Orelabrutinib in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma patients: Multi‐center, single‐arm, open‐label, phase 2 study

Orelabrutinib is a novel, small molecule, selective irreversible Bruton's tyrosine kinase inhibitor. The aim of this study was to evaluate the efficacy and safety in patients with refractory or relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This is single‐arm, multi‐center, open‐label, phase 2 study in 80 eligible Chinese patients, who were treated with monotherapy of orelabrutinib at 150 mg once daily. Overall response rate evaluated by an independent review committee was the primary endpoint, and secondary endpoints include progression‐free survival, overall survival, and safety. Independent review committee assessed overall response rate was 92.5% (74/80); complete response 21.3% (17/80), partial response 60.0% (48/80), partial response with lymphocytosis 11.3% (9/80). At a 32.3‐month median follow‐up, the median progression‐free survival had not been achieved, while the 30‐month progression‐free survival rate and overall survival rates were 70.9% (95% confidence interval [CI], 59.5–79.6) and 81.3% (95% CI, 70.8–88.2), respectively. Orelabrutinib also revealed substantial response in patients with high prognostic risks: overall response rates of patients carrying positive TP53 mutational status or del(17p), del(11q), as well as unmutated immunoglobulin heavy‐chain variable region gene were 100%, 94.7%, and 93.9%, respectively. Most adverse events were in low grade, with 86.8% of AEs being Grade 1 or 2. Nearly 67% of patients were still receiving orelabrutinib after almost a 3‐year follow‐up. In conclusion, Orelabrutinib demonstrated compelling efficacy as well as safety profiles, with a noteworthy number of patients obtaining complete response in refractory or relapsed CLL/SLL.

Center for Cancer Personalized Medicine, Nanjing, People's Republic of China. Email: jianyong.lijsh@outlook.com
Orelabrutinib also revealed substantial response in patients with high prognostic risks: overall response rates of patients carrying positive TP53 mutational status or del(17p), del(11q), as well as unmutated immunoglobulin heavy-chain variable region gene were 100%, 94.7%, and 93.9%, respectively. Most adverse events were in low grade, with 86.8% of AEs being Grade 1 or 2. Nearly 67% of patients were still receiving orelabrutinib after almost a 3-year follow-up. In conclusion, Orelabrutinib demonstrated compelling efficacy as well as safety profiles, with a noteworthy number of patients obtaining complete response in refractory or relapsed CLL/SLL.

| INTRODUCTION
Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), one of the most widespread leukemia types, is a B lymphocyte malignancy with indolence, mainly affecting the elderly population, who are prone to have comorbidities. Although CLL/SLL is indolent, some patients will progress over time. The morbidity and mortality are closely related to immunosuppressive and myelosuppressive sequelae.
There are 191 000 newly diagnosed CLL cases and 61 000 deaths every year globally. 1 Chemotherapy agents are the traditional treatment for CLL/SLL. In recent decades, newer therapies such as chemoimmunotherapy (CIT) with rituximab have been introduced and become the standard of care. However, CIT is less effective for certain patients, especially those with high prognostic risks, including the 11q deletion (del(11q)) and 17p deletion (del(17p)), as well as the immunoglobulin heavy-chain variable region gene (IGHV) that is unmutated. 2,3 Novel treatment options are currently available, namely inhibitors targeting B cell receptor (BCR) signaling. 4 Bruton's tyrosine kinase (BTK) plays critical role in hematopoietic cells during the development of B cell lymphomas and leukemia. The first BTK inhibitor developed for CLL/SLL therapy is ibrutinib, which was approved based on phase 3 studies that demonstrated improvements in clinical outcomes among CLL/SLL patients diagnosed as relapsed/refractory (R/R) and treatment naïve. 5,6 However, there are concerns for the clinical use of ibrutinib because of adverse events (AEs), which mostly due to off-target activities. 7 Especially, bleeding, atrial fibrillation, as well as diarrhea have been widely noticed. These AEs were likely due to ibrutinib's low target selectivity causing off-target effects. 5,6,[8][9][10][11][12] The safety concerns are more prominent in the elderly population.
Additionally, long-term treatment for CLL/SLL is very important, since early discontinuation will compromise the efficacy. Thus, novel BTK inhibitors with higher selectivity and improved safety profiles are in urgent need.
Orelabrutinib is a new, irreversible BTK inhibitor that is highly selective ( Figure S1). It is highly potent against BTK (half maximal inhibitory concentration [IC 50 ], 1.6 nM) with remarkably less offtarget inhibition against other tyrosine kinases. 13 In a screening test of 456 kinases in vitro at a concentration of 1 μM, orelabrutinib had significant inhibition only on BTK (> 90%). 14 Compared with other BTK inhibitors, 15 orelabrutinib exhibited a high selectivity profile. Orelabrutinib exhibited linear pharmacokinetic characteristics with doseproportional increases in plasma exposure. The BTK occupancy was nearly complete at dose of ≥50 mg/day and lasted for 24 h. 13,14 The high selectivity and persistent occupancy of the BTK target are expected to lead to substantial improvement of safety and efficacy.
Here we show the results of nearly 3-year follow-up of orelabrutinib in Chinese R/R CLL/SLL patients.

| Study design and participants
Eligibility for this study included patients that had R/R disease after at least one chemotherapy or/and targeted therapy. Additional requirements to be included were Eastern Cooperative Oncology Group (ECOG) ≤ 2 score, minimum age of 18 years old, and adequate organ function and blood cell count (more details in the study protocol of Appendix S1).
Excluded patients had the characteristics: lymphoma of the central nervous system; Richter transformation; uncontrolled or significant cardiovascular disease; past occurrence of pulmonary embolism or deep vein thrombosis; intracranial hemorrhage, stroke, or organ or allogeneic hematopoietic stem cell transplant within the past 6 months; prior exposure to a BTK inhibitor or PI3K, SYK, or BCL2 inhibitor; active infections or uncontrolled human immunodeficiency virus, hepatitis C virus antibody positive, or/and hepatitis B virus (HBV); inducers and inhibitors of cytochrome P450 family 3A (CYP3A) known to be moderate or strong; and other conditions considered not suited by the investigator to take part in the trial (more details in the study protocol of Appendix S1).

| Procedures
This is an open-label and single-arm phase 2 study of orelabrutinib in Chinese patients with R/R CLL/SLL. Two stages were included in this study. Six patients were enrolled in the first stage and received 150 mg orelabrutinib once daily (QD) orally to evaluate safety and tolerability. If dose-limiting toxicity (DLT) events happened in two or more patients, the orelabrutinib dose will be decreased to 100 mg QD. The total enrollment was 80 patients at the recommended dose (150 mg, QD) who continuously received orelabrutinib (28 days/cycle) until progressive disease, death, unaccepted toxicity, withdrawn consent, or loss to follow-up.

| Response and outcome definitions
Independent review committee (IRC)-assessed overall response rate (ORR) described the primary endpoint, defined per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria as the percentage of partial response (PR) or complete response (CR) 16 patients. The primary data analysis was done when the last subject had completed 6 cycles of treatment, or disease progression or early withdrawal or death occurred (whichever occurred first). Secondary endpoints were ORR evaluated by investigator, overall survival (OS), time to response (TTR), progression-free survival (PFS), duration of response (DOR) as well as safety, which were assessed by IRC or investigator. Assessments for response for CLL patients were carried out till progressive disease (PD) following IWCLL 2008 criteria, with modification for partial response with lymphocytosis (PR-L), 16,17 as well as Lugano Classification for patients with SLL. 16,18 The exploratory endpoint was to evaluate the correlation between tumor markers of IGHV or TP53 mutation status, del(11q) or del(17p) (Supplementary Text) as well as ORR, DOR, and PFS. Enhanced computed tomography (CT), otherwise magnetic resonance imaging (MRI), were the imaging assessments conducted every 2 cycles up to cycle 12, then every 3 cycles up to disease progression. Aspirate and biopsy assessments of bone marrow were implemented at screening as well as during the study to confirm CR status. Safety assessments included AEs and measurements of laboratory tests, vital signs, and electrocardiograms (ECGs) conducted at each visit, the end of treatment, and at the investigator's discretion.
The grading of AEs was completed following the National Cancer Institute Common Terminology Criteria for AEs, version 4.03.

| Statistical analysis
It was assumed that orelabrutinib would achieve a 65% ORR versus a 45% ORR for the historical controls (based on the efficacy of medications, which was outlined in National Comprehensive Cancer Network [NCCN] guidance) with 90% power, a 1-sided significance level equaling 0.025, and 95% lower confidence interval (CI) > 45%; therefore, approximately 80 patients were planned to enroll in this study. All patients with confirmation of R/R CLL/SLL that received one or more study drug doses were included in data analysis sets of efficacy as well as safety. The primary efficacy analysis of ORR included the response rates and 95% CIs using the exact binomial test. DOR was the duration beginning from the first response up to disease progression or death. PFS was evaluated from the beginning of first dose to disease progression or death. TTR was measured from the first dose to the first response. Kaplan-Meier methodology was employed for estimating OS, PFS, DOR as well as TTR along with their respective 95% CIs. Completion of statistical analysis was done by SAS software, the version was 9.4 (SAS Institute, Inc.). The study (NCT03493217) has been registered at ClinicalTrials.gov.  carrying IGHV unmutated status. The median time to treatment was 37.7 months (time range was between 3 and 352 months) since initial diagnosis. Nearly half (46.3%) of the patients had been exposed to ≥2 lines of treatment.

| Efficacy
On August 10th 2021, which was the data cutoff, the median follow-  (Table S2). The concordance rate for IRC and investigator evaluations was 96.3%.
The best response rate (CR and PR) increased with treatment time ( Figure S2). Compared with the data at median follow-up of 8.7 months, the CR/CRi rate increased from 3.8% to 21.3% and ORR from 88.8% (95% CI: 79.7-94.7) to 92.5% (95% CI: 84.4-97.2) at median follow-up of 32.3 months. PR-L was converted to PR over time, which contributed to the increase of ORR following long-term treatment. All patients except one exhibited tumor burden reductions, with the majority reduced 50% or more ( Figure S3). The median of the best reduction percentage assessed by IRC was 89.4%.
Orelabrutinib showed a substantial overall response in subgroup analyses, which were preestablished, including subgroups with highly prognostic risks and also other subgroups following clinical features and demographic at baseline ( Figure S4). Observed results were consistent between the subgroup analysis and that of the overall popula-   Figure 2A). Of the 17 patients who achieved CR as the best overall response, the PFS rate was 88.2% (95% CI: 60.6-96.9) at 30 months ( Figure S5A). The 24-month, as well as the 30-month OS rates, were stable at 81.3% ( Figure 2C).

| Safety
At data cutoff, nearly 3-year median follow-up time, 79 (98.8%) patients reported at least one AE ( for both R/R as well as naïve CLL/SLL patients according to the NCCN guidelines. However, ibrutinib's tolerability is quite concerning in real-world treatment. The discontinuation rate was 41% when treated with ibrutinib, and the median time to drug discontinuation was only 7 months in a real-world analysis. 7 Significantly, some AEs of ibrutinib are mainly related to off-target effects, most of which led to drug discontinuation. The rate of toxicity accounting for discontinuation of ibrutinib in patients with treatment naïve CLL/SLL and R/R CLL/SLL were 63.1% and 50.2%, respectively. 7 Orelabrutinib is a novel and highly selective BTK inhibitor with good potential. Compared with ibrutinib, 19  in this group of patients ( Figure S5). In the current study, the median PFS has not been achieved, and the PFS rate at 30 months was 70.9%. DOR was sustained over time from 82.3% (95% CI: 71.4-89.3) at 12 months to 67.5% (95% CI: 54.6-77.5) at 30 months. It is intriguing that the PFS curve was much improved in patients who achieved CR/CRi over those of PR/PR-L ( Figure S5). Similar results were seen in DOR, which demonstrated prolonged survival of patients with sustained deeper responses. In the RESONATE study, the ORR was 91% during the ibrutinib treatment period, and the best response of CR/CRi was 9%. Moreover, the 36-month PFS rate was 59% when treated with ibrutinib. 23 Results of the ASCEND study demonstrated that the ORR for acalabrutinib was 93%, the percentage of patients achieving CR/CRi was 5%, and the 36-month PFS rate showed 63% as evaluated by investigator. 24 In the BGB-3111-205 study, after a median follow-up of 34 months, response was achieved in 87.9% of zanubrutinib-treated patients, and the CR/CRi was 6.6% based on IRC assessments, with 68.1% PFS at 36 months. 22 The baseline characteristics of the patient population in BGB-3111-205 were similar to those in our study, while patients in RESONATE and ASCEND were older with more high-risk prognoses. 22 infections. 21 In acalabrutinib versus ibrutinib head-to-head comparative trial, rates of ≥3 Grade infections were 30.0% in ibrutinib and 30.8% in acalabrutinib. 26 Recently, a systematic review and metaanalysis showed that 25.84% (95% CI: 20.65%-31.39%) patients with R/R CLL/SLL who received BTK inhibitor-based treatments developed severe infections. 33 The incidence of Grade ≥3 infections (TEAEs) was in 30% of the patients in our current study, which was comparable with other BTK inhibitors. Other common AEs associated with ibrutinib include muscle spasms and joint pain, both occurring in ≥20% of relapsed CLL patients. 8 Headache is a common AE of acalabrutinib, with an incidence of 43%. 20 Although the incidence of these AEs (i.e., headache, muscle spasms, and joint pain) at Grade 3 or 4 is relatively low, the impact on patients' quality of life is still a consideration.
In the current study, incidences of all these AEs were very low in patients treated with orelabrutinib, and there were no muscle spasms reported. Orelabrutinib was well tolerated, with a low discontinuation rate of only 7.5%, where the discontinuation rate for ibrutinib was 16%-41% in patients with R/R CLL/SLL. 7,25,34 Overall, orelabrutinib demonstrated a favorable safety profile originating from its high kinase selectivity in this study. Safety data summarized from this study comprise a limited sample size, and a larger randomized study is currently ongoing to further assess safety events of low occurrence.