Combination therapy has significant potential to fill the niche of developing resistance to BTK inhibitors and rational pairings of ibrutinib with other standard treatments, including chemoimmunotherapy and CD20-targeting monoclonal antibodies (mAbs) are rapidly gaining ground.
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 = 0.005).
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.
*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.
Strategies for Moving Beyond Monotherapy
Results from a variety of preclinical and early-stage clinical studies suggested that combination therapy with ibrutinib might provide additional benefit and potentially be curative by helping to overcome resistance. The exciting potential of combination therapy is highlighted by the fact that Pharmacyclics, which developed ibrutinib in collaboration with Janssen Biotech, partnered in clinical trials with the makers of other promising anticancer drugs, including AstraZeneca, Bristol-Myers Squibb, Celgene, and Roche.
More than 30 clinical trials of ibrutinib combination therapy are currently ongoing, seven of which are phase III studies, with thousands of patients enrolled (Table 2). Currently, ibrutinib is only FDA-approved as monotherapy, but it is highly likely that combination therapy will be incorporated into standard of care for patients with B-cell malignancies in the near future.
Enhancing Efficacy of Standard Therapies
Furthest along in clinical development are combination strategies pairing ibrutinib with other standard therapies for B-cell malignancies, including CD20-targeting mAbs like rituximab and chemoimmunotherapy regimens, such as bendamustine/rituximab (BR).
The combination of ibrutinib and BR is garnering significant attention. Following demonstration of an ORR over 90% in a phase I/II study, this triplet therapy is currently being evaluated in the phase III HELIOS trial in patients with relapsed/refractory CLL/SLL (NCT01611090).
In March 2015, an Independent Data Monitoring Committee unanimously recommended unblinding of the trial after an interim analysis indicated a significant improvement in PFS for the combination compared with BR alone. Patients in the BR arm will now be allowed to cross over to receive ibrutinib. Full data from this trial are expected to be reported at the American Society of Clinical Oncology Annual Meeting in Chicago at the end of May. This combination is also being examined in phase III trials in patients aged 65 years or older with newly diagnosed MCL (SHINE; NCT01776840) and in patients with previously treated indolent NHL (NCT01974440).
*Trial is ongoing but not recruiting participants.
ALL indicates acute lymphoblastic leukemia; BR, bendamustine/rituximab; CDK, cyclin-dependent kinase; CLL, chronic lymphocytic leukemia; CNS, central nervous system; CRM1, chromosome region maintenance 1; EPOCH-R, etoposide, prednisone, doxorubicin, cyclophosphamide, vincristine, rituximab; FCR, fludarabine, cyclophosphamide, rituximab; FL, follicular lymphoma; MCL, mantle cell lymphoma; NHL, non-Hodgkin lymphoma; PI3K, phosphatidylinositol-3-kinase; R-CHOP, rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone; R-TEDD, rituximab-temozolomide, etoposide, doxorubicin, dexamethasone; SLL, small lymphocytic leukemia.
Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute and associate professor of Medicine at Harvard Medical School, and colleagues recently reported the results of a phase 1b study of ibrutinib in combination with BR or another chemoimmunotherapy regimen, fludarabine, cyclophosphamide, rituximab (FCR), in patients with relapsed/refractory CLL. The FCR arm closed early after only three patients enrolled, but all of those participants experienced a complete response (CR). Among 30 patients in the ibrutinib-BR arm, ORR was 93.3%, including 16.7% CR, which increased to 40% within the extension period. There were no unexpected toxicities beyond those expected for monotherapy with either agent.
The combination of ibrutinib and R-CHOP (rituximab- cyclophosphamide, doxorubicin, vincristine, prednisone) is also the subject of an ongoing phase III clinical trial (NCT01974440). The results of a phase Ib/II, open-label, nonrandomized study of this combination were recently reported in The Lancet Oncology. Among 33 patients with CD20-positive B-cell NHL, the combination was well tolerated; the most common adverse events of grade 3 or higher severity were neutropenia, thrombocytopenia, and febrile neutropenia and anemia. The ORR was 94%, with a 72% CR rate.
Eighteen patients with DLBCL were evaluated in the phase II portion of the study at a dose of 560-mg ibrutinib and all responded, with 15 CR and three partial responses (PR).
Combining ibrutinib with CD20-targeted mAbs is another promising strategy and phase III trials are under way evaluating ibrutinib with obinutuzumab or ublituximab in patients with CLL, or with rituximab in patients with CLL or WM.
In a phase II study of ibrutinib and rituximab that was presented at the 2014 annual meeting of the American Society of Hematology (ASH) in December 2014, almost 90% of patients with relapsed or refractory MCL responded, with 38% CR and 49% PR, and the combination was well tolerated.
Boosting Antitumor Immune Response
A number of preclinical studies have found that not only does ibrutinib act directly on tumors, but it may also have an effect on the antitumor immune response. At least in part, this is thought to be because ibrutinib also inhibits the interleukin 2-inducible T-cell kinase (ITK), which is involved in the survival of a subset of T helper cells; that is, Th2 cells. Thus, ibrutinib may boost antitumor immunity by shifting the balance between Th1 and Th2 cells and favoring a Th1 response.
Preclinical studies have also demonstrated that this effect may be particularly beneficial when ibrutinib is combined with immunomodulatory drugs. Synergistic activity has been demonstrated between ibrutinib and drugs such as lenalidomide and dexamethasone, as well as immune checkpoint inhibitors targeting programmed cell death receptor 1 (PD-1) and its ligands. This has provided the rationale for a number of ongoing clinical trials. Furthest along in development is the combination of ibrutinib and nivolumab, the PD-1-targeting antibody, which is being evaluated in an ongoing phase II trial in patients with CLL (NCT02420912).
Outwitting Resistant Tumors
The issue of resistance has spawned significant research efforts to greater understand the mechanisms underlying both primary and acquired resistance to ibrutinib and other BTK-targeted agents, and to develop novel drugs that might overcome this resistance.
Combinatorial drug screens are being used to identify synergistic drug combinations and high throughput genome and transcriptome studies are helping to unravel some of the mechanisms of resistance. The focus has been on identifying alternate survival pathways that become activated in resistant cancer cells and allow them to bypass BTK.
Several mutations in the BTK gene have been identified that drive initial unresponsiveness to ibrutinib and the development of resistance following treatment. Reports of the first relapsespecific BTK mutation in patients with MCL, identified as C481S, emerged in 2014. Since this mutation is only found in patients with acquired resistance, researchers suggest that different molecular mechanisms are at play in patients who are initially insensitive to ibrutinib or who have relapsed following treatment.
Potentially promising combinations have emerged from this avenue of investigation and, though most are currently being evaluated in the preclinical setting, a few have now progressed to early-stage clinical trials.
Researchers at Weill Cornell Medical College in New York who were responsible for identifying the C481S mutation in sequencing studies of patients with ibrutinib-resistant MCL also determined that the phosphatidylinositol-3-kinase (PI3K)/AKT pathway remains active in patients with both primary and acquired resistance to ibrutinib and that cell cycle genes, including cyclin-dependent kinase 4 (CDK4) are often upregulated. This prompted a study of combined inhibition of BTK and PI3K/AKT and CDK4, using the inhibitors idelalisib and palbociclib, respectively.
The research team observed synergy between ibrutinib and palbociclib in patients with primary resistance and between palbociclib and idelalisib in patients with acquired resistance to ibrutinib.
Phase I trials of the PI3K inhibitor TGR-1202 and the CDK4 inhibitor palbociclib in combination with ibrutinib are currently under way in patients with MCL (NCT02268851 and NCT02159755, respectively).
A preclinical study presented at the 2014 ASH Annual Meeting demonstrated how B-cell lymphoma 2 (Bcl-2), a regulatory protein involved in apoptotic pathways, and spleen tyrosine kinase (Syk), a nonreceptor tyrosine kinase that is involved in signal transduction downstream of various membrane receptors including the BCR, may function in an alternate survival pathway in DLBCL cells following ibrutinib treatment.
Cells expressing the BTK C481S mutant or the PLCG2 R665W mutant (a mutant form of the phospholipase C gamma 2 gene, a downstream target of activated BTK, which is also implicated in ibrutinib resistance), were subsequently shown to be sensitive to a combination of ibrutinib and Bcl-2 or Syk inhibitors. A phase I study of the Bcl-2 inhibitor ABT-199 in combination with ibrutinib in patients with relapsed/refractory MCL is now ongoing (NCT02419560).