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iLLUMINATE™: IMBRUVICA® + OBINUTUZUMAB VS CHLORAMBUCIL + OBINUTUZUMAB ACROSS SEVERAL PATIENT TYPES1

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*In both arms, patients received 1000 mg of obinutuzumab on Days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided between Day 1 (100 mg) and Day 2 (900 mg).
Chlorambucil was administered at a dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for 6 cycles.
  • PFS and ORR (CR and PR) were assessed by an IRC per iwCLL criteria

iLLUMINATE™ included patients with select high-risk characteristics1,2

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  • At baseline, 65% of patients presented with CLL/SLL with high-risk factors (unmutated IGHV, del 17p/TP53 mutation, or del 11q)1,2
CLL=chronic lymphocytic leukemia, CR=complete response, del=deletion, ECOG=Eastern Cooperative Oncology Group, IGHV=immunoglobulin heavy-chain variable, IRC=Independent Review Committee, iwCLL=International Workshop on CLL, ORR=overall response rate, PFS=progression-free survival, PR=partial response, PS=performance status, SLL=small lymphocytic lymphoma.

iLLUMINATE™: SUPERIOR PFS WITH IMBRUVICA® + OBINUTUZUMAB FOR FRONTLINE CLL/SLL1

Primary endpoint: IRC-assessed PFS with IMBRUVICA® + obinutuzumab vs chlorambucil + obinutuzumab1,2

  • Median follow-up was 31 months1
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ORR IN COMBINATION FOR FRONTLINE CLL/SLL1

Secondary endpoint: IRC-assessed ORR with IMBRUVICA® + obinutuzumab vs chlorambucil + obinutuzumab2

  • 89% ORR with IMBRUVICA® + obinutuzumab vs 73% with chlorambucil + obinutuzumab1
    • 20% of patients in the IMBRUVICA® + obinutuzumab arm achieved a complete response*
    • 8% of patients in the chlorambucil + obinutuzumab arm achieved a complete response
    • 69% of patients in the IMBRUVICA® + obinutuzumab arm achieved a partial response
    • 66% of patients in the chlorambucil + obinutuzumab arm achieved a partial response
  • Median follow-up was 31 months
*Includes 1 patient in the IMBRUVICA® + obinutuzumab arm with a complete response with incomplete marrow recovery (CRi).
PR = nPR + PR
CI=confidence interval, CLL=chronic lymphocytic leukemia, HR=hazard ratio, IRC=Independent Review Committee, nPR=nodular partial responses, PFS=progression-free survival, SLL=small lymphocytic lymphoma.

IMBRUVICA® safety and tolerability data in the iLLUMINATE™ trial

Median duration of exposure was 29 months for IMBRUVICA® + obinutuzumab vs 5 months for chlorambucil + obinutuzumab1

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*The data are not an adequate basis for comparison of rates between treatment arms.
Includes multiple ADR terms.
Includes one event with a fatal outcome.

ADR=adverse drug reaction, AR=adverse reaction, CLL=chronic lymphocytic leukemia, SLL=small lymphocytic lymphoma.

References: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC. 2019. 2. Moreno C, Griel R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia: primary results from the randomised phase 3 iLLUMINATE study. Lancet Oncol. In press. 3. Data on file. Pharmacyclics LLC.

RESONATE™-2: IMBRUVICA® VS CHLORAMBUCIL ACROSS SEVERAL PATIENT TYPES1

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  • PFS and ORR (CR and PR) were assessed by an IRC iwCLL criteria3
*Patients with IRC-confirmed progressive disease enrolled in an extension study for follow-up and second-line treatment per investigator's choice (including ibrutinib for patients progressing on chlorambucil per the International Workshop on CLL criteria).

RESONATE™-2 included patients with select high-risk characteristics1,3

pat_characteristics_resonate2 
CLL=chronic lymphocytic leukemia, CR=complete response, del=deletion, ECOG=Eastern Cooperative Oncology Group, IGHV=immunoglobulin heavy-chain variable, IRC=Independent Review Committee, iwCLL=International Workshop on CLL, OR=overall response, ORR=overall response rate, OS=overall survival, PFS=progression-free survival, PR=partial response, PS=performance status, SLL=small lymphocytic lymphoma.

RESONATE™-2 PRIMARY ENDPOINT: PFS WITH IMBRUVICA® VS CHLORAMBUCIL3

Primary analysis: Superior PFS by IRC assessment with IMBRUVICA® with a median follow up of 18 months1,3

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*Estimated PFS at 18 months.

Secondary endpoint: OS with IMBRUVICA® vs chlorambucil1,3

Based on a median follow-up of 28 months, IMBRUVICA® resulted in a 56% statistically significant reduction in the risk of death vs chlorambucil (HR=0.44 [95% CI: 0.21, 0.92])1

  • The estimated survival rate at 24 months was 95% with IMBRUVICA® (95% CI: 89, 97) vs 84% with chlorambucil (95% CI: 77, 90)
  • 41% of chlorambucil-treated patients crossed over to IMBRUVICA® upon disease progression

Long-term follow-up: Investigator-assessed median PFS was not reached with IMBRUVICA® with an overall follow-up of 55 months1,2

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Median PFS was not reached with IMBRUVICA® with an overall follow-up of 55 months2

  • Median time on study was 48.1 months (0.1 - 55 months)
  • 74% of patients estimated to be progression free and alive at 4 years in the IMBRUVICA® arm (95% CI: 65, 81)
  • 16% of patients estimated to be progression free and alive at 4 years in the chlorambucil arm (95% CI: 9, 24)

Complete long term follow up results are not included in the Prescribing Information for IMBRUVICA®. The timing for long-term follow-up data was not prespecified and the analysis was descriptive in nature.

AN ESTABLISHED SAFETY PROFILE IN CLL/SLL1

IMBRUVICA® safety and tolerability data in the RESONATE™-2 trial

Median duration of exposure was 17 months for IMBRUVICA® vs 7 months for chlorambucil1

  • Results from the primary analysis on a median of 18 months of follow-up3
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Subjects with multiple events for a given ADR term are counted only once for each ADR term.
*Includes multiple ADR terms.
  • ARs ≥10% were primarily grades 1/2 in frontline CLL/SLL patients ≥65 years1

Long-term safety2

The long-term safety data over 4 years from 330 patients with CLL/SLL (from RESONATE™† and RESONATE™-2) treated with IMBRUVICA® were analyzed. The median treatment duration was 46 months, with 74% and 40% of patients receiving treatment for more than 2 and 4 years, respectively.

Prevalence trends for adverse events were assessed based on IMBRUVICA® treatment duration by yearly intervals and generally decreased or remained stable over time except for hypertension.

The prevalence of hypertension (all grades) increased and was reported as 11% (year 0-1), 14% (year 1-2), 20% (year 2-3), and 21% (year 3-4), with overall incidence being 22% (years 0-4). The prevalence of hypertension grade ≥3 remained stable and was reported as 4% (year 0-1), 6% (year 1-2), 4% (year 2-3), and 4% (year 3-4), with overall incidence being 8% (years 0-4).

The long-term safety follow-up results are not included in the Prescribing Information for IMBRUVICA®.

RESONATE™ is a randomized, multicenter, open-label, phase 3 study with previously treated CLL/SLL patients.1
ADR=adverse drug reaction, AR=adverse reaction; CLL=chronic lymphocytic leukemia, SLL=small lymphocytic lymphoma.

References: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC. 2019. 2. Data on file. Pharmacyclics LLC. 3. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.

 

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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 (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,124 patients exposed to IMBRUVICA® in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% 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 and patients should be monitored for signs of bleeding.

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 (including bacterial, viral, or fungal) have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA® in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA®.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA® therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA® in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA® treatment and follow dose modification guidelines.

Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA® in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA® and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA® as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA® in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA® therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

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® and for 1 month after cessation of therapy. 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. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%), and pneumonia (14%).

Approximately 7% of patients discontinued IMBRUVICA® due to adverse reactions. Adverse reactions leading to discontinuation included pneumonia (1.1%), hemorrhage (1%), atrial fibrillation (0.9%), rash (0.7%), diarrhea (0.6%), neutropenia (0.5%), sepsis (0.4%), thrombocytopenia (0.4%), interstitial lung disease (0.3%), and bruising (0.2%). Nine percent of patients had a dose reduction due to adverse reactions.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Modify IMBRUVICA® dose as described in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA® in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA® dose.

Please see full Prescribing Information.

Indication

IMBRUVICA® (ibrutinib) is a kinase inhibitor indicated for the treatment of adult patients with:

  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).

  • CLL/SLL with 17p deletion.


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IMBRUVICA® (ibrutinib) is covered by U.S. Patents, which are listed in FDA's Orange Book (available at https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm).

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