Background: BTK (Bruton's tyrosine kinase), a central regulator of the B cell receptor signaling pathway, has been targeted for treating a variety of B cell malignancies and autoimmune diseases. The use of the first generation covalent BTK inhibitors (BTKis) have often resulted in the development of resistance, commonly associated with the mutation at the cysteine 481 where the inhibitor binds covalently; therefore, a non-covalent BTKi will offer greater therapeutic benefits. HBW-3220 is a novel reversible BTKi binding to BTK non-covalently. HBW-3220 has potent inhibitory effects on BTK wild-type and BTK mutants (C481S, C481R, T474I, T316A, etc.). HBW-3220 also has a superior preclinical profile, including better anti-tumor efficacy, PK properties and safety, validating its clinical study in cancer patients. Methods: This is a phase I dose-escalation study in patients with r/r B-cell non-Hodgkin's lymphoma. The dose escalation was performed with the accelerated titration and the "3+3" design. Adverse events (AEs) were assigned according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response assessment for chronic lymphocytic leukemia (CLL) was based on the iwCLL 2018 guidelines, for Waldenström macroglobulinemia (WM) was based on the IWWM-7 consensus, and for all other lymphomas (such as small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), etc.) was based on the Lugano 2014 guidelines. Results: A total of 11 patients were enrolled, and the doses were 15, 30, 60, 90 or 120 mg QD. No dose-limiting toxicity (DLT) occurred in any patient, implicating good tolerability. AEs were similar to other BTKis. Common AEs (≥2 cases, grade 1-3) were neutropenia (n = 2), reduced platelet count (n = 3) and reduced white blood cell count (n = 2). Drug-related grade 3 AEs were neutropenia (n = 1) and pulmonary infection (n = 1). There was no AE leading to discontinuation or dose reduction. 8 patients underwent at least one response assessment, with 1 complete remission (CR) and 5 stable disease (SD). 1 patient (30 mg) with MZL achieved CR at the first response assessment, and her extranodal lesion (2cm*1cm) in the nasopharynx completely disappeared; she remains CR after 20 weeks of medication, and no obvious AEs has been observed! 3 patients in the 60 mg dose group (2 FL and 1 DLBCL) were assessed as SD during the first assessment, and all had tumor shrinkages! 1 MCL patient in the 90 mg dose group has had his lesion reduced by 43%. After oral administration of HBW-3220, the drug exposures show dose-dependent increases, and the time to maximum plasma concentration (Tmax) is 1-4 hours, and elimination half-life (T1/2) is 11-25 hours. Conclusions: The current data show that HBW-3220 is well tolerated and of efficacy in patients with B-cell lymphoma. Its clinical PK characteristics support once-a-day administration. Clinical trial information: ChiCTR20221130.