A review of a novel, Bruton's tyrosine kinase inhibitor, ibrutinib.

XML Template (2014) [19.11.2014–3:26pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/140098/APPFile/SG-OPPJ140098.3d

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Oncology Pharmacy Practice

Original Article

A review of a novel, Bruton’s tyrosine kinase inhibitor, ibrutinib

J Oncol Pharm Practice 0(0) 1–13 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214561281 opp.sagepub.com

Chung-Shien Lee, Mohammad A Rattu and Sara S Kim

Abstract Ibrutinib, a Bruton’s kinase inhibitor, was granted an accelerated approval by the US Food and Drug Administration in November, 2013, for the treatment of relapsed or refractory mantle cell lymphoma and subsequently for the treatment of relapsed refractory chronic lymphocytic leukemia in February, 2014. In the pivotal phase 2 study of 111 patients with relapsed or refractory mantle cell lymphoma, the overall response rate in patients who received ibrutinib 560 mg daily was 68%. The median progression-free survival was 13.9 months, and the overall survival was 58% at 18 months. In a recently published phase 3 trial (RESONATE) that compared ibrutinib and ofatumumab for the treatment of relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, ibrutinib at the daily dosage of 420 mg demonstrated a significantly higher overall response rate (43% in ibrutinib vs. 4% in ofatumumab) and a significantly improved overall survival at 12 months (90% ibrutinib vs. 81% ofatumumab). Similar clinical benefits were shown regardless of del (17 p). Ibrutinib was well tolerated, and dose-limiting toxicity was not observed. Ibrutinib has shown durable remission, improved progression-free survival and overall survival, and favorable safety profile in indolent B-cell lymphoid malignancies. Ibrutinib, as a monotherapy, is an effective treatment modality as a salvage therapy for treatment of mantle cell lymphoma and chronic lymphocytic leukemia / small lymphocytic lymphoma, particularly in older patients (age 70 years) who are not a candidate for intensive chemotherapy and/or those with del (17 p). In patients with chronic lymphocytic leukemia and del (17 p), the current practice guideline recommends ibrutinib as an upfront treatment option. Current on-going trials will further define its role as upfront therapy and/or as a combination therapy in indolent B-cell lymphoid malignancies.

Keywords Ibrutinib, PCI-32765, mantle cell lymphoma, chronic lymphocytic leukemia, Bruton’s tyrosine kinase inhibitor

Introduction Non-Hodgkin lymphoma (NHL) represents a heterogeneous group of hematologic malignancies involving either B- or T-cell lymphocytes.1 Approximately 85% of NHLs are B-cell malignancies, including chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Burkitt lymphoma, immunoblastic large cell lymphoma, and precursor B-lymphoblastic lymphoma.1 In 2013, there were about 70,000 new cases and 19,000 deaths from NHL in the United States (US).1 Traditional chemotherapy (mostly purine analog- or bendamustine-based regimens) and chemoimmunotherapy (rituximab- and obinutuzumab-based regimens) are

the typical treatment strategies for the indolent B-cell lymphoid malignancies. However, this approach leads to variety of adverse effects (AEs), most notably severe hematologic toxicities. In attempts to avoid most of the undesirable effects manifested by traditional chemotherapy, direct-targeted therapies were developed and are continuously under investigation. Bruton’s tyrosine kinase (BTK) has been found to play a role in B-cell lymphocyte development.2,3 BTK is a cytoplasmic enzyme located in all hematopoietic cells (except for plasma cells and T-cell lymphocytes), Department of Pharmacy, The Mount Sinai Hospital, New York, NY, USA Corresponding author: Chung-Shien Lee, Department of Clinical Pharmacy Practice, St. John’s University, 8000 Utopia Parkway, Queens, NY, 11439, USA. Email: [email protected]

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with an essential role in B-cell lymphocyte development.2,3 It has been implicated in the development of CLL/SLL, DLBCL, FL, MCL, and acute lymphocytic leukemia (ALL).2 Ibrutinib (PCI-32765) is a novel, orally active, irreversible inhibitor of BTK that has demonstrated considerable efficacy in a variety of B-cell malignancies.2,4–6 The US Food and Drug Administration (FDA) formally designated ibrutinib as a breakthrough therapy, and it was approved for the treatment of relapsed and refractory MCL on November 2013 and for relapsed and refractory CLL on February 2014.7–10 Breakthrough therapy designation is meant to expedite the development and review of drugs that are intended to treat a serious condition and have sufficient preliminary clinical evidence that indicates that the drug may demonstrate substantial improvement in at least one clinically significant endpoint over currently available therapies.11 Other anticancer drugs that received breakthrough therapy designation included obinutuzumab in 2013 and, ofatumumab, ceritinib, and idelalisib in 2014.12,13

Data selection Literature searches were performed in PubMed MEDLINE (July 2010 to July 2014), Google Scholar, and ClinicalTrials.gov using the search terms ibrutinib OR PCI-32765. Limits applied to the PubMed MEDLINE search results included human and full text availability. Abstracts presented at meetings of the American Society of Clinical Oncology (June 2010 to March 2014), the American Society of Hematology (December 2008 to March 2014), and the European Hematology Association (June 2010 to March 2014) were also reviewed for data from ongoing studies. Multiple phase 1 and 2 trials were identified, which examined the safety and efficacy of ibrutinib in patients with various NHL. More complete data from ongoing phase 3 trials is expected later this year. PubMed MEDLINE searches for pharmacological and pharmacokinetic data were also conducted. Published data were supplemented with the manufacturer’s prescribing information.

Pharmacology In the B-cell receptor (BCR) signaling pathway, after an antigen triggers the BCR, tyrosine protein kinases Lyn and Syk activate BTK.2 BTK then Activates phosphatidylinositol 3 kinase (PI3K), which converts phosphatidylinositol (4,5)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3).2 This leads to an increase in intracellular calcium release, activation of AKT (Protein Kinase B), and downstream

activation of the mammalian target of rapamycin (mTOR) pathway.2 In addition, BTK activates 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 (PLCg2), which promotes the release of intracellular calcium, diacylglycerol (DAG), and inositol triphosphate (IP3).2 This leads to an increase in nuclear factor kappa B (NF-kB), thereby inhibiting apoptosis of the B-cell and promoting cancer (Figure 1).2 Ibrutinib is a small-molecule inhibitor of BTK that binds covalently to Cys-481 on the BTK active site, leading to an irreversible inhibition at Tyr-223.2,4–6 BTK inhibition by ibrutinib prevents malignant B-cell substrate adhesion, migration, proliferation, and survival.6

Pharmacokinetics/pharmacodynamics The pharmacokinetic properties of ibrutinib have been evaluated in healthy participants, as well as in patients with renal and hepatic impairment.6 After oral administration of a single dose of ibrutinib, the median time to maximum serum concentrations (Tmax) was between 1 and 2 hours.6 There were dose-related increases in the steady-state area-under-the-curve (AUCSS); with a daily dose of 420 mg, the mean AUCSS standard deviation was 680 517 ngh/mL, while with 560 mg daily, it was 953 705 ngh/mL.6 When ibrutinib was taken with food (vs. overnight fasting), there were two-fold increases in systemic exposure.6 In patients with recurrent B-cell lymphoma, more than 90% of the BTK active site was occupied in peripheral blood mononuclear cells after ibrutinib doses of 2.5 mg/kg/day (175 mg/day for a 70 kg adult) were observed for up to 24 hours.6 Ibrutinib is highly protein-bound (97.3%), and it has a large volume of distribution at steady state (VdSS), estimated to be around 10,000 liters.6 Ibrutinib is metabolized primarily by cytochrome P450 (CYP) 3 A; a smaller proportion of the drug is metabolized by CYP 2D6.6 The drug has several metabolites, including an active, dihydrodiol metabolite (PCI-45227) with inhibitory activity toward BTK approximately 15 times lower compared to ibrutinib.6 At steady state, the PCI-45227 to ibrutinib ratio is 1:2.8, implying that almost three times as much of the active, parent drug will be present in the blood compared to its metabolite.6 Ibrutinib has a clearance of about 1000 L/h and a terminal half-life of 4 to 6 hours. In the feces, about 1% of the drug is eliminated unchanged and 80% as metabolites. Less than 10% of the drug is eliminated as metabolite via the urine. There was no difference in the systemic clearance of ibrutinib between male and female patients.6 A creatinine clearance (CrCl) greater than 25 mL/min did not cause variations in the systemic exposure of ibrutinib.6 There is no data available in patients with a CrCl less



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antigen

antigen B-cell receptor complex

extracellular intracellular

Lyn

e

mbran

me holipid

PIP2

phosp

PI3K Syk

Igα

PIP3

AKT

Igβ

BTK Ca2+ PLCγ2

mTOR

ibrutinib DAG

B Iymphocyte

Ca2+

IP3

NF-κB

Figure 1. B-cell receptor and BTK signaling pathways, highlighting the site of action of ibrutinib.2,16,19

than 25 mL/min or in patients on dialysis.6 In patients with hepatic impairment (Child-Pugh B), there was roughly a six-fold higher exposure to ibrutinib compared to healthy volunteers.6

Therapeutic uses Advani et al.16 conducted a phase 1, dose-finding study evaluating the use ibrutinib in 56 patients (median age, 65 years; range, 41 to 82) with relapsed or refractory CLL/SLL, DLBCL, FL, MCL, marginal zone lymphoma (MZL), or Waldenstrom macroglobulinemia (WM) who failed at least one prior therapy. Of the 50 patients who were evaluable for tumor response, 60% achieved an objective response, with 54% achieving an overall response rate (ORR) in the intention-to-treat (ITT) population. Responses were seen in patients with all histologies, with the highest response rates seen in MCL (79%) and CLL/SLL (69%).16 The median progression-free survival (PFS) was 13.6 months and 20 patients remained on the study at the time of data cutoff.16 The results of this study then led to further investigation of ibrutinib.

MCL A phase 2 study by Wang et al.17 evaluated 111 patients (median age, 68 years; range, 40 to 84) with relapsed or

refractory MCL. These patients received a median of three prior therapies (but up to five prior therapies) and 43% received bortezomib as a prior treatment. The ORR for all patients was 68% (21% complete response (CR); 47% partial response (PR)) and the responses did not differ with the presence of risk factors associated with treatment failure.17 The median PFS was 13.9 months and overall survival (OS) rate was 58% at 18 months among all treated patients.17 The results of this pivotal trial led to an accelerated approval of ibrutinib for previously treated MCL by the FDA in November 2013.7,17

CLL/SLL In the previously mentioned phase 1 study conducted by Advani et al.,16 11 of 16 (69%) heavily pretreated (up to 10 prior therapies) patients with CLL/SLL achieved responses to treatment. A phase 1 b/2, openlabel, multicenter study examined daily doses of ibrutinib 420 mg and 840 mg in patients with relapsed or refractory CLL/SLL.18 The majority of patients (96%) in this trial had CLL with various unfavorable features, such as del (17) (p13.1) (33%), del (11) (q22.3) (36%), bulky (>5 cm in diameter) lymph nodes (52%), and/or a Rai stage of III or IV (65%).18 Deletion 17 p is associated with the worst outcomes, short median survival and short treatment-free intervals compared to other cytogenetic abnormalities. Patients in this study



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had a median of four previous treatments (range, 1 to 12).18 The ORR was 71% in patients who received either ibrutinib 420 mg or 840 mg daily.18 Similar responses were seen between various clinical and genomic risk factors present before treatment, as previously mentioned.18 The 26-month PFS was 75% and OS was 83%, suggesting a durable response.18 In patients with a del (17) (p13.1), PFS and OS was 57% and 70%, respectively.18 The discontinuation rate was greater in higher dose arm (840 mg) of ibrutinib (12%) compared to those who received 420 mg (4%).18 This study is still ongoing, and it highlights the activity of ibrutinib in patients with poor prognostics (or high risk) and those who are difficult to treat.18 The encouraging results of the previous study led to the investigation of ibrutinib in patients 65 years of age or older with CLL/SLL who were treatment-naı¨ ve or received minimal number of prior treatments.19 The study was initially designed to assess ibrutinib 420 mg and 840 mg daily, but the 840 mg cohort was closed because there was no difference in the clinical activity between the two dosing arms.18,19 Of the 31 enrolled patients, 29 had CLL and two had ALL.19 Furthermore, 27 patients received ibrutinib 420 mg and four received 840 mg.19 Objective response was seen in 71% of the patients (13% CR), with a median initial time to response of 1.9 months (interquartile range (IQR) 1.8–4.6).19 At 24 months, PFS was 96.3% and OS was 96.6%.19 There were no significant differences in responses based on prognostic variables. This study presented an impressive 24-month diseasefree survival (DFS) in elderly patients.19 Prior to this study, 50% was the best PFS at 24 months with the combination of chlorambucil and obinutuzumab.19 In an open-label, multicenter, phase 3 study (RESONATE) comparing ibrutinib 420 mg daily to ofatumumab in patients with relapsed or refractory CLL/SLL,20 the median follow-up time was 9.4 months (range, 0.1 to 16.6).20 Patients in the ibrutinib arm had a significantly prolonged PFS (median not reached with ibrutinib vs. 8.1 months with ofatumumab).20 This was observed regardless of the risk factors or molecular features, such as del (17) (p13.1), bulky disease, or Rai stage. In patients with del (17) (p13.1), the median duration of PFS was not reached in the ibrutinib arm, whereas the median PFS was 5.8 months in the ofatumumab arm.20 Ibrutinib significantly improved OS at 12 months (90% in ibrutinib vs. 81% in ofatumumab).20 A total of 57 patients in the ofatumumab arm had crossed over to the ibrutinib arm after disease progression. Patients receiving ibrutinib had a significantly higher ORR compared to those receiving ofatumumab (43% PR in ibrutinnib vs. 4% PR in ofatumumab) (odds ratio, 17.4; 95% CI, 8.1 to 37.3; p < 0.001).20

There have been encouraging data for ibrutinib as monotherapy for relapsed/refractory CLL/SLL, but there is also data supporting its use in combination with other agents.21–24 In a phase 1 trial, ibrutinib is being evaluated in combination with rituximab in 40 patients with high-risk features of CLL/SLL.21 In a preliminary analysis at a median of four months of follow-up, the ORR was 85%, which appears better than responses seen with bendamustine and rituximab in previous studies.25 A separate phase 1 trial has also demonstrated benefits with the addition of ibrutinib to bendamustine and rituximab, showing a 93% ORR at 8.5 months.22 Furthermore, ibrutinib has been found to be effective as a combination therapy with ofatumumab for the treatment of relapsed or refractory CLL/SLL.23

FL In a phase 1, dose escalation study, Fowler et al.26 investigated the use of ibrutinib in 16 patients with relapsed or refractory FL. Patients in this trial received a median of three prior therapies (range, 1 to 5) and all of the patients had received rituximab in one of their prior therapies.26 Dose initiation was started at ibrutinib 1.25 mg/kg, and of the 11 (69%) patients who received 2.5 mg/kg, the ORR was 54.5% and median PFS of 13.4 months.26

NHL A phase 1 trial was performed in 11 patients with advanced NHL who had received a median of three prior therapies (range, 0 to 10).27 Of 11, 8 (73%) evaluable patients yielded an ORR of 38%.27 Of the 11 patients, 3 (27%) patients had MCL, all of whom responded to the therapy.27 In a separate phase 1 b study of 17 patients with previously untreated NHL, ibrutinib was added to RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), and all patients responded to the therapy.24

Safety Adverse events Ibrutinib has been associated with modest toxicities. Commonly reported AEs were mostly grade 1–2, and usually resolved without interruption of treatment. In clinical trials, the most common reversible AEs were non-hematologic, including diarrhea (47–68%), nausea/vomiting (16–48%), fatigue (32–41%), decreased appetite or dyspepsia (21–34%), peripheral edema (21–29%), muscle spasms or myalgia (13–38%), dizziness (18–26%), hypertension (18–29%), dyspnea (27%), rash (13–27%), and pyrexia (18–27%)



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(Table 1).6,16–19 The most common grade 3–4 AEs were neutropenia (13–29%), thrombocytopenia (3–17%), and infections (specifically pneumonia (6–12%)). One study noted that severe infections most frequently occurred early in the course of therapy.18 In O’Brien et al.19 two patients discontinued treatment from AEs; one from grade 3 fatigue and one from grade 2 viral infection.19 Wang et al.17 reported grade 3 bleeding in five patients of whom four had subdural hematomas; however, all had multiple contributing factors, such as falls and/or head trauma.17 Furthermore, all four had received either aspirin or warfarin two days before or on the date of occurrence of the event. The mechanism by which ibrutinib causes bleeding is not well understood, but the drug may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.6,16 Ibrutinib should be held for at least 3–7 days pre- and post-surgery.6 Byrd et al.18 reported that eight out of 85 patients (9%) died within 30 days of receiving the last dose of ibrutinib: three (38%) from pneumonia; one (13%) from systemic inflammatory response syndrome, one (13%) from sarcoma, and three (38%) related to CLL progression. There has been one case report of a patient who experienced visual deterioration with ibrutinib.61 Neffendorf et al.61 described an 80-year-old woman with CLL who reported deteriorating vision, which lasted for a month, after being treated with ibrutinib for six months. In the RESONATE trial, 10% of patients reported blurred vision.20 Clinicians should be vigilant in monitoring for this adverse event. Potentially fatal cases of renal failure have also been associated with ibrutinib.6 Renal function should be periodically monitored and patients should be encouraged to stay adequately hydrated.6 Second primary malignancies, such as skin cancer and carcinomas have also occurred in up to 10% of patients on ibrutinib.6 Responses to ibrutinib have been notable, but patients may develop resistance over time.19 Patients who relapse could develop Richter’s transformation (CLL transformation to DLBCL), which is potentially fatal.19 The favorable safety profile of ibrutinib may suggest its high specificity for the BTK receptor with minimal off-target toxicity. The rate of myelosuppression seen with ibrutinib monotherapy is minimal in comparison to traditional myelotoxic chemotherapy. However, ibrutinib, in combination with bendamustine and rituximab, has shown to be associated with high rate of grade 3–4 hematologic toxicities, including lymphopenia (64%), neutropenia (27%), and thrombocytopenia (18%).27

Table 1. Adverse events associated with ibrutinib.6,14–17 Adverse events Hematologic Neutropenia Thrombocytopenia Anemia Non-hematologic Gastrointestinal Diarrhea Nausea/Vomiting Constipation Gastroesophageal reflux disease Stomatitis Decreased appetite/ dyspepsia Abdominal pain Infections Urinary tract infection Upper respiratory tract infection Cellulitis Pain Oropharyngeal pain Back pain Peripheral sensory neuropathy Musculoskeletal Muscle spasms/myalgia Arthralgia Other Fatigue Dizziness Hypertension Sinusitis Cough Pyrexia Dyspnea Peripheral edema Anxiety Epistaxis Petechiae Insomnia Headache Contusion Rash Bleeding events Dry eye Erythema Pruritus

Drug-drug interactions Ibrutinib is a major substrate of CYP 3 A and a minor substrate of 2D6. Therefore, co-administration with


All grades (%)

Grade 3–4 (%)

15–18 13–18 0–16

12.5–29 3–17 0–9

46.5–68 16–48 14.3–25 19 16 21–34 17–19 23 23–33 13

2–13 1–1.8 0–1 0 0 0–3.6 0–5 25 3 0 0

15 13 13

0 3 0

13–37.5 16.1–27

0–1 0

32–41.1 18–26 18–29 13–18 18–32.1 18–27 27 21–29 16 16 16 10.7–16 18–25 16–17 13–27 N/A 13 13 13

3–5 1–3 5–6 0–5 0 1–5 5 0–2 0 0 0 0 0–3 0 0–2 5–6 0 0 0


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moderate/strong inhibitors or inducers of these enzymes may potentially lead to clinically significant drug–drug interactions.6 In a phase 1 study, ibrutinib 120 mg was given on day 1 and 40 mg on day 7, along with a strong CYP 3 A inhibitor, ketoconazole 400 mg on days 4 to 9.6,62 Ketoconazole increased the maximum plasma concentration (Cmax) of ibrutinib by 29fold and AUC by 24-fold.6,62 Moderate CYP 3 A inhibitors, such as diltiazem and erythromycin may increase the AUC by 6 - to 9-fold when ibrutinib is taken in a fasted state.6 In contrast, strong CYP 3 A inducers may decrease the Cmax and AUC by more than 10-fold, while moderate CYP 3 A inducers may decrease the AUC up to three-fold.6 The dose of ibrutinib should be reduced to 140 mg when given concomitantly with a moderate CYP3A inhibitor.6 Ibrutinib and its active metabolite (PCI-45227) are unlikely to inhibit CYP isoforms and both of these compounds are weak inducers of CYP in vitro.6 Although ibrutinib is not a P-glycoprotein (P-gp) substrate, it may lead to clinically significant effects on other P-gp substrates in the gastrointestinal tract.6 Specifically, the plasma levels of drugs with narrow therapeutic indices may be increased when ibrutinib is co-administered.6 Ibrutinib has also been implicated in affecting platelet aggregation in animal studies. Concomitant use of anticoagulants, such as warfarin and antiplatelet drugs, including aspirin, clopidogrel, prasugrel, should be used with caution due to the potential risk of bleeding.6,17,63

Some notable ongoing trials are: a phase 3 trial comparing ibrutinib vs. chlorambucil in patients with treatment-naı¨ ve CLL/SLL (RESONATE-2); a phase 3 trial evaluating the addition of ibrutinib to bendamustine and rituximab in patients with relapsed or refractory CLL/SLL; and a phase 3 trial evaluating the addition of ibrutinib to R-CHOP in newly diagnosed DLBCL. Targeting BTK may also have anti-myeloma activity as shown in in vitro studies.66 It is believed that the drug could block the cell growth in myeloma and reduce cellular survival within in vitro and in vivo MM cell lines.66 This activity is thought to be due to the inhibitory effects of ibrutinib on the NF-kB pathway.66 Ibrutinib may also inhibit RANKL-induced phosphorylation of BTK in osteoclasts, inhibit bone resorption activity, and reduce cytokine and chemokine release from bone marrow stromal cell cultures and osteoclasts in patients with MM.66 Hyperactive osteoclast activity and inactive osteoblast function are some of the pathologic features of MM.66 When ibrutinib was added to cell lines treated with bortezomib or lenalidomide, the drug exhibited synergistic cytotoxic effects on these cells.66 There is an ongoing phase 1/2b study in relapsed or refractory MM patients investigating the use of ibrutinib in conjunction with carfilzomib, as well as a phase 2 study with dexamethasone.59,60

Therapeutic and economic issues

Ibrutinib is supplied as a 140-mg immediate-release, white, opaque, hard-gelatin, size 0 capsule for oral administration.6,67 The recommended dose is 560 mg daily for MCL and 420 mg daily for CLL.6 Ibrutinib should be taken with a glass of water around the same time every day, and the capsules should not be opened, broken, or chewed.6 Ibrutinib should be held for hematologic toxicity (grade 3 neutropenia with infection/fever or any grade 4) or non-hematologic toxicity (any grade 3).6 After improvement to grade 1 toxicity or baseline, the drug should be resumed at the starting dose.6 Of note, for each recurrence of toxicity, the daily dose should be reduced by 140 mg (one capsule), and if toxicity persists after the doses have been reduced two times, therapy should be discontinued.6 Generally, concomitant use of a CYP3A inhibitor or inducer with ibrutinib should be avoided.6 Patients should be instructed to avoid grapefruit/juice, pomegranate/juice, and Seville oranges to prevent potentially significant interaction with ibrutinib. In patients requiring moderate or strong CYP3A inhibitors, options include changing to an alternative drug with a lesser degree of CYP3A inhibition, withholding ibrutinib therapy if the CYP3A inhibitor will be used for a

The average wholesale price (AWP) of ibrutinib for 90 capsules (30 day supply for CLL therapy) is $9840 and 120 capsules (30 day supply for MCL therapy) is $13,120.64 The manufacturer (Pharmacyclics, Inc) offers patient assistance program called ‘‘You&i Access’’ through which patients may be eligible to obtain a free 30-day supply if the insurance coverage is delayed by more than 5 business days and it is prescribed for FDA-approved indications; and patients with private insurance may be eligible to receive the drug with a monthly copay of $10 for up to 12 months.65

Approved labeling and possible off-label uses Ibrutinib is FDA-approved as a monotherapy for the treatment of relapsed and refractory MCL and CLL in patients who have received at least one prior therapy.6 Recent data also demonstrated its clinical activity in treatment-naı¨ ve patients.16–24,26,27 These promising data have paved the way for further investigation of the drug’s safety and efficacy in the clinical setting (Table 2).

Dosage and administration


III

II

NCT0172248729 (RESONATE 2)

NCT0174469130 (RESONATE 17) NCT0161109031 (HELIOS)

Relapsed or refractory CLL or SLL Relapsed or refractory CLL or SLL, MCL or other B-cell lymphoproliferative disorders Treatment naı¨ve CLL or SLL Relapsed or refractory CLL Relapsed or refractory CLL Special cases of CLL or SLL Relapsed or refractory high risk CLL or SLL Relapsed or refractory MCL

Treatment naı¨ve MCL

III

I I/II

III III II II II

III

III

NCT0188687234

NCT0188685935 NCT0201312836

NCT0204881337 NCT0197338738 NCT0184926339 NCT0150073340 NCT0152051941

NCT0164602142 (RAY) (MCL3001) NCT0177684043 (SHINE)

Ibrutinib + rituximab vs. FCR Ibrutinib 420 mg daily vs. rituximab Ibrutinib Ibrutinib 420 mg daily Ibrutinib 420 mg daily + rituximab 375 mg/m2 on days 1, 8, 15 and 22 then once every 4 weeks on cycles 2 to 6 Ibrutinib 560 mg daily vs. temsirolimus 175 mg daily IV on days 1, 8 and 15 on first cycle, then 75 mg on days 1, 8 and 15 on subsequent cycles Ibrutinib 560 mg daily + bendamustine 90 mg/m2 IV on days 1 and 2 cycles 1 to 6 + rituximab 375 mg/m2 on day 1 cycles 1 to 6 vs. Placebo + bendamustine 90 mg/m2 IV on days 1 and 2 cycles 1 to 6 + rituximab 375 mg/m2 on day 1 cycles 1 to 6

Ibrutinib + rituximab vs. bendamustine + rituximab vs. ibrutinib Ibrutinib + lenalidomide Ibrutinib + ublituximab

Ibrutinib 420 mg daily + bendamustine 70 mg/m2 days 2 and 3 on cycle 1 and days 1 and 2 on cycles 2-6 + rituximab 375 mg/m2 on day 1 cycle 1 and then 500 mg/m2 on day on cycles 2-6 vs. Placebo + bendamustine + rituximab Ibrutinib 420 mg daily vs. Ibrutinib 420 mg daily + rituximab 375 mg/m2 weekly for cycle 1 then monthly cycle 2-6 Ibrutinib 420 mg daily

Ibrutinib 420 mg daily vs. chlorambucil 0.5 mg/kg on days 1 and 15 on cycle 1 (can increase in increments of 0.1 mg/ kg on day of each cycle to a max of 0.8 mg/kg) Ibrutinib 420 mg daily

Treatment regimen


520

280

519 150 40 86 40

10 60

523

78

208

578

111

272

Targeted sample size (n)

PFS

PFS

PFS PFS ORR ORR PFS

MTD Safety

PFS

PFS

PFS

PFS

ORR

PFS

Primary outcome

(continued)

OS, ORR, DOR

ORR, OS, DOR

OS ORR, OS, EFS OS, PFS, DOR OS, PFS N/A

RR ORR

OS, TTP, DOR, ORR

ORR, DOR, OS

N/A

ORR, OS

DOR, PFS, OS

ORR, EFS

Secondary coutcomesa

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Relapsed or refractory CLL, SLL or Bcell PLL Treatment naı¨ve CLL

II

NCT0158930233

Relapsed CLL

II

Relapsed or refractory CLL with 17 p deletion Relapsed or refractory CLL or SLL

Treatment naı¨ve CLL

Malignancy

NCT0200704432

III

Phase

Protocol name

Table 2. Clinical trials with ibrutinib: ongoing trials.

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I I II II I/IIb II

NCT0147984255 NCT0170496356 NCT0198151257 NCT0161482158 NCT0196279259 NCT0147858160

48 24 44 60 176 164

130

MTD Safety ORR ORR MTD, PFS PFS

MTD/OR

ORR EFS MTD MTD

ORR MTD PFS

ORR ORR

ORR

Primary outcome

ORR, DOR N/A PFS, OS PFS ORR, DOR, OS, TTP N/A

DOR, PFS, OS

DOR, PFS, OS PFS, OS, CRR DOR, PFS RR, DOR, PFS, OS

DOR, PFS, OS ORR, OS, PFS OS, ORR, DOR

N/A DOR, PFS, OS, TTR

OS, PFS

Secondary coutcomesa

8

Relapsed or refractory B-cell NHL Recurrent Mature B-cell neoplasms Relapsed HCL Relapsed or refractory WM Relapsed or refractory MM Relapsed or refractory MM

80 33 400

Ibrutinib 560 mg daily + rituximab 375 mg/m2 Ibrutinib + rituximab + lenalidomide Ibrutinib 560 mg daily + bendamustine + rituximab or R-CHOP Ibrutinib 560 mg daily Ibrutinib + R-CHOP vs. Placebo + R-CHOP Ibrutinib + lenalidomide Ibrutinib + R-DHAP vs. Ibrutinib + R-DHAOx Ibrutinib + lenalidomide + rituximab vs. Ibrutinib + lenalidomide Ibrutinib + rituximab + bendamustine Ibrutinib Ibrutinib 420 mg daily Ibrutinib Ibrutinib + carfilzomib Ibrutinib + dexamethasone

50 110

Ibrutinib 560 mg daily + rituximab 375 mg/m2 Ibrutinib 560 mg daily

60 800 34 60

120

Ibrutinib 560 mg daily

Treatment regimen

Targeted sample size (n)

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CLL: chronic lymphocytic leukemia; CRR: complete response rate; DLBCL: diffuse large B-cell lymphoma; DOR: duration of response; EFS: event free survival; FCR: fludarabine, cyclophosphamide, rituximab; FL: follicular lymphoma; HCL: hairy cell leukemia; MCL: mantle cell lymphoma; MM: multiple myeloma; MTD: maximum tolerated dose; MZL: marginal zone lymphoma; NHL: Non-Hodgkin lymphoma; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; TTP: time to progression; PLL: prolymphocytic leukemia; R-CHOP: rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone; R-DHAOx: rituximab + dexamethasone, cytarabine, oxaliplatin; R-DHAP: rituximab + dexamethasone, cytarabine, cisplatin; RR: response rates; SLL: small lymphocytic lymphoma; WM: waldenstrom macroglobulinemia. a Selected secondary outcome.

Ib/II

Relapsed or refractory MZL Treatment naı¨ve DLBCL Relapsed or refractory B-cell NHL Relapsed or refractory B-cell lymphomas Relapsed or refractory DLBCL

Treatment naı¨ve FL Treatment naı¨ve FL Relapsed or refractory FL, MZL

II I III

II III I Ib

Relapsed or refractory MCL Relapsed or refractory FL

II II

NCT0198062850 NCT0185575051 NCT0195549952 NCT0205592453 (BIBLOS) NCT0207716654

Relapsed or refractory MCL after bortezomib therapy

II

NCT0159994944 (SPARK) (MCL2001) NCT0188056745 NCT0177979146 (DAWN) (FLR2002) NCT0198065447 NCT0182956848 NCT0197444049

Malignancy

Phase

Protocol name

Table 2. Continued.




III

II

Treatment naı¨ve B-cell NHL Relapsed or refractory DLBCL Relapsed or refractory CLL

Relapsed or refractory Bcell NHL

I

I

Relapsed or refractory FL

I

Ibrutinib 420 mg daily vs. ofatumumab 300 mg for the first dose, then 2000 mg weekly during weeks 2-8, then 2000 mg every 4 weeks


Ibrutinib 420 mg daily + ofatumumab 300 mg for the first dose, then 2000 mg weekly during weeks 2-8, then 2000 mg every 4 weeks Ibrutinib 1.25 mg/kg, 2.5 mg/kg, 5 mg/kg, 8.3 mg/ kg, 12.5 mg/kg or 560 mg daily Ibrutinib 280 mg or 560 mg on days 1 to 28 every 28 days + rituximab 375 mg/m2,a on day 1 + bendamustine 90 mg/m2 days 2 and 3 Ibrutinib + R-CHOP

Ibrutinib 420 mg + rituximab 375 mg/m2 weekly for cycle 1 then monthly cycle 2-6 Ibrutinib + bendamustine + rituximab

Ibrutinib 420 mg daily or 840 mg daily


Ibrutinib 420 mg daily or 840 mg daily

Ibrutinib 1.25 mg/kg, 2.5 mg/kg, 5 mg/kg, 8.3 mg/kg, 12.5 mg/kg or 560 mg daily

Treatment regimen

42.6% vs. 4.1%

9.4 (0.1 to 16.6)

100%

90%

54.5%

100%

23%

(5.3-

93%

85%

71%

68%

71%

60%

NR

N/A

4.9 (2.7 to 8.3)

N/A

6.5 10.2)

8.5

15.3 (1.9 to 22.3) 22.1 (20.3 to 23.2) 4

20.9 (0.7 to 26.7)

N/A

ORR

Not reached vs. 8.1 months

NR

N/A

N/A

Median: 13.4

Median: 9.8 100%

N/A

96.3% at 24 months N/A

75% estimated at 26 months Median: 13.9

Median: 13.6

PFS (months)

90% vs. 81%

9.76 months

NR

N/A

N/A

100%

N/A

58% estimated at 18 months 96.6% at 24 months N/A

83% estimated at 26 months

N/A

OS

CLL: chronic lymphocytic leukemia; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; MCL: mantle cell lymphoma; MZL: marginal zone lymphoma; NHL: Non-Hodgkin lymphoma; NR: not reported; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PLL: prolymphocytic leukemia; SLL: small lymphocytic lymphoma; WM: waldenstrom macroglobulinemia. a Subsequent doses increased to 500 mg/m2.

Younes et al.24 (n ¼ 17) Wilson et al.28 (n ¼ 70) Byrd et al.20 (n ¼ 391)

Fowler et al.26 (n ¼ 16) Blum et al.27 (n ¼ 11)

I

I

Relapsed or refractory CLL or SLL Relapsed or refractory CLL or SLL Relapsed or refractory CLL or SLL, PLL

Relapsed or refractory MCL Untreated CLL or SLL

Relapsed or refractory CLL or SLL, MCL, WM, FL, DLBCL, MZL Relapsed or refractory CLL or SLL

Malignancy

Median Follow-up (months) (range)

(OPP)

I

Ib/II

II

Ib/II

Bryd et al.18 (n ¼ 85)

Wang et al.17 (n ¼ 111) O’Brien et al.19 (n ¼ 31) Burger et al.21 (n ¼ 40) Brown et al.22 (n ¼ 30) Jaglowski et al.23 (n ¼ 27)

I

Phase

Advani et al. 2013 (n ¼ 56)

16

Reference (sample size, n)

Table 3. Clinical trials with ibrutinib: completed trials.


Lee et al. 9


(OPP)


10


short period (7 days), or reducing the dose of ibrutinib to 140 mg daily.6 Likewise, patients who are taking a strong CYP3A inducer with ibrutinib, an alternative drug with a lesser degree of CYP3A induction should be selected.6 Ibrutinib is a white to off-white solid powder with the empirical formula of C25H24N6O2 and molecular weight of 440.50.6 It is freely soluble in dimethyl sulfoxide (DMSO), soluble in methanol, and practically insoluble in water.6 Each capsule has several inactive ingredients, including croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.6,67 The shell contains gelatin, titanium dioxide, and black ink.6,67 The capsules should be stored at room temperature (20 C to 25 C, (68 F to 77 F)), with excursions permitted between 15 C and 30 C (59 F to 86 F).6,67 Although stability data submitted to the FDA supports a 24-month expiration period, ibrutinib should be retained in its original packaging.6,67

and MCL. Ibrutinib has shown durable responses and survival benefits in heavily pretreated patients with MCL and CLL/SLL, including those with high-risk features, such as del (17) (p13.1). Since it has been shown to be associated with modest toxicities, it is an ideal treatment modality for older patients (age 70 years) with relapsed or refractory CLL who are not candidates to receive intensive chemotherapy. In patients with CLL and del (17 p), current practice guidelines recommend ibrutinib as an upfront treatment option. BTK also plays a role in other B-cell lymphoid malignancies, and inhibition of this target pathway may also provide meaningful clinical benefits to patients with FL, MZL, and MM, all of which are currently being researched. Results of controlled randomized trials will further define the role of ibrutinib as an upfront treatment and/or as a combination therapy in indolent B-cell lymphoid malignancies. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Formulary consideration Ibrutinib is a promising new treatment option for several indolent B-cell lymphoid malignancies. It has shown notable response rates in patients who have relapsed and refractory disease, as well as in patients who are treatment-naı¨ ve. Several completed and ongoing studies support the role of ibrutinib in a variety of malignancies (see Tables 2 and 3). Currently, ibrutinib, as a monotherapy, is indicated in MCL and CLL as a salvage therapy. Current National Comprehensive Cancer Network (NCCN) Guidelines also recommend ibrutinib as a viable salvage therapy for MCL and CLL, and as an upfront CLL therapy in patients with del (17 p).68 The cost of monthly therapy (based on 2014 US AWP) of ibrutinib ranges from $10,000 to $14,000. However, the high treatment cost of ibrutinib should be weighed against the use of traditional chemotherapy or chemoimmunotherapy, which may require either hospitalization or long hours of intravenous infusion in the clinic. Since ibrutinib is an oral chemotherapy agent, nursing time and either chair time in the clinic or hospital admission can be avoided. Furthermore, ibrutinib has a favorable toxicity profile when compared to traditional treatment, and its incidence of severe hematological AEs have shown to be lower than that of traditional chemotherapy and chemoimmunotherapy.

Summary Ibrutinib is a novel, first-in-class agent that irreversibly inhibits BTK, and it is FDA-approved as a monotherapy for the treatment of relapsed or refractory CLL

Conflict of interest The author(s) declared no potential conflicts of interests with respect to the research, authorship, and/or publication of this article.

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Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.

The promising impact of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the management of lymphoid malignancies.

Response of renal cell carcinoma to ibrutinib, a bruton tyrosine kinase inhibitor, in a patient treated for chronic lymphocytic leukemia.

The Bruton's tyrosine kinase inhibitor ibrutinib exerts immunomodulatory effects through regulation of tumor-infiltrating macrophages.

The Bruton tyrosine kinase inhibitor ibrutinib abrogates triggering receptor on myeloid cells 1-mediated neutrophil activation.

Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes.

Targeting Bruton's tyrosine kinase with ibrutinib in B-cell malignancies.

Ibrutinib: a new frontier in the treatment of chronic lymphocytic leukemia by Bruton's tyrosine kinase inhibition.

Antitumor activity of S116836, a novel tyrosine kinase inhibitor, against imatinib-resistant FIP1L1-PDGFRα-expressing cells.

A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation.

Regorafenib: a novel multitargeted tyrosine kinase inhibitor for colorectal cancer and gastrointestinal stromal tumors.

Direct and two-step bioorthogonal probes for Bruton's tyrosine kinase based on ibrutinib: a comparative study.

serine kinase.

Emodin, a protein tyrosine kinase inhibitor from Polygonum cuspidatum.

A Tec kinase BTK inhibitor ibrutinib promotes maturation and activation of dendritic cells.

Imbruvica (Ibrutinib), First-in-Class Bruton's Tyrosine Kinase Inhibitor, Receives Expanded Indications for Patients with Relapsed Chronic Lymphocytic Leukemia.

Skin problems and EGFR-tyrosine kinase inhibitor.

Tyrosine kinase inhibitor induced isolated pericardial effusion.

Clinical response to sunitinib as a multitargeted tyrosine-kinase inhibitor (TKI) in solid cancers: a review of clinical trials.

Establishment of a Novel Method for Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance Mutations in Lung Cancer.

New therapeutic strategies in neuroblastoma: combined targeting of a novel tyrosine kinase inhibitor and liposomal siRNAs against ALK.

Oncogene swap as a novel mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor in lung cancer.

The bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) blocks hairy cell leukaemia survival, proliferation and B cell receptor signalling: a new therapeutic approach.

SAHA and S116836, a novel tyrosine kinase inhibitor, synergistically induce apoptosis in imatinib-resistant chronic myelogenous leukemia cells.