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Efficacy Summary by Cancer Type

Previously Treated

Chronic Lymphocytic Leukemia

In the phase 3 RESONATE™ trial vs ofatumumab,* IMBRUVICA® demonstrated:1

PFS (primary endpoint)

  • A statistically significant 78% reduction in risk of disease progression or death (HR=0.22; 95% CI: 0.15, 0.32); P<0.0001
  • Median PFS was not reached for IMBRUVICA® vs 8.1 months for ofatumumab

OS (secondary endpoint)

  • A statistically significant 57% reduction in risk of death (HR=0.43; 95% CI: 0.24, 0.79); P<0.05
  • Median OS not reached in either arm

ORR (secondary endpoint)

  • 42.6% vs 4.1% for ofatumumab
    (none of the patients achieved a complete response)
In the phase 1b/2 trial, IMBRUVICA® demonstrated:

ORR§

  • A 58.3% ORR (none of the patients achieved a complete response)1

Duration of Response (DOR)

  • A 1.9 month median time to response2
  • Median duration of response not reached (range, 5.6 to 24.2+ months)1

Chronic Lymphocytic Leukemia

With 17p Deletion

In the phase 3 RESONATE™ trial vs ofatumumab in patients with 17p deletion,|| IMBRUVICA® demonstrated:1

PFS

  • A 75% reduction in risk of disease progression or death (HR: 0.25; 95% CI: 0.14, 0.45)
  • Median PFS was not reached with IMBRUVICA® vs 5.8 months with ofatumumab

ORR

  • A 47.6% ORR vs 4.7% for ofatumumab
    (none of the patients achieved a complete response)
PFS=progression-free survival; HR=hazard ratio; CI=confidence interval; OS=overall survival; ORR=overall response rate.
*N=391.
Assessed by an Independent Review Committee (IRC) according to the modified International Workshop on CLL (iwCLL) criteria.
N=48.
||N=127.

References: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC 2015. 2. Data on File. Pharmacyclics LLC 2015.

Previously Treated

Mantle Cell Lymphoma

In a single-arm, phase 2 trial,* IMBRUVICA® demonstrated:1

ORR (CR+PR)

  • A 65.8% ORR (95% CI: 56.2, 74.5)
  • A CR of 17.1%

DOR (duration of response)

  • A median DOR of 17.5 months (95% CI: 15.8, NR)
  • A median time to response of 1.9 months
ORR=overall response rate; CR=complete response; PR=partial response; CI=confidence interval; NR=not reached.
*N=111.
Assessed according to the revised International Working Group for non-Hodgkin's lymphoma (NHL) criteria.

Reference: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC 2015.

Previously Treated

Waldenström’s Macroglobulinemia

In a single-arm, phase 2 trial,* IMBRUVICA® demonstrated:1

RR (CR+VGPR+PR)

  • A 61.9% RR (95% CI: 48.8, 73.9)
  • 11.1% of patients had a very good partial response (VGPR) and 50.8% had a partial response (PR)

Duration of Response (DOR)

  • Median duration of response was not reached (range, 2.8+ to 18.8+ months)
  • A median time to response of 1.2 months (range, 0.7 to 13.4 months)
RR=Response rate; CR=complete response; VGFR=very good partial response; PR=partial response; CI=confidence interval.
*N=63.
Adapted from response criteria developed by the International Workshop on WM.

Reference: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC 2015.

How does IMBRUVICA® (ibrutinib) work?

A first-in-class covalent BTK inhibitor

 

IMBRUVICA® affects key processes in malignant B cells*1-9
Imbruvica® affects key processes in malignant B cells*1-9
Inhibits proliferation and survival -
 
Inhibits adhesion (binding to other cells in the micro environment) +
 
Modulates chemotaxis (migration of B cells in/out of lymphatic tissue) +
 
How does IMBRUVICA® (ibrutinib) work?
How does IMBRUVICA® (ibrutinib) work?
How does IMBRUVICA® (ibrutinib) work?
 

*As demonstrated by in vitro and in vivo studies.
BTK=Bruton’s tyrosine kinase.

IMBRUVICA® binds covalently to BTK, an essential mediator of B cell signaling1,9-17

• Correlation to clinical effect has not been established

References: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC 2015. 2. Herman SEM, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287-6296. 3. de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594. 4. Binsky I, Lantner F, Grabovsky V, et al. TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner. J Immunol. 2010;184(9):4761-4769. 5. Davids MS, Burger JA. Cell trafficking in chronic lymphocytic leukemia. Open J Hematol. 2012;3(S1)-3. Published online February 21, 2012. 6. Chang BY, Francesco M, Steggerda S, et al. Ibrutinib inhibits malignant cell adhesion and migration and reduces tumor burden in lymph node and bone marrow in a murine model of mantle cell dissemination and progression. Presented at: 104th Annual Meeting of the American Association for Cancer Research; April 6-10, 2013; Washington, DC. Abstract 923. 7. Chang BY, Francesco M, De Rooij MFM, et al. Egress of CD19+CD5+ cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122:2412-2424. 8. Cinar M, Hamedani F, Mo Z, et al. Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by ibrutinib induces apoptosis. Leuk Res. 2013;37:1271-1277. 9. Ponader S, Chen S-S, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119(5):1182-1189. 10. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase. ChemMedChem. 2007;2(1):58-61. 11. Burger JA, Buggy JJ. Bruton tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765). Leuk Lymphoma. 2013;54(11):2385-2391. 12. Liu Q, Sabnis Y, Zhao Z, et al. Developing irreversible inhibitors of the protein kinase cysteinome. Chem Biol. 2013;20(2):146-159. 13. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107(29):13075-13080. 14. Buggy JJ, Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol. 2012;31(2):119-132. 15. Kindt TJ, Goldsby RA, Osborne BA. Kuby Immunology. 6th ed. New York, NY: W.H. Freeman; 2007. 16. Ponader S, Balasubramanian S, Pham LV, et al. Activity of Bruton’s tyrosine kinase (Btk) inhibitor PCI-32765 in mantle cell lymphoma (MCL) identifies Btk as a novel therapeutic target. Presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. Abstract 3688. 17. Wang L, Martin P, Blum KA, et al. The Bruton’s tyrosine kinase inhibitor PCI-32765 is highly active as single-agent therapy in previously-treated mantle cell lymphoma (MCL): preliminary results of a phase II trial. Presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. Abstract 442.

IMBRUVICA® binds covalently to BTK, an essential mediator of B-cell signaling1,9-17

Safety Summary by Cancer Type

Clinical safety data in chronic lymphocytic
leukemia (CLL) phase 3 and phase 1b/2 trials

  • The most commonly occurring adverse reactions in the phase 1b/2 and phase 3 trials (≥20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia1

Clinical safety data in the CLL phase 3 RESONATE™ trial

  • Median duration of exposure was 8.6 months for IMBRUVICA® vs 5.3 months for ofatumumab1

Adverse reactions (ARs) in ≥10% of CLL patients1

Adverse reactions in Chronic Lymphocytic Leukemia (CLL) patients
Adverse reactions in Chronic Lymphocytic Leukemia (CLL) patients
 

Subjects with multiple events for a given adverse drug reaction (ADR) term are counted only once for each ADR term.

*Includes multiple ADR terms.

 

Treatment-emergent decrease of platelets, neutrophils, or hemoglobin in the phase 3 trial1

Treatment-emergent decrease of hemoglobin, platelets, or neutrophils in the Phase 3 Chronic Lymphocytic Leukemia (CLL) clinical trial
 

Based on laboratory measurements per iwCLL (International Workshop on Chronic Lymphocytic Leukemia) criteria. Sorted by IMBRUVICA® Grade 3 or 4 percentages in descending order.

 
Discontinuation and dose reduction rates in the CLL trials1
  • Approximately 5% of patients discontinued due to adverse events (AEs)
    -AEs included infections, subdural hematoma, and diarrhea

  • Approximately 6% of patients had dose reduction due to AEs

Geriatric Use1

  • Of the 391 patients randomized in the phase 3 trial, 61% were 65 years of age or older. No overall differences in effectiveness were observed between age groups

  • Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA® (61% of patients age 65 and older vs 51% of younger patients)

Reference:

1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC 2015.

Nonhematologic adverse reactions from the CLL phase 1b/2 clinical trial1

Non-hematological adverse reactions from the Chronic Lymphocytic Leukemia (CLL) Phase 1b/2 clinical trial
Non-hematological adverse reactions from the Chronic Lymphocytic Leukemia (CLL) Phase 1b/2 clinical trial
 

*One patient death due to histiocytic sarcoma.

 
Infectious adverse reaction clinical trial results from Chronic Lymphocytic Leukemia (CLL) Phase 1b/2 clinical trial
 
Adverse reactions from the Chronic Lymphocytic Leukemia (CLL) Phase 1b/2 clinical trial
 

Based on laboratory measurements per iwCLL criteria and adverse events.

 
 
Discontinuation and dose reduction rates in the CLL trials1
  • Approximately 5% of patients discontinued due to adverse events (AEs)
    -AEs included infections, subdural hematoma, and diarrhea

  • Approximately 6% of patients had dose reduction due to AEs

Reference: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC 2015.

Clinical safety data in the mantle cell lymphoma (MCL) clinical trial

  • ARs and laboratory abnormalities described below reflect exposure to IMBRUVICA® (ibrutinib) with a median treatment duration of 8.3 months1

Nonhematologic adverse reactions (ARs) in ≥10% of MCL patients1

Non-hematologic adverse reactions in Mantle Cell Lymphoma (MCL) patients
Non-hematologic adverse reactions in Mantle Cell Lymphoma (MCL) patients
 
Infectious adverse reactions in  Mantle Cell Lymphoma (MCL) patients
 
  • Fatal and serious cases of renal failure have occurred. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients1

  • Grade 3 or 4 atrial fibrillation occurred in 5% of patients2

 

Treatment-emergent* decrease of platelets, neutrophils, or hemoglobin1

Treatment-emergent decrease of hemoglobin, platelets, or neutrophils in patients with MCL

*Based on laboratory measurements and ARs.

 
 
Discontinuation and dose reduction rates in the MCL trials1
  • 9% of patients discontinued due to adverse reactions (ARs)
    -Most frequent AR leading to discontinuation was subdural hematoma (1.8%)

  • 14% of patients had a dose reduction due to ARs

Geriatric Use1

  • Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients

  • Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis), and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients

References: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC. 2015. 2. Data on File. Pharmacyclics LLC 2015.

Clinical safety data in the Waldenström's macroglobulinemia (WM) clinical trial

  • ARs and laboratory abnormalities described below reflect exposure to IMBRUVICA® with a median duration of 11.7 months1

Nonhematologic adverse reactions (ARs) in ≥10% of WM patients1

Non-hematologic adverse reactions in 20% of WM patients
Non-hematologic adverse reactions in 20% of WM patients
 

*Includes multiple adverse drug reaction (ADR) terms.

 
Recommendation: Infectious adverse reactions in  Mantle Cell Lymphoma (MCL) patients
 

Includes multiple ADR terms.

 

Treatment-emergent decrease of neutrophils, platelets, or hemoglobin1

Treatment-emergent decrease of hemoglobin, platelets, or neutrophils in Waldenström's macroglobulinemia patients
 

Based on laboratory measurements.

 
 
Discontinuation and dose reduction rates in the WM trial1
  • 6% of patients discontinued due to adverse events (AEs)

  • 11% of patients had a dose reduction due to AEs

 

Geriatric Use1

  • Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients

  • Cardiac adverse events (atrial fibrillation and hypertension) and infections (pneumonia and urinary tract infection), occurred more frequently among elderly patients

Reference:

1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC 2015.

 

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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA®. Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification.

Second Primary Malignancies - Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).

Tumor Lysis Syndrome - Tumor lysis syndrome has been reported with IMBRUVICA® therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden).

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 52%, 43%), neutropenia* (47%, 51%, 44%), diarrhea (51%, 48%, 37%), anemia* (41%, 36%, 13%), fatigue (41%, 28%, 21%), musculoskeletal pain (37%, 28%, NA), bruising (30%, 12%, 16%), nausea (31%, 26%, 21%), upper respiratory tract infection (34%, 16%, 19%), and rash (25%, 24%, 22%).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

 †Includes multiple ADR terms.

 ‡Not applicable; no associated ADRs.

The most common Grade 3 or 4 non-hematological adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse events.

Approximately 5% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse events. Most frequent adverse events leading to discontinuation were infections, subdural hematomas, and diarrhea in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors - Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.

CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA® dose.

Please review the full Prescribing Information.

Indications

IMBRUVICA® (ibrutinib) is indicated for the treatment of:

  • Patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.

  • Patients with chronic lymphocytic leukemia (CLL) with 17p deletion.

  • Patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

    • Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

  • Patients with Waldenström's macroglobulinemia (WM)


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IMBRUVICA® (ibrutinib) capsules are covered by U.S. Pat. Nos. 7,514,444; 8,008,309; 8,497,277; 8,476,284; 8,697,711 and 8,703,780.

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