%) resulted in drug discontinuation.
Conclusion
Orelabrutinib has demonstrated substantial efficacy in treating r/r WM patients under short-term follow-up. It has shown favorable safety and tolerability profile with limited off-target adverse effects. It has the potential to be a promising treatment option for r/r WM patients.

Disclosures
Hu: Astellas Pharma, Inc.: Research Funding. Tian: Innocare pharma: Current Employment. Zhu: Innocare pharma: Current Employment. Zhang: Innocare pharma: Current Employment. Zhao: Innocare pharma: Current Employment. Zhang: Innocare pharma: Current Employment.