Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm, multicenter study

Advances in the development of novel targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), particularly those who have either failed or are not candidates for standard immunochemotherapy regimens and/or have high-risk prognostic features (e.g., del[17p], del[11q], complex karyotype cytogenetics, and unmutated immunoglobulin heavy-chain variable region [IGHV]). Principal among these are the inhibitor of phosphoinositide triphosphate kinase delta isoform, idelalisib [1], the B cell lymphoma-2 homology 3 mimetic, venetoclax [2], and the first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib [3].

Constitutive B cell receptor signaling is an important contributor to the survival and proliferation of CLL/SLL [4, 5]. Inhibition of BTK and other proximal kinases in the B cell receptor signaling pathway has been shown to induce profound inhibition of proliferative signaling stemming from the interactions of leukemic cells and their microenvironment [6‐8]. In preclinical studies, ibrutinib inhibited malignant B cell proliferation and survival in vivo, as well as cell migration and substrate adhesion in vitro. Based on the demonstration of clinical benefit in phase 3 studies of relapsed or refractory [9] and treatment-naïve [10] CLL/SLL patients, ibrutinib was granted approval by the US Food and Drug Administration for the treatment of patients with CLL/SLL with or without 17p deletion [11].

Despite the relative clinical success of ibrutinib in the management of CLL/SLL, it is not curative, and complete responses (CR) are relatively uncommon with single-agent therapy. The frequency of adverse events (AE) is also treatment-limiting, resulting in the need for discontinuation in 21% of relapsed/refractory clinical trial participants after a median treatment duration of 39 months [12]; in a clinical practice setting, the discontinuation rate among patients with relapsed/refractory CLL is reported to be as high as 50% [13]. The most frequent AEs leading to discontinuation of ibrutinib include arthralgia, atrial fibrillation, bleeding, second malignancy, general debility, infection, and pneumonitis [14].

Zanubrutinib (BGB-3111) is a novel, oral BTK inhibitor which, like other active BTK inhibitors, forms an irreversible covalent bond at Cys₄₈₁ within the adenosine triphosphate binding pocket of BTK. Zanubrutinib is highly potent against BTK (IC₅₀, 0.3 nM). Compared with ibrutinib, it exhibited less off-target inhibition of other tyrosine kinases, such as EGFR, JAK3, TEC, ITK, and others, in both kinase inhibition and cell-based assays [15]. Off-target kinase inhibition is thought to mediate ibrutinib-associated toxicities, such as diarrhea and rash (associated with EGFR inhibition) [3, 9, 10], bleeding or bruising [16, 17], and atrial fibrillation [18, 19]. In two phase 1/2 studies conducted within (BGB-3111-1002 [NCT03189524]) and outside (BGB-3111-AU-003 [NCT02343120]) of China, zanubrutinib demonstrated generally good tolerability without dose-limiting toxicities at daily doses up to 320 mg, the highest dose tested in both studies. The recommended phase 2 dose was determined to be 160 mg administered twice daily by mouth, based on pharmacokinetic, pharmacodynamic, preliminary safety, and efficacy results in patients with a variety of B cell malignancies [15, 45]. Based on promising preliminary results in the BGB-3111-AU-003 study, including an overall response rate (ORR) of 96% in patients with CLL/SLL [15], we initiated this phase 2 trial of zanubrutinib in Chinese patients with relapsed/refractory CLL/SLL.

Ibrutinib has demonstrated clinically meaningful activity in patients with relapsed/refractory CLL/SLL and has become a standard of care for patients with CLL/SLL, both in the frontline (especially those who are not candidates for immunochemotherapy) and relapsed/refractory settings. Toxicities, some likely related to off-target effects, are relatively frequent causes for ibrutinib discontinuation both in clinical trial [12] and clinical practice settings [13]. Zanubrutinib has shown improved specificity for BTK compared with ibrutinib; at doses of 160 mg twice daily, zanubrutinib steady-state plasma levels were approximately eightfold higher (after adjusting for 94.2% plasma protein binding) compared with those observed for ibrutinib at a daily dose of 560 mg [30, 31]. No ethnic differences in the pharmacokinetics of zanubrutinib have been observed between Asian and non-Asian patients [32]. Similar to other BTK inhibitors, zanubrutinib is primarily metabolized by CYP3A. Concurrent administration with strong or moderate CYP3A inhibitors (e.g., some antimicrobial agents) has been shown to significantly increase exposure levels of ibrutinib in drug-drug interaction studies [11, 32, 34]. The impact of CYP3A inhibitors on the exposure of zanubrutinib (2.6-fold increase in maximal plasma concentration [C_max] upon itraconazole coadministration) [32] is significantly lower than that noted for ibrutinib (6.7-fold and 29-fold increase in C_max upon voriconazole and ketoconazole coadministration, respectively) [33, 34]. In the current study, 1 patient exhibited grade 4 neutropenia 4 weeks after completion of an extended course of fluconazole (a moderate CYP3A inhibitor) while concurrently receiving full dose zanubrutinib; 6 additional patients treated with a concurrent strong or moderate CYP3A inhibitor reported neither grade ≥ 3 nor serious AEs from the time of antimycotic therapy initiation until 30 days after completion (Supplemental Table 4). Unlike acalabrutinib, zanubrutinib can be coadministered with gastric acid-reducing agents (including PPIs) without restriction, as these have not been shown to impact its absorption [35].

In the current study, Chinese patients with relapsed/refractory CLL/SLL achieved an ORR of 84.6%, as assessed by an IRC after a median study follow-up of 15.1 months. Responses were observed in 19 (86.4%) of 22 patients with either del(17p) or TP53 mutation, 19 (95%) of 20 patients with del(11q), and 42 (82%) of 51 patients with unmutated IGHV. Consistent with previous experience with other BTK inhibitors, CRs were uncommon and restricted to patients with SLL [3, 9, 10, 29]. Efficacy results reported herein were generally consistent with those observed in a cohort of zanubrutinib-treated patients with CLL/SLL from clinical trial sites outside of China (Australia, New Zealand, South Korea, the USA, the UK, and Italy), who were enrolled in the phase 1/2 BGB-3111-AU-003 study [15]. Among 56 relapsed/refractory patients in this cohort, the ORR was 94.6% (one CR, 45 PRs, seven PRs with lymphocytosis); all response-evaluable patients with del(17p) (n = 16) achieved a response to zanubrutinib. At a median study follow-up of 13.7 months (range, 0.4–30.5 months), 94.7% of CLL/SLL patients in BGB-3111-AU-003 were continuing zanubrutinib treatment [15]. Responses to zanubrutinib in the current study were durable, with an estimated 93% of responders free from progression after a median follow-up of 10.2 months; to date, one patient has developed Richter transformation. Progression-free survival at 12 months was 87.2%. Longer follow-up is needed to more precisely define efficacy outcomes for this CLL/SLL cohort. Similar results have been reported in the RESONATE study of patients with R/R CLL/SLL comparing ibrutinib with the anti-CD20, ofatumumab: 90% of ibrutinib-treated patients achieved a response after a median follow-up of 19 months, based on investigator assessments, with 76% progression-free at 18 months [36]. Despite the similarity of outcomes between the RESONATE population and the current study, there were some notable differences in baseline characteristics: patients in the former study were older (median age, 67 vs 61 years, respectively) had more advanced disease (median time from initial diagnosis 92 vs 39 months, respectively) and were more heavily pretreated (median of 3 vs 1 prior regimens, respectively). The last consideration is particularly relevant given that ibrutinib-treated patients in RESONATE with only 1 prior regimen had superior outcomes both in terms of ORR and 18-month PFS compared with those with ≥ 2 prior regimens [36]. Response rates were also higher in the current study among patients with 1 vs ≥ 2 prior regimens (91.3% and 77.8%, respectively, Fig. 2). Among relapsed/refractory CLL patients, similar response rates to those for both ibrutinib and zanubrutinib have been reported with the second-generation BTK inhibitor acalabrutinib (81%-95%) [29, 37].

After a median exposure of 13.7 months, adverse events reported in the current study were mostly of mild or moderate severity and generally consistent with the known toxicity profile for BTK inhibitors as well as the natural history of relapsed/refractory CLL/SLL. Similar to ibrutinib clinical trials in this disease setting [3, 9, 38], infections figure prominently in the spectrum of AEs (Table 3; Supplemental Table 3) with 38.5% of patients having reported at least one grade ≥ 3 infection compared with 24 to 30% for ibrutinib [9, 38]. Predictably, these were mainly respiratory tract infections, both all grade and grade ≥ 3. In particular, the frequency of grade ≥ 3 lung infection/pneumonia reported in the current study (13.2%) is consistent with that reported among ibrutinib-treated patients both outside (12 to 13%) [9, 38] and within China (16.3%) [39]. Most infections were effectively managed with adequate resolution and without the need for dose reduction or treatment discontinuation.

Infectious complications are commonplace in CLL and account for 50 to 60% of CLL deaths [40]. Multiple etiologies including disease-related immuno- and myelosuppression as well as treatment with alkylating agents and corticosteroids are major contributors to the risk of primarily mucosal infections (e.g., tracheobronchitis, pneumonias, urinary tract infections), but also more serious systemic bacterial infections. More recently, opportunistic bacterial, viral (including HBV reactivation), and fungal infections have become more prominent with the increasing use of T cell-depleting agents such as purine nucleoside analogs and the anti-CD52 monoclonal antibody alemtuzumab. Anti-CD20 antibodies contribute to infection risk by causing B cell depletion, hypogammaglobulinemia, and worsening neutropenia. Tyrosine kinase inhibitors likely cause increased infection risk through a variety of mechanisms, including B cell dysfunction, worsening neutropenia, and, possibly, due to inhibitory effects on IL-2–inducible T cell kinase (in the case of ibrutinib); idelalisib, in particular, appears to be associated with a heightened risk of opportunistic infections including disseminated herpes virus infections and P. jirovecii pneumonia [40, 41].

Diarrhea of any grade was reported in 19.8% of patients with two (2.2%) having reported a grade 3 event, one of which required a brief treatment interruption and subsequent dose reduction. Considering the incidence of diarrhea reported among ibrutinib-treated patients in this disease setting (48 to 49%; grade ≥ 3, 2 to 4%) [3, 9], the lower incidence reported in the current study may be a consequence of less zanubrutinib-associated EGFR inhibition. An important component of the safety evaluation for this study was the assessment of AEs of interest, identified on the basis of the clinical experience with other BTK inhibitors. Hypertension was reported in nine (9.9%) patients (2 with grade 3 events), 6 of whom had a history of hypertension. Only 2 patients with treatment-emergent hypertension required new antihypertensive therapy and no patient required zanubrutinib treatment modification for hypertension management. The incidence of hypertension among ibrutinib-treated patients in this disease setting has been 18 to 27% (grade ≥ 3, 5 to 13%) after a median follow-up of 20.9 to 27.6 months [3, 38]. Over longer ibrutinib treatment intervals (median, 39 months), the incidence of grade ≥ 3 hypertension in relapsed/refractory patients has been reported at 25%, which may indicate increasing incidence with longer exposures [12]. Importantly, there were no occurrences of atrial fibrillation/flutter in the current study compared with grade ≥ 3 atrial fibrillation reported in 4 to 8% of ibrutinib-treated patients with relapsed/refractory CLL/SLL [9, 12]. This finding is consistent with results from the BGB-3111-AU-003 study of zanubrutinib in a cohort of 94 CLL/SLL patients treated at trial sites outside of China in which only one occurrence of atrial fibrillation in a patient with a history of hypertension and hyperlipidemia was reported [15]. Risk factors for atrial fibrillation were generally uncommon among patients in the current study with the notable exceptions of a history of hypertension (in 29% of patients) and diabetes mellitus (in 18%) (Supplemental Table 5). Other factors that may account for the absence of atrial fibrillation in the current study include the younger patient population (as previously noted), as well as epidemiologic evidence for a lower age-standardized incidence of atrial fibrillation among elderly Chinese compared with Western populations [42], although it is noteworthy that in a recent study of ibrutinib in mostly Chinese R/R CLL/SLL patients (median age, 65 years), 5.8% of patients reported treatment-emergent atrial fibrillation [39]. While minor mucocutaneous bleeding events were relatively common, only 2 (2.2%) patients reported major bleeding (gastrointestinal hemorrhage in the setting of newly diagnosed colon cancer and post-traumatic right thalamic hemorrhage). Nineteen (20.9%) patients received medications with anti-thrombotic properties while on study; 17 received analgesic/anti-inflammatory medications (e.g., NSAIDs, aspirin), 1 received enoxaparin sodium alone, and 1 received calcium heparin and clopidogrel. All exposures were short term, lasting 1–5 days; neither of the patients with major hemorrhage were receiving concurrent antithrombotic agents. By comparison, 1 to 9% of ibrutinib-treated patients reported major hemorrhage (including intracranial hemorrhage) [9, 38]. The incidence of grade ≥ 3 neutropenia and thrombocytopenia reported in the current study was high in comparison with that reported in populations of R/R CLL/SLL patients enrolled to ibrutinib clinical studies outside of China [3, 9, 36]. Despite indications that patients in the RESONATE trial [9] were more heavily pretreated than patients in the current study, there was less myelosuppression in the former study. In particular, grade ≥ 3 neutropenia was reported in 20% of ibrutinib-treated RESONATE patients in extended follow-up (median 19 months) [36] vs 44% of patients in our study after a median follow-up of 15.1 months. Since neutropenia is an on-target toxicity of BTK inhibitors and ibrutinib and zanubrutinib inhibit BTK via the same mechanism, the higher incidence of grade ≥ 3 neutropenia among zanubrutinib recipients can be attributed, at least in part, to its greater bioavailability as measured by relative plasma exposures for the two agents [15]. Predictably, the relatively low incidence of grade ≥ 3 neutropenia in a cohort of treatment-naive CLL/SLL patients treated with zanubrutinib (10%) [43] is consistent with a role for prior myelotoxic agent and anti-CD20 exposures in the pathogenesis of severe neutropenia reported herein (Table 1). The frequency and severity of other AEs of interest (e.g., mild or moderate mucocutaneous bleeding) were generally consistent with those reported in ongoing clinical studies of zanubrutinib in other B cell malignancies [44]. Other less serious but potentially bothersome toxicities reported with ibrutinib, including arthralgias (18%), headache (15%), vomiting (14%), myalgias (11%), muscles spasms (13%), and blurred vision (10%) [9], were uncommon in the current study (≤ 6%).

A limitation of the current study is the single-arm design, which limits both efficacy and safety comparisons with other BTK inhibitors. Two ongoing randomized studies of zanubrutinib versus ibrutinib, one in treatment-naïve and one in relapsed/refractory CLL/SLL patients (NCT03053440 and NCT03734016), aim to determine whether consistent, continuous BTK blockade with a more selective inhibitor results in fewer off-target effects and translates into improvements in disease control.

This phase 2 study of patients with relapsed/refractory CLL/SLL recruited from trial sites in China demonstrated that twice-daily administration of zanubrutinib resulted in a high rate of durable responses. As a selective BTK inhibitor with favorable pharmacokinetic and pharmacodynamic properties, zanubrutinib offers the potential for improved safety and tolerability over existing treatment options and thereby potentially confers a favorable benefit-risk profile for patients with relapsed/refractory CLL/SLL.