Efficacy and Safety of Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies

B-cell malignancies are a heterogeneous subset of non-Hodgkin lymphomas in which treatment has remained essentially unchanged for the past 3 decades.¹ However, greater understanding of the key pathways that drive proliferation, survival, and resistance patterns to commonly used therapeutics has led to the identification of novel therapeutic targets, thereby offering to significantly change the prognosis for patients affected by B-cell malignancies.¹

Of these, the B-cell receptor (BCR) signaling pathway has been recognized to play a central role in the proliferation and trafficking of malignant B cells, in addition to playing a role in regulating stroma-mediated extrinsic lymphoma cell survival and interactions with the microenvironment.^1,2

Ligation of BCR in healthy B cells, recruits the kinase SYK, which is phosphorylated by the SRC-family kinases. This interaction subsequently catalyzes and phosphorylates several other signaling molecules, including the lipase PLCγ2 (a lipase), B-cell linker protein, and Bruton tyrosine kinase (BTK).^1,3,4 BTK is ultimately responsible for activation of cell survival mechanisms and is fundamental for B-cell migration, adhesion, selftolerance, immune activation, and cytokine secretion.^1,3 However, BTK deficiency is associated with reduced numbers of mature B cells.¹

Malignant B-cells take advantage of the BCR pathway as a survival and proliferation mechanism by 1 or more mechanisms: activating mutations in BCR signaling domains, antigen-dependent BCR activation, and/or ligand-independent, and autonomous BCR pathway activation.² In vivo and ex vivo studies confirm that BCR and BTK have a prominent role in malignant B-cell homing, survival, and microenvironment- mediated drug resistance.¹ Furthermore, the exact mechanism by which malignant B cells use this pathway likely varies by the subtype of B-cell malignancy and may influence how profoundly BTK is involved in cell proliferation.² Thus, BTK does not appear to have a direct role in tumor development,⁵ but it is nonetheless consequential for promoting malignant cell survival and proliferation.⁵ Correspondingly, targeted inhibition of the BTK pathway has been shown to interfere with migration and adhesion of malignant cells in vivo and in animal models of different B-cell malignancies.^2,3

In human patients, the novel BTK inhibitor, ibrutinib, has been shown to affect normalization of lymphocyte counts and remissions in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, and other B-cell malignancies.² Additionally, BTK is suspected to play a role in the development or pathogenesis of other malignancies, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, multiple myeloma, and marginal zone lymphoma.³ The discovery of off-target activity associated with BTK inhibition, has prompted investigation into the potential role for these agents in solid tumors, such as ovarian, prostate, colorectal, and brain cancer.^3,4

This article provides a brief overview of the role of the BCR signaling pathway in B-cell malignancies, focusing on MCL and CLL. It also reviews the available preclinical and clinical trial data with 2 novel BTK inhibitors, ibrutinib and acalabrutinib in MCL and CLL.

BTK in B-Cell Malignancies: CLL and MCL

Despite associations with considerable genetic heterogeneity, CLL is noted to have a complex pathogenesis that is heavily influenced by genetic factors.⁶ The genetic heterogeneity of CLL suggests a potential need for multiple drugs or multitargeted agents to effectively address the variety of manifestations. However, as BCR signaling has been implicated to play a central role in CLL pathogenesis and cell proliferation, inhibition of this pathway yields compartment shift of malignant B cells from the tissues into the blood, resulting in transient lymphocytosis and eventual lymph node shrinkage.⁷ A consequence of interfering in BCR signaling in malignant B cells in this manner permits normalization of peripheral lymphocyte counts, leading to disease remission in an appreciable number of treated patients.^2,7

Given the central role of BTK in normal B-cell survival, B cells develop a survival advantage.^1-3 Correspondingly, BTK has been found to be consistently amplified in CLL cells.⁶ The notion that the BCR pathway plays an important role in CLL development is supported by additional lines of evidence. CLL prognosis is known to differ according to IGHV mutation status. Somatic mutations in IGHV occur as a part of the natural process of affinity maturation of antibodies, in which B cells in germinal centers located in the lymph nodes experience hypermutation during an immune response. This differentiation process leads to maturation, permitting normal physiologic functions associated with healthy B-cell activity.⁸

Nevertheless, CLL cells expressing unmutated IGHV status are progeny of cells that did not undergo differentiation, thus displaying immune incompetence.⁸ Notably, mutant IGHV status is associated with a much more favorable prognosis. The correlation with worse prognosis in IGHV-unmutated CLL thus implicates BCR signaling in the pathogenesis of CLL.³ Moreover, CLL cells typically express a limited repertoire of immunoglobulin molecules, and much more so in unmutated IGHV CLL.⁸ The implication is that cells with limited somatic mutational activity gain a survival advantage in CLL clonal populations, which highlights the importance of expressed surface immunoglobulin molecules for cell selection, and, again, implicates the BCR pathway in CLL proliferation.⁸ Finally, CLL cells typically display higher levels of kinases that result from the activated BCR signal pathway.³

The role of BTK in influencing these events may be inferred from studies showing that this pathway is consistently amplified in CLL cells leading to prosurvival signals through its effects on PI3K, PLC- γ2, and NF-κB.⁶ MCL is considered a paradigm of cell dysregulation.⁹ Most patients with MCL express a translocation of the cyclin D1 (CCND1) gene at chromosome 11q13 to the immunoglobulin heavy chain gene (IGH) at chromosome 14q32, leading to constitutional overexpression of the protein cyclin D1, a cell cycle regulator that promotes transition from the G1 to S phase of the cell cycle.⁹ These conditions establish the circumstances for unregulated proliferation of MCL cells, with a host of chromosomal and molecular alterations that regulate the cell cycle and senescence (ie, BMI1, INK4a, ARF, CDK4, and RB1) and interfere with the cellular response to DNA damage (ie, ATM, CHK2, and P53), likely playing a supporting role.¹⁰ Signaling that derives from the microenvironment, appears to also be important for driving MCL pathogenesis.³ Similar to CLL, BCR-associated kinases are significantly upregulated in MCL, including BTK.^7,11 In turn, BTK has been found to help retain MCL cells in lymphoid tissue.³

Ibrutinib

Ibrutinib blocks BTK activity by covalently binding to cysteine at position 481 in the kinase domain.³ Preclinical studies in a mouse model of autoimmune disease and a treatment trial in dogs with spontaneous B-cell non-Hodgkin lymphoma, confirmed the activity of this molecule. Early studies in human patients with various relapsed or refractory B-cell malignancies noted clinical safety and promising durable objective responses. Reduction in lymphadenopathy and transient lymphocytosis were common among responding patients; these findings that were later confirmed in a phase IB/II multicenter trial among patients with relapsed or refractory CLL. In the latter, lymphocyte counts normalized or dropped below baseline with continued treatment, and an overall response rate (ORR) of 71% was reported independent of clinical or genomic risk factors.³

Ibrutinib has a dual therapeutic mode of action, as it inhibits both intrinsic B-cell signaling pathways to compromise their proliferation and survival, and modulates interactions with the microenvironment.³ Of note, ibrutinib is thought to prevent homing and retention of malignant cells in survival niches. In the early treatment period, it is not uncommon for patients to exhibit a rise in leukemic cells in the circulation, most likely reflecting displacement of malignant B cells from their protective tissue niches. Upon mobilization, these cells likely undergo anoikis, a form of programmed cell death that occurs after cells separate from their protective extracellular matrices.³

Analogous to experience with targeted small molecules used in treatment of other cancer types, both primary and secondary resistance patterns with ibrutinib have been described. Importantly, outgrowth of resistant subclonal CLL cells has been described in patients who relapse on ibrutinib.³ Therapy-associated resistance mechanisms involving BTK C481S mutation at the site of action of ibrutinib and activating mutations in PLCy2 (R665W, S707Y and L845F) have been described. Long-term therapy with BTK inhibitors appear to result in the emergence of a population of neoplastic B cells with anergic phenotype, with implications for reduced signaling capacity and surface IgM expressions, while also prompting more efficient internalization.¹²

Relapsed/Refractory MCL

In a phase II study of 111 patients with relapsed or refractory MCL, in which 86% of patients had intermediate- or high-risk MCL, the response rate (RR) was 68%, and complete response (CR) and partial response (PR) was 21% and 47%, respectively.¹³ Notably, the response did not vary by baseline characteristics or the presence of risk factors associated with treatment failure with chemoimmunotherapy, and prior treatment with chemoimmunotherapeutic agents had no effect on the RR. Among patients who responded, the median duration of response (DOR) was 17.5 months. Median overall survival (OS) was not reached, and estimated progression-free survival (PFS) was 13.9 months. Grade 3 or higher hematologic events were infrequent and included neutropenia (16%), thrombocytopenia (11%), and anemia (10%).

A subsequent phase III clinical trial enrolled patients with relapsed or refractory MCL who had previously received 1 or more rituximab-containing treatments.¹⁴ PFS significantly improved in patients treated with ibrutinib (median 14.6 months, range: 10.4 to not reached [NR]) compared with temsirolimus (6.2 months, range: 4.2-7.9 months). Notably, patients with blastoid variant MCL displayed minimal benefit from therapy, although low numbers of patients may confound that result. However, overall, 86% of patients in the ibrutinib group compared with 50% in the temsirolimus group had clinically meaningful improvements in lymphoma symptoms. Regarding safety, grade 3 or higher treatment-related adverse events (AEs) were reported for 94 (68%) patients treated with ibrutinib compared with 121 (87%) for patients treated with temsirolimus, and fewer ibrutinib-treated patients discontinued treatment due to AEs (9% vs 36%).

Relapsed and Refractory CLL

A phase IB/II study assessed the safety, efficacy, pharmacoki- netics, and pharmacodynamics of ibrutinib in 85 patients with relapsed or refractory CLL.15 The ORR was 71% and an additional 20% and 15% of patients administered a 420-mg or 840-mg dose, respectively, had a PR with lymphocytosis. Response was found to be independent of clinical and genomic risk factors. At 26 months, PFS was 75% and the rate of OS was 83%. Reported AEs were more commonly grade 1 or 2, including transient diarrhea, fatigue, and upper respiratory tract infection.

These results were confirmed in the phase III RESONATE clinical trial in 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).16 At 9.4 months, ibrutinib was associated with a significantly prolonged duration of PFS compared with ofatumumab (NR vs 8.1 months), which corre- sponded to a 78% reduction in the risk of death. Significant improvement in OS was noted with ibrutinib compared with ofatumumab, and the ORR was 42.6% and 4.1% in the ibrutinib and ofatumumab groups, respectively.

Ibrutinib as Initial Therapy in CLL

Cytotoxic chemotherapy agents, including alkylating agents and purine analogues, form the basis for initial therapy in the majority of patients, although ibrutinib is a consideration for the subset of patients with a known 17p13.1 deletion.¹⁷ Unfortunately, the RR after chemoimmunotherapy is variable overall, and the use of these agents may induce outgrowth of subclonal populations and/or secondary cancers.¹⁸ Additionally, aged older than 65 years is associated with poor response to chemoimmunotherapy regimens and increased risk of toxicity.¹⁹ Individuals with 17p13.1 deletions have corresponding loss of TP53 function, which has also been associated with poorer response to chemoimmunotherapy agents.¹⁹ These factors have spurred efforts to investigate the role of novel agents in first- line settings, which may be especially important for patients considered to be at higher risk.

The open-label, phase III RESONATE-2 clinical trial evaluated ibrutinib versus chlorambucil as initial therapy in 269 previously untreated patients with a median age of 73 years.¹⁷ In the study, ibrutinib was associated with a significantly higher RR (86% vs 35%), longer PFS (NR vs 18.9 months), and prolonged OS (98% survival rate at 24 months with ibrutinib vs 85% with chlorambucil). The authors reported that positive treatment effects were found even in high-risk patients.

A study by Farooqui and colleagues investigated the role of ibrutinib in patients with TP53 deletions.²⁰ The investigator-led trial recruited both previously treated and treatment-naïve patients. At 24 weeks, the objective response among treatment-naïve patients was 97% (n = 32/33), including PR in 55% (n = 18), and PR with lymphocytosis in 42% (n = 14). By contrast, the objective response in previously treated patients was 80% (n = 12/15), including PR in 40% (n = 6).

Other B-Cell Malignancies

In addition to indications for treatment of refractory or relapsed MCL and CLL, and in select patients with CLL in the front-line setting, ibrutinib is also approved for use with patients with relapsed or refractory Waldenström macroglobulinemia. The approval was based on a phase II study showing a 90.5% ORR, and 2-year PFS and OS rates of 69.1% and 95.2%, respectively.²¹ In addition, ibrutinib has demonstrated a treatment effect in other B-cell malignancies, such as patients with refractory or relapsed follicular lymphoma, mantle zone lymphoma, and primary central nervous system lymphoma.³

Unmet Needs and the Development of Second- Generation BTK Inhibitors

Although a growing body of evidence suggests that BTK inhibition leads to decreased CLL cell proliferation, the efficacy of ibrutinib in this setting is somewhat paradoxical, as there is no uniform mutation or genetic modification associated with CLL.²² Instead, activation of the BCR signaling pathway, even in the absence of an observable genetic mutation, establishes the conditions for malignant B-cell proliferation. The relevance of the BCR pathway in CLL pathogenesis—and other B-cell malignancies—is supported by robust demonstration of efficacy in treatment trials. Despite this, ibrutinib has demonstrated off-target activity, and it may be the case that ibrutinib derives at least some of its therapeutic benefit from interactions with interleukin-2 inducible T-cell kinase, TEC, and B lymphocyte kinase.²² Furthermore, the genetic heterogeneity of CLL and the complexity of the BCR signaling pathway suggest there may be multiple opportunities for targeted inhibition.⁶

Additionally, although ibrutinib is associated with a generally favorable safety profile, with most events limited to grade 1 or 2 in severity, it can cause bleeding in treated patients, including major bleeding events in about 3% of patients and atrial fibrillation in up to 16% of patients on ibrutinib therapy.³ Some of the toxicities associated with ibrutinib may be explainable by the fact that the drug is not an exclusive inhibitor of BTK. For example, off-target inhibition of the TEC-family kinases may have consequences for increasing the risk of bleeding.³

Combined, these factors, coupled with recognition of incomplete efficacy with ibrutinib and the potential for primary and secondary resistance, has led to the development of second- generation BTK inhibitors.

Acalabrutinib

Table 1. Ongoing Clinical Trials for Acalabrutinib as Monotherapy for MCL and CLL¹⁰

CLL indicates chronic lymphocytic leukemia; MCL, mantle cell lymphoma; SLL, small lymphocytic lymphoma

Acalabrutinib is a novel irreversible second-generation BTK inhibitor. The molecule has been designed to be more potent and selective than ibrutinib, which is suggested to yield fewer off-target effects.²³ Similar to ibrutinib, acalabrutinib binds covalently to Cys481, albeit with greater selectivity for BTK.²³ In contrast to ibrutinib, however, acalabrutinib does not affect EGFR, TEC, or ITK.23 The latter is substantiated by a mouse thrombosis model in which thrombus sizes in acalabrutinib- treated platelets were similar to healthy controls, but thrombus formation was arrested in ibrutinib-treated platelets.²³ In humans, ibrutinib was found to cause dysfunctional thrombus formation, whereas acalabrutinib does not. This suggests that ibrutinib, but not acalabrutinib, inhibits SRC-family kinases that have a role in platelet adhesion to collagen.²⁴ This hypothesis is supported by studies finding that ibrutinib produces more profound off-target effects on SRC family kinases in healthy T lymphocytes.²⁵ Acalabrutinib is also thought to more powerfully inhibit BTK, suggested by its 5.1 nM half maximal inhibitory concentration, as compared with the 1.5 nM inhibitory concen- tration of ibrutinib.²⁵The activity of acalabrutinib has been demonstrated in preclinical studies and in animal models. Acalabrutinib has been shown to reduce tumor burden in a dose-dependent manner in a xenograft model.²³ Similar to the treatment effect demonstrated with ibrutinib, increased CLL cell counts were recorded in the peripheral blood after treatment with acalabrutinib. A separate murine study noted on-target effects, including decreased phosphorylation of PLCγ2 and ERK and significant inhibition of CLL cell proliferation.²⁶ In the latter, tumor burden in the spleen of mice was found to be significantly decreased compared with treatment with vehicle, and acalabrutinib was associated with increased survival.

Clinical Trials in MCL and CLL

Acalabrutinib was first studied in humans in a phase I/II, multicenter, open-label, dose-escalation clinical trial.²⁷ Among 61 patients with relapsed CLL, 31% of patients expressing a 17p13.1 deletion and 75% identified as IGHV unmutated. After a median 14.3 months of follow-up, the ORR was 95%, with 85% having a PR, 10% demonstrating a PR with lymphocytosis, and 5% achieving stable disease. Responses were seen among all cohorts and were noted to have continued improvement over time. Of note, RR was 100% in 4 patients with previous idelalisib therapy. The most common AEs were headache, diarrhea, and weight gain, and there were no dose-limiting toxicities, Richter transformations, or reports of atrial fibrillation. In the open-label, phase II ACE-LY-004 study, acalabrutinib was associated with an 81% OR among patients with relapsed or refractory MCL and 40% achieved a CR.²⁸ The rates of DOR, PFS, and OS after 12 months were 72%, 67%, and 87%, respectively.

The drug was found to be well tolerated with many AEs of grade 1 or 2 severity, including headache (38%), diarrhea (31%), fatigue (27%), and myalgia (21%). There were no cases of atrial fibrillation and 1 case of grade 3 or worse hemorrhage, and the most common grade 3 or worse events were neutropenia (10%), anemia (9%), and pneumonia (5%). These results led to acalabrutinib gaining approval from the Food and Drug Administration (FDA) for treatment of relapsed or refractory MCL.²⁹

Ongoing Trials

The early results for acalabrutinib in both MCL and CLL are promising, but longer-term data will be of benefit. Resistance mechanisms, for instance, have not yet emerged, thus it remains unclear whether resistance patterns will resemble those of ibrutinib.²³ Results from several ongoing clinical trials may further elucidate the role of acalabrutinib for the treatment of B-cell malignancies (Table 1).30-35 As a monotherapy, 2 phase III trials are currently underway: NCT02477696, a head to head trial of acalabrutinib versus ibrutinib in previously treated patients with high risk of CLL, and NCT02970318, in which investigators are evaluating acalabrutinib versus either idelalisib plus rituximab or bendamustine plus rituximab in relapsed/refractor CLL.^30,31 Estimated primary completion dates for NCT02477696 and NCT02970318 are June 2019 and March 2020, respectively.

Several phase II studies are also underway, including NCT02717611, which is designed to evaluate acalabrutinib in patients with relapsed/refractory CLL who are intolerant of ibrutinib therapy.³² Estimated primary and study completion date is February 2020. In NCT02337829, investigators are evaluating acalabrutinib in treatment-naïve and relapsed/refractory del 17p CLL/SLL.³³ Other phase II trials include the first-in-human study of acalabrutinib in the treatment of patients with naïve relapsed/refractory CLL (NCT02029443) and a study of acalabrutinib in patients with relapsed/refractory MCL in which recruitment is complete (NCT02213926).^34,35 Both studies are expected to be complete in 2019.

Table 2. Ongoing Clinical Trials of Acalabrutinib in Combination With Other Agents for MCL and CLL¹⁰

CLL indicates chronic lymphocytic leukemia; MCL, mantle cell lymphoma; PLL, prolymphocytic leukemia; SLL, small lymphocytic lymphoma; PLL, prolymphocytic leukemia.

Additionally, acalabrutinib is being investigated in combina- torial approaches across a number of B-cell malignancies.^23,36 For example, early data suggest that venetoclax, when combined with acalabrutinib, shows optimal complementary activity in vitro, ex vivo, and in vivo in a TCL-1 adopt transfer mouse model.³⁶ Combinations of acalabrutinib and agents such as CD19 and CD20 antibodies, PI3 kinase inhibitors, ALK inhibitors, andBCL-2 inhibitors may also potentially increase RR and duration in B-cell malignancies. Acalabrutinib is also being studied in the treatment of solid tumors, including glioblastoma, urothelial carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, ovarian cancer, and pancreatic cancer.³ In MCL and CLL, specifically, several trials evaluating acalabrutinib in combination with various agents are ongoing (Table 2).^37-41 Phase III trials include a study that is evaluating acalabrutinib versus acalabrutinib plus obinutuzumab versus obinutuzumab plus chlorambucil in patients with previously untreated CLL (NCT02475681), and another study investigating bendamustine and rituximab alone versus in combination with acalabrutinib in patients with previously untreated MCL (NCT02972840).^37,38 At least 3 phase I trials are also in development, including 1 study evaluating acalabrutinib plus bendamustine plus rituximab in patients with treatment- naïve and relapsed/refractory MCL (NCT02717624), another study investigating acalabrutinib plus ACP-319 in patients with relapsed/refractory CLL (NCT02157324), and another evaluating acalabrutinib plus obinutuzumab in patients with treatment- naïve and relapsed/refractory CLL, SLL, and prolymphocytic leukemia (NCT02296918).^39-41

Other BTK Inhibitors in Development and Combination Approaches

At least 2 other BTK inhibitors are in development.⁴² BGB-3111 is believed to have higher selectivity and stronger oral bioavailability compared with ibrutinib, and has demonstrated activity in inhibiting proliferation of MCL and DLBCL cell lines, but due to weaker ITK inhibition, it is less effective than ibrutinib in inhibiting rituximab-induced antibody dependent cellular cytotoxicity.³ In a phase I/II study, BGB-3111 was well tolerated and associated with a RR of about 90% after 1.43 months.⁴² ONO/GS-4059, also a highly potent and more specific BTK inhibitor, was first described in a DLBCL xenograft model and has demonstrated activity in DLBCL, follicular lymphoma, MCL, and CLL cell lines.⁴² In addition to encouraging prelim- inary safety and efficacy results, ONO/GS-4059 is also being investigated in combinations in both MCL (idelalisib) and CLL (ABT-199, a BCL2 inhibitor).⁴² Combination approaches involving BTK inhibitors for the treatment of B cell malignancies appear to have great promise, in both second-generation and first-generation agents. For example, ibrutinib was found to be effective and well tolerated in combination with chemotherapy regimens.⁴²

Conclusions

The emerging understanding of the central role of BCR signaling in the development and pathogenesis of various B-cell malignancies indicates a role for targeted small molecules that inhibit relevant interactions along this pathway. The central role of BTK signaling for promoting malignant B-cell survival, trafficking, and homing has indicated that this may be a relevant target. Indeed, clinical trials involving the first-in-class BTK inhibitor ibrutinib demonstrated about 70% ORR in refractory or relapsed MCL and CLL. Subsequently, this molecule was granted FDA approval for treatment of patients with MCL who failed prior therapy in 2013, for treatment of patients with CLL who failed prior therapy in 2014, and for treatment of patients with Waldenström macroglobulinemia in 2017.

Despite suggestion of robust clinical activity in MCL, CLL, Waldenström macroglobulinemia, and potentially other B-cell malignancies, ibrutinib is known to have off-target activity, which may be both beneficial in some regards (ie, potential to use in treatment of solid malignancies) and detrimental (ie, potential to induce unwanted AEs). Both primary and secondary resistance to ibrutinib has been recognized. Consequently, the second-generation BTK inhibitor, acalabrutinib, was rationally designed to be more potent and have higher specificity for binding BTK, with fewer off-target interactions. Similar to ibrutinib, this molecule presumptively has a dual therapeutic mode of action, in that it inhibits intrinsic cell signaling while also modulating interactions with the microenvironment that seem to foster cell proliferation, trafficking, and homing. Acalabrutinib has already garnered FDA approval for the treatment of relapsed or refractory MCL and studies are ongoing in patients with CLL and other B-cell malignancies.

The rapidly developing trajectory from first to second generation agents suggests that BTK inhibitors will continue to play an essential role in the treatment of B-cell malignancies. As these agents continue to be used in real-world settings, further research will elucidate their efficacy and safety profiles. Although ibrutinib highlights the promise of BTK inhibition and may prove more efficacious in combination with other modalities, second-generation of BTK inhibitors offer a more targeted and potentially more tolerable therapeutic option. Collectively, the emergence of these novel agents suggests a shifting paradigm in treatment of B-cell malignancies, with the promise to develop targeted and personalized treatment approaches that would serve to significantly improve outcomes and survival.

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