Safety, Tolerability and Efficacy of Orelabrutinib, Once a Day, to Treat Chinese Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Cell Leukemia

Bruton's Tyrosine Kinase (BTK) plays a critical role in B-cell receptor (BCR) signaling, which mediates B-cell proliferation, migration, and adhesion. As a therapeutic target, its clinical significance has been well established in multiple subtypes of non-Hodgkin's lymphoma (NHL). Orelabrutinib (ICP-022) is a novel, potent irreversible BTK inhibitor with much improved target selectivity in comparison to Ibrutinib and Acalabrunitib, which leads to improved safety profiles. With a proprietary formulation, Orelabrutinib achieves high bioavailability comparing to other BTK inhibitors. Results of Phase I study (another presentation on Orelabrutinib) demonstrated favorable pharmacokinetic and pharmacodynamic properties for Orelabrutinib. Sustained BTK occupancy at 24 hr was achieved with daily dosing regimen. In this presentation, we will report results from clinical study of Orelabrutinib in Chinese patients with r/r CLL/SLL. This is an open-label, multicenter, Phase II study with objectives to evaluate its safety, tolerability and efficacy following oral daily administration. The primary endpoint was objective response rate (ORR). The duration of response (DOR), progression-free survival (PFS) and safety were chosen as secondary endpoints. Response was assessed per 2008 IWCLL criteria with modification for PR with lymphocytosis (PR-L) (Cheson, Hallek 2012). This study is composed of two stages. The stage I was to assess the safety and tolerability of Orelabrutinib at 150 mg, QD in pts with r/r CLL/SLL, while the stage II was to evaluate its therapeutic benefits (N=80, 150 mg, QD). Total of 80 patients with r/r CLL (n=70)/SLL (n=10) were enrolled. As of 31 May 2019, 40 pts had completed six cycles of treatment (28 days/cycle). The Median follow-up was 6.3 months (range, 0.4-13.7 months). Safety: The most frequent (≥15%) any grade adverse events (AEs) of any cause were well characterized hematological toxicities: thrombocytopenia, neutropenia, and anemia; and respiratory system infections as well as purpura. No case of atrial fibrillation or secondary malignancy was reported. The most frequently (≥10%) reported ≥ Grade 3 AEs of any cause were neutropenia, thrombocytopenia, lung infection. Twenty-five pts experienced at least one serious AE. Of those, 13 were considered related to Orelabrutinib treatment, including platelet count decrease (3 pts), pneumonitis, pyrexia (2 pts each) and herpes zoster etc. (1 pt each). Efficacy: Of the 80 enrolled pts, seventy-eight pts were evaluable for response (by 31 of May 2019), the ORR was 88.5% (69/78). Among them, one patient was reported as CR, 39 pts were PR and 29 pts were PR-L. Stable disease was seen in 6/78 (7.7%). Total disease control rate is 96.2%. The median DOR was not reached, 6 months DOR rate was 89.8%. Subgroup analysis (age, disease stage, previous treatment, 17p deletion, 11q deletion, IGHV mutation) did not reveal significant differences. Conclusion: Orelabrutinib is safe and well tolerated. No significant adverse events like atrial fibrillation/flutter or secondary malignancies were reported. Orelabrutinib is efficacious to treat pts with r/r CLL/SLL. The improved safety, resulting from high target selectivity, and daily dosing regimen enable Orelabrutinib to be a valuable therapeutic choice both as monotherapy and likely in combination with other agents to treat B-cell malignancies.