Safety and Efficacy of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Mantle Cell Lymphoma: A Multicenter, Open-Label, Phase II Study

Mantle cell lymphoma (MCL), a subtype of aggressive B-cell non-Hodgkin lymphoma (NHL), remains challenging with unsatisfied outcomes from standard therapy. The clinical significance of Bruton's Tyrosine Kinase (BTK) inhibitors has been validated in multiple subtypes of NHL. Ibrutinib, the first BTK inhibitor, has been approved by FDA for the treatment of refractory and relapse (r/r) MCL. In spite of encouraging efficacy, clinically often referred adverse events such as diarrhea, bleeding and atrial fibrillation, respectively following ibrutinib treatment. It has been hypothesized that poor target selectivity (inhibitive effect on EGFR, TEC, BMX and others) may partially explain the occurrence of these adverse events. As such, there are focused efforts to develop new BTK inhibitor with high target selectivity aiming to improve the safety. Orelabrutinib (ICP-022) is a novel, potent irreversible BTK inhibitor with high selectivity for BTK vs other kinases including TEC- and EGFR-family members. Results from Phase I study demonstrated excellent safety/tolerability profiles as well as favorable pharmacokinetic and pharmacodynamic properties. Sustained BTK occupancy at 24 hr was achieved with once daily dosing regimen. In this presentation, we describe the clinical results of orelabrutinib in Chinese patients with r/r MCL. This is an open-label, multicenter, two stages, phase II study. The primary endpoint was objective response rate (ORR) and the duration of response (DOR) and safety were chosen as secondary endpoints. The stage I was designed for regimen selection (RP2D, N=20 for 100 mg, bid and 150 mg, qd each, respectively), while the stage II for efficacy at RP2D (N=86 150 mg, qd). Response was assessed per Lugano criteria (2014). Total of 106 pts with r/r MCL were enrolled. As of 31 May 2019, sixty-two pts had completed six cycles of treatment (28 days/cycle). The median duration of treatment was 197.5 days. Safety: A total of 106 pts were enrolled and treated at 22 centers in China. The most frequent (>15%) adverse events (AEs) of any cause were mostly hematological toxicities including thrombocytopenia and neutropenia; and respiratory system infections as well as rash. The frequently reported (>10%) grade 3 or higher AEs of any cause were thrombocytopenia (12.3%). No grade 2 or higher hemorrhage was reported. No treatment related grade 3 GI or cardio toxicity was observed. Of the 106 patients, twenty-five experienced serious AEs and 13 of them were treatment-related (primarily occurred as hematologic toxicities and / or infections). Efficacy: Forty patients, divided into two cohorts (n=20 each), were enrolled in stage I. The regimen, 150 mg, qd, was selected as RP2D based on a better ORR and the convenience of once daily dosing. All patients who were enrolled in the stage I continued their treatment. At the time of reporting (the 31 May 2019), 97 patients had response assessments. The response rate was assessed by traditional CT image technology. The ORR was 82.5% (80/97) for combining both regimens with the complete response rate (CR) 24.7% (24/97), partial responses 57.7% (56/97). Stable disease was seen in 9.3% (9/97). The total disease control rate is 91.8%. Six (6.2%) patients progressed by the first response assessment. The median duration of response rate (DOR) has not been reached. Conclusion: Orelabrutinib is safe and well tolerated with no reported treatment related grade 3 or higher GI toxicity, atrial fibrillation/flutter and severe bleeding in this study. Orelabrutinib is efficacious to treat patients with r/r MCL. The improved safety, resulting from high target selectivity, and the convenience of daily dosing regimen provides orelabrutinib as the potential of preferred therapeutic choice for B cell malignancy.