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Progression-Free Survival for IMBRUVICA® in CLL/SLL Trials

IMBRUVICA® study results in efficacy endpoint: PFS

RESONATE™-2 Primary Endpoint: PFS WITH IMBRUVICA® VS CHLORAMBUCIL1

Primary analysis: Superior PFS by IRC assessment with IMBRUVICA® with a median follow-up of 18.4 months1,2

PFS Resonate2


Long-term follow-up:
Investigator-assessed median PFS was not reached with IMBRUVICA® with an overall follow-up of 55 months.2,3

LTFU PFS Resonate2 

Median PFS was not reached with IMBRUVICA® with an overall follow-up of 55 months2,3:

  • Median time on study was 48.1 months (0.1-55.2 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 was not prespecified and the analysis was descriptive in nature.

Descriptive subgroup analysis of RESONATE™-2 Forest Plot1

Results from primary analysis at 18-month median follow-up:

  • The study was not designed to test treatment effect in subpopulations, and was not powered to show statistical differences among these subgroups

  • No subgroups were adjusted for multiplicity, and there is no P value

  • In RESONATE™-2, all subgroups were prespecified in the protocol, except for IGHV mutational status, which was exploratory1

  • IGHV status was unknown in 69 patients

resonate2-forest-plot

*Not all characteristics were evaluable for every patient.

CI=confidence interval, CLB=chlorambucil, CR=complete response, ECOG=Eastern Cooperative Oncology Group, HR=hazard ratio, IGHV=immunoglobulin heavy-chain variable, IMB=IMBRUVICA®, IRC=Independent Review Committee, iwCLL=International Workshop on CLL, NR=not reached, OS=overall survival, PFS=progression-free survival, ULN=upper limit of normal.

iLLUMINATE™: Superior PFS with IMBRUVICA® + obinutuzumab for frontline CLL/SLL2

  • PFS and ORR (CR and PR) were assessed by an IRC per iwCLL criteria2,4-6

  • Median follow-up of 31 months2

IMBRUVICA® (ibrutinib) against ofatumumab—an approved agent for use in patients with previously treated Chronic lymphocytic leukemia (CLL) 

Improved PFS with IMBRUVICA® + obinutuzumab in high-risk patients2

  • At baseline, 65% of patients presented with CLL/SLL high-risk factors:

    • Unmutated IGHV (54%), del 17p/TP53 mutation (18%), or del 11q (15%)

Prolonged progression-free survival in previously treated patients with del 17p 

85% risk reduction of disease progression or death with IMBRUVICA® + obinutuzumab in high-risk patients3,4

  • Median PFS was not reached with IMBRUVICA® + obinutuzumab

  • Median PFS was 14.7 months with chlorambucil + obinutuzumab (95% CI (12.4, 16.9))

Analysis of the high-risk group consisting of unmutated IGHV, del 17p/TP53 mutation, or del 11q was supplemental and not prespecified.

CI=confidence interval, CLL=chronic lymphocytic leukemia, CR=complete response, del=deletion, HR=hazard ratio, IGHV=immunoglobulin heavy-chain variable, IRC=Independent Review Committee, ORR=overall response rate, PFS=progression-free survival, PR=partial response, SLL=small lymphocytic lymphoma.

RESONATE™: Prolonged progression-free survival in relapsed/refractory patients

Primary analysis: IRC-assessed PFS with IMBRUVICA® vs ofatumumab with a median follow-up of 9.4 months2,7

IMBRUVICA® (ibrutinib) against ofatumumab—an approved agent for use in patients with previously treated Chronic lymphocytic leukemia (CLL) 
  • Median PFS not reached for IMBRUVICA® vs 8.1 months with ofatumumab (95% CI: 7.2, 8.3)3

Long-term follow-up analysis: Investigator-assessed PFS with an overall follow-up of 63 months2,3

Prolonged progression-free survival in previously treated patients with del 17p 

Investigator-assessed median PFS2,3:

  • Median time on study was 56 months (range, 0.1 to 63 months)3

  • 44.1 months in the IMBRUVICA® arm (95% CI: 38.5, 56.9)2

  • 8.1 months in the ofatumumab arm (95% CI: 7.8, 8.3)2

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

Addressing the treatment gap in high-risk del 17p CLL/SLL

Addressing the treatment gap in high-risk del 17p CLL/SLL 

Del 17p is a strong genetic predictor of poor outcomes10

Del 17p is a strong genetic predictor of poor outcomes 

Results from an independent, prospective, single-center, observational analysis of patients with CLL (N=325). The primary endpoint was survival from the time of diagnosis based on mutation status (high-risk cytogenetics included del 17p, del 11q, or 12q trisomy). Median follow-up was 70 months.12 (Note: This was not an IMBRUVICA® study.)

Prolonged progression-free survival in relapsed/refractory patients with del 17p2,3,7

Primary analysis for del 17p subgroup: IRC-assessed PFS with IMBRUVICA® vs ofatumumab with a median follow-up of 9.7 months2,3

PFS Previously treated resonate

PFS results for IMBRUVICA® (n=63) vs ofatumumab (n=64) in the del 17p subset of RESONATE™ patients2

  • Median PFS not reached for IMBRUVICA® vs 5.8 months with ofatumumab (95% CI: 5.3, 7.9)2

Long-term follow-up analysis for del 17p subgroup: Investigator-assessed PFS with an overall follow-up of 63 months2

PFS LTFU Previously Treated Resonate

Investigator-assessed median PFS in patients with del 17p per iwCLL criteria 2,3-4

  • Median time on study was 56 months (range, 0.1 to 63 months)3

  • 40.6 months in the IMBRUVICA® arm (95% CI: 25.4, 44.6)2

  • 6.2 months in the ofatumumab arm (95% CI: 4.6, 8.1)2

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

CI=confidence interval, CLL=chronic lymphocytic leukemia, del=deletion, HR=hazard ratio, IMB=IMBRUVICA®, IRC=Independent Review Committee, iwCLL=International Workshop on CLL, Ofa=ofatumumab, OS=overall survival, PFS=progression-free survival, SLL=small lymphocytic lymphoma.

HELIOS: Prolonged progression-free survival in combination for relapsed/refractory patients2,16

Primary endpoint: PFS16

  • Median follow-up was 17 months (N=579)16

  • Median PFS not evaluable with IMBRUVICA® + BR vs 13.3 months (95% CI: 11.3, 13.9) with placebo + BR2

  • 31% of patients crossed over from placebo to IMBRUVICA® upon disease progression16

IMBRUVICA® (ibrutinib) against ofatumumab—an approved agent for use in patients with previously treated Chronic lymphocytic leukemia (CLL) 
  • PFS was assessed by an IRC per iwCLL criteria5-6,12

AR=adverse reaction, BR=bendamustine and rituximab, CI=confidence interval, CLL=chronic lymphocytic leukemia, HR=hazard ratio, IRC=Independent Review Committee, iwCLL=International Workshop on CLL, ORR=overall response rate, PFS=progression-free survival, SLL=small lymphocytic lymphoma.

 
 
 

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IMBRUVICA® (ibrutinib) is now approved in a new
formulation as one pill, once daily.

As of May 15, 2018, the original 140 mg capsules will no longer be available.
Every IMBRUVICA® patient will need a new prescription for the new pill.

Learn More
05/18 PRC-04135
References: 1. Burger JA, Tedeschi A, Barr PM, et al; for the RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. 2. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC. 2019. 3. Data on file. Pharmacyclics LLC. 4. 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. 2019;20(1):43-56. 5. Hallek M, Cheson BD, Catovsky D, et al; for the International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456. Erratum in: Blood. 2012;112(13):5259. 6. Hallek M, Cheson BD, Catovsky D, et al. Response assessment in chronic lymphocytic leukemia treated with novel agents causing an increase of peripheral blood lymphocytes (e-Letter). Blood. 2012;119(23):5348. 7. Byrd JC, Brown JR, O’Brien S, et al; for the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. 8. Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup phase III trial E2997. J Clin Oncol. 2007;25(7):799-804. 9. Stilgenbauer S, Zenz T, Winkler D, et al. Genomic aberrations, VH mutation status and outcome after fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR) in the CLL8 trial. Abstract presented at: 50th Annual ASH Meeting; December 6-9, 2008; San Francisco, CA. Abstract 781. 10. Schnaiter A, Stilgenbauer S. 17p deletion in chronic lymphocytic leukemia: risk stratification and therapeutic approach. Hematol Oncol Clin North Am. 2013;27(2):289-301. 11. Stilgenbauer S, Kröber A, Busch R, et al. 17p deletion predicts for inferior overall survival after fludarabine-based first line therapy in chronic lymphocytic leukemia: first analysis of genetics in the CLL4 trial of the GCLLSG. In: Blood (ASH Annual Meeting Abstracts). 2005;106(11):Abstract 715. 12. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916. 13. Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103(9):3278-3281. 14. Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2009;27(24):3994-4001. 15. Zenz T, Häbe S, Denzel T, et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood. 2009;114(13):2589-2597. 16. Chanan-Khan A, Cramer P, Demirkan F, et al. lbrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200-211.
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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

B-cell malignancies: 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% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA® in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*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.

Indications

IMBRUVICA® (ibrutinib) is a kinase inhibitor indicated for the treatment of adult 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 and description of clinical benefit in a confirmatory trial.

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

  • CLL/SLL with 17p deletion.

  • Waldenström's macroglobulinemia (WM).

  • Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.

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

  • Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.


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