Key Elements of BTK Signaling
BCR indicates B-cell receptor; BTK, Bruton tyrosine kinase. Source: GeneCards, www.genecards.org.
A greater understanding of the molecular mechanisms underlying lymphoid malignancies has fostered the development of targeted therapies, including those aimed at B-cell signaling pathways. In the past few years, overwhelmingly positive results have been observed with small-molecule inhibitors of Bruton tyrosine kinase (BTK), a downstream component of B-cell antigen receptor (BCR) signaling.
The excitement over these new agents has been growing since the FDA approved ibrutinib (Imbruvica) as a treatment for mantle cell lymphoma (MLC) late last year under the agency’s Breakthrough Therapy program. In mid-February, ibrutinib gained approval for patients with chronic lymphocytic leukemia (CLL) who have received at least one previous therapy.
BTK-targeted agents have the potential to alter the treatment landscape for patients with lymphoma and leukemia and, indeed, we are already beginning to see treatment guidelines adapted.
BTK: A Key Conduit of BCR Signaling Pathways
The proliferation, differentiation, and survival of the B cells of the immune system are controlled by biochemical signals transmitted via the BCR, an antigen-specific receptor protein found in the membrane of these cells. Binding of a specific antigen to the immunoglobulin component of the BCR triggers a cascade of downstream molecules to become activated. Among them is BTK, a nonreceptor tyrosine kinase that was originally discovered in the early 1950s by the American pediatrician Ogden C. Bruton, MD, who linked BTK to a rare X-linked immunodeficiency syndrome.
BTK is expressed on other hematopoietic cells, including macrophages and neutrophils, though not on T cells or normal plasma cells, and is involved in the activation of a number of other signaling pathways; however, its best understood canonical role is in the BCR pathway. BTK is typically found in the cytoplasm but moves to the membrane during B-cell activation, whereupon it is phosphorylated by a number of different kinases. In turn, BTK then phosphorylates a range of downstream targets, ultimately resulting in the activation of cellular pathways that govern vital B-cell processes.
Although the gene that encodes BTK is not considered a classical oncogene, the inappropriate activation of BTK has been demonstrated to be involved in the maintenance of a wide variety of malignancies; for example, constitutive activation of BTK is an absolute prerequisite for the development of CLL, but BTK mutations have also been identified in patients with acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and more recently, in solid tumors such as colorectal carcinoma. As such, researchers recognized the potential for developing BTK-targeted anticancer agents and the class has become an area of substantial clinical interest in recent years.
Emergence of Ibrutinib
Among the earliest small-molecule inhibitors of BTK to be described was LFM-A13. This agent was widely used in preclinical studies, but mostly to further delineate the cellular role of BTK. Since the agent also inhibited polo-like kinase (PLK) and Janus kinase (JAK) 2, it has not progressed beyond this stage of development. Things really began to move forward in this field after Zhengying Pan, PhD, now at Peking University, and colleagues designed ibrutinib in the mid-2000s. The compound, formerly identified as PCI-32765, is a small molecule that irreversibly inhibits BTK enzymatic activity by covalently binding to cysteine- 481 in the tyrosine kinase domain.
Following promising preclinical studies in which it displayed dose- and time-dependent cytotoxicity in tumor cells, ibrutinib entered clinical trials. At the phase I stage, it was shown to be highly efficacious and safe in various B-cell malignancies. Both intermittent and continuous dosing schedules demonstrated similar efficacy and toxicity. However, a continuous dosing schedule was ultimately pursued in later trials since there was a possibility of reversed effects during the off-drug days with an intermittent schedule.
Phase I and II trials in a range of different lymphoid malignancies subsequently began, many of which are still ongoing. In November 2013, positive results from a phase II trial led to ibrutinib’s approval in MCL. The subsequent approval in CLL was based on phase IB/II clinical trial results. Ibrutinib also has been designated as a Breakthrough Therapy in Waldenström macroglobulinemia.
A multitude of phase III clinical trials of ibrutinib are under way in the hopes of expanding the indications of this agent. Ibrutinib is currently approved for use as a single agent in MCL and CLL, and many trials continue to evaluate its efficacy as mono therapy.
The RESONATE trials are examining ibrutinib versus the anti-CD20 antibody ofatumumab (RESONATE) and the chemotherapeutic agent chlorambucil (RESONATE-2) in patients with CLL or small lymphocytic leukemia (SLL). While RESONATE-2 is expected to complete enrollment in mid-2014, a planned interim analysis of RESONATE has already been completed. In fact, the Independent Data Monitoring Committee has recommended that the RESONATE trial be stopped early since the interim data showed a statistically significant improvement in both the primary endpoint (progression-free survival [PFS]) and a key secondary endpoint (overall survival [OS]).
Its impressive synergistic activity in combination with chemoimmunotherapy regimens has garnered the most significant attention in late-stage trials. Two other phase III studies are examining the efficacy of ibrutinib in combination with the chemotherapeutic bendamustine and the anti-CD20 antibody rituximab in patients with MCL (SHINE) and CLL/SLL (HELIOS). These studies started recruiting participants in late 2012 and early 2013, with targets of 520 and 580 patients, respectively. Final data from a phase II trial presented at the 2013 American Society of Hematology (ASH) meeting in December reported an overall response rate (ORR) of 93% with this combination in patients with CLL/SLL. Excellent response rates have also been reported in phase II trials in patients wth MCL, providing the rationale for phase III trials of this combination.
Data from several other phase I and II trials of combination therapy with ibrutinib were reported at ASH. This included a study of ibrutinib in combination with rituximab in high-risk patients with CLL, defined as those with 17p or 11q chromosomal deletions, TP53
mutations, or a PFS of <36 months after chemoimmunotherapy. Among the 39 patients evaluable for response, there was an ORR of 95%, with 16 partial responses (PR) and 2 complete responses (CRs).
There have also been recent reports of ibrutinib monotherapy efficacy. A phase IB/II study of ibrutinib monotherapy in patients aged ≥65 years with previously untreated CLL/SLL, presented at ASH and subsequently published in Lancet Oncology
, demonstrated an ORR of 71% in this patient population over a median follow-up of 22.1 months. In a second report, among the first 53 patients in a phase II single-center trial in elderly patients with CLL/SLL, ibrutinib was equally effective in patients with or without a 17p chromosomal deletion; nodal response was 100% in both cohorts.
An appealing pharmacodynamic phenomenon observed following ibrutinib treatment is rapid, but transient, lymphocytosis in patients with CLL that has been shown to result from lymphocytes exiting the solid lymphoid tissue after destabilization of the tumor microenvironment, rather than from disease progression. Interestingly, there was a slower clearance of lymphocytosis in patients with 17p deletion in this study cohort.
As well as demonstrating significant efficacy, ibrutinib also has been generally well tolerated in these and other clinical trials. The most common adverse events (AEs) of any grade reported for ibrutinib include pneumonia, abdominal pain, atrial fibrillation, diarrhea, nausea, fatigue, and skin infections. Most toxicities are mild to moderate in severity. In combination studies, the safety profiles have typically been consistent with those of monotherapy ibrutinib and the combinatorial agent(s) being studied, with few unexpected toxicities. A combination of ibrutinib and rituximab has also been reported to improve quality of life in a phase II study of patients with CLL/SLL.
Other BTK Inhibitors in the Wings
Several other BTK inhibitors are in the early stages of clinical development, and demonstrate promise in patients with various B-cell malignancies. These include CC-292 and ONO-4059, both currently in phase I trials.
In data presented at ASH, patients with relapsed/refractory CLL/SLL treated with single-agent CC-292 had high nodal and partial response rates, including patients with high-risk features. Dosages ranging from 125 mg to 1000 mg once daily and from 375 mg to 500 mg twice daily were examined, with continuous dosing on 28-day schedules. No maximum tolerated dose was established and CC-292 was well tolerated with a similar safety profile to single-agent ibrutinib. The most common grade 3 or 4 AEs were neutropenia, thrombocytopenia, pneumonia, and anemia.
Meanwhile, two studies of ONO-4059 were reported in patients with relapsed/ refractory CLL/SLL and in patients with B-cell lymphoma, respectively. In the first trial, the best ORR across dosages ranging from 20 mg to 320 mg was 70% (7 of 10 evaluable patients), including 2 PRs and 2 patients who experienced stable disease (SD). In the latter, the best ORR across dosages of 40 mg, 80 mg, and 160 mg was 42%, with 5 PRs and 4 patients experiencing SD. ONO-4059 displayed good pharmacokinetic and pharmacodynamic properties and was well tolerated in all individuals (16 patients and 14 patients, respectively), with no dose-limiting toxicities.
Several other agents in preclinical development make this a growing and promising field with the potential to change practice. Indeed, the National Comprehensive Cancer Network updated its oncology practice guidelines in January 2014 and included several suggested treatment regimens with ibrutinib. These included relapsed/ refractory CLL/SLL patients, MCL in second- line therapies, and salvage therapy in patients with relapsed Waldenström macroglobulinemia.
The BTK Inhibitor Landscape
Pharmacyclics Inc/Janssen Biotech Inc.
—Oral, irreversible, and highly selective small-molecule inhibitor with subnanomolar activity against BTK. Also inhibits JAK3 and Tec.
Approved tumor types
—International, multicenter, single-arm trial of 111 MCL patients demonstrated ORR of 65.8%, with a 17% CR, 49% PR, and median duration of response of 17.5 months. In CLL, a study involving 48 previously treated participants resulted in an ORR of nearly 58% and duration of response ranging from 5.6 months to 24.2 months.
—Designated as Breakthrough Therapy in Waldenström macroglobulinemia
—Approximately 40 trials either recruiting or awaiting results, 12 of which are in phase III, including these studies:
RESONATE—Ibrutinib vs ofatumumab in relapsed/refractory CLL or SLL (NCT01578707)
RESONATE-2—Ibrutinib vs chlorambucil in patients aged ≥65 years with treatment-naïve CLL or SLL (NCT01722487)
SHINE—Ibrutinib plus bendamustine and rituximab vs bendamustine, rituximab, and placebo in newly diagnosed MCL (NCT01776840)
HELIOS—Ibrutinib plus bendamustine and rituximab vs bendamustine, rituximab, and placebo in relapsed/ refractory CLL (NCT01611090)
3-arm trial of ibrutinib alone and in combination with rituximab vs rituximab plus bendamustine in previously untreated CLL (NCT01886872)
Ibrutinib with either bendamustine/rituximab or R-CHOP versus placebo plus either bendamustine/rituximab or R-CHOP in previously treated indolent NHL (NCT01974440)
—Oral acrylamide derivative that potently inhibits BTK
CLEAR—CC-292 plus lenalidomide in relapsed/refractory B-cell lymphoma (NCT01766583)
Combination trial with rituximab and CC-223 or CC-122 in DLBCL (NCT02031419)
Safety study of CC-292 plus rituximab in CLL or SLL (NCT01744626)
ONO Pharmaceutical Co Ltd
—Oral, highly selective BTK inhibitor with an IC50
of approximately 2 nmol/L
Dose escalation study of ONO-4059 as monotherapy in relapsed/refractory NHL and CLL (NCT01659255)
BTK indicates Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; CR, complete response; DLBCL, diffuse large B-cell lymphoma; MLC, mantle cell lymphoma; NHL, non-Hodgkin lymphoma; ORR, overall response rate; PR, partial response; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; SLL, small lymphocytic leukemia.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in Davis, California.
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