Jennifer R. Brown, MD, PhD
The Bruton tyrosine kinase (BTK)-targeting drug ibrutinib has demonstrated substantial success as a single agent in advancing the treatment of B-cell malignancies, and a number of novel BTK-targeting agents are now hot on its heels. Yet the ultimate development of resistance to these inhibitors limits long-term curative potential.
Combination therapy has significant potential to fill this niche and rational pairings of ibrutinib with other standard treatments, including chemoimmunotherapy and CD20-targeting monoclonal antibodies (mAbs) are rapidly gaining ground.
Early reports from the phase III HELIOS trial suggest that the combination of ibrutinib with the chemotherapeutic bendamustine and CD20-targeting mAb rituximab may soon be available as a novel FDA-approved option and numerous other combinations are in late-stage trials, with results eagerly anticipated.
Meanwhile, genomic sequencing studies are offering insight into the mechanisms of resistance to ibrutinib and, in addition to high-throughput combinatorial screens for drugs that show synergistic activity with ibrutinib, are yielding an ever-increasing number of potential partners for BTK-targeted therapy.Unprecedented Success of Ibrutinib
Researchers have begun to shed light on the molecular pathways driving the development of B-cell malignancies, spawning a plethora of targeted agents that have potential for significant therapeutic impact. One particular class of drugs arousing substantial interest are those targeting the B-cell receptor (BCR) signaling pathway, following the discovery that abnormalities in this axis play a pivotal role in the progression of B-cell tumors.
Agents targeting this pathway have predominantly been aimed at BTK, a member of the Tec family of kinases that is activated downstream of the BCR. Although not a typical oncogene—no oncogenic mutations or gene fusions have been discovered—it plays a key role in several pathways that maintain B cell survival.
Pursuing BTK as a drug target has paid off; the first-in-class small molecule inhibitor ibrutinib has displayed dramatic efficacy in several forms of mature B-cell malignancies. Since November 2013, the FDA has approved indications for ibrutinib in three malignancies: mantle cell lymphoma(MCL), chronic lymphocytic leukemia (CLL) and, most recently, Waldenström macroglobulinemia (WM).
Approvals were based on the demonstration of tolerable toxicity profiles and response rates in the 58% to 66% range with duration of responses lasting more than 24 months for single oral doses of ibrutinib as monotherapy in single-arm, multicenter phase II trials.
In CLL, these studies were followed up by the phase III RESONATE trial, in which ibrutinib was compared with the CD20-targeting monoclonal antibody ofatumumab. The trial was stopped early based on an interim analysis that demonstrated favorable results; the study authors reported that median progression-free survival (PFS) had not yet been reached in the ibrutinib arm compared with an 8.1-month median PFS with ofatumumab. At 12 months, the overall survival (OS) rate with ibrutinib was 90% versus 81% with ofatumumab (HR, 0.43; P
Ibrutinib has shown significant efficacy in other B-cell malignancies, including in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) and in multiple myeloma.More BTK Agents in Development
Other BTK-targeting agents are in early-stage clinical trials (Table 1)
. CC-292 and ONO-4059 both bind to the cysteine 481 residue in BTK and prevent its phosphorylation and activation, but are more specific inhibitors of BTK than ibrutinib, which also inhibits other kinases.
In a phase I study, CC-292 was well tolerated and demonstrated an overall response rate (ORR) of 67% among 86 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), WM, and CLL/small lymphocytic leukemia (SLL). Two phase I studies of ONO-4059 have been reported; response rates were 42% across all histologies in the first study (50% in patients with MCL) and were 70% among 10 patients with relapsed/refractory and high-risk CLL in the second study.
Table 1. BTK-Targeting Agents in Development
*Trial is ongoing but not recruiting participants.
ABC indicates activated B cell; BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large b-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; NHL, non-Hodgkin lymphoma; PI3K, phosphatidylinositol 3-kinase; PLL, prolymphocytic leukemia; SLL, small lymphocytic leukemia.
Despite the impressive clinical efficacy and tolerability of BTK-targeted agents, further research is required to identify optimal dosing schedules and patients who are most likely to benefit from this type of therapy. Furthermore, BTK inhibitor monotherapy is not curative; approximately one-third of patients do not respond to ibrutinib therapy at all, and the majority of those who do ultimately develop resistance.