IMBRUVICA® (ibrutinib) receives regular approval by U.S. FDA in chronic lymphocytic leukemia (CLL) and CLL patients with del 17p

The update to the IMBRUVICA label is based on data from the Phase 3 RESONATE^™ study, which demonstrated IMBRUVICA significantly improved progression-free survival (PFS) and overall survival (OS) versus ofatumumab in patients with previously treated CLL or small lymphocytic leukemia (SLL).³

IMBRUVICA was initially approved in February 2014 under Subpart H regulation, the FDA’s accelerated approval process, based on data from a Phase 1b/2 study for patients with CLL who have received at least one prior therapy.¹ This indication was based on an overall response rate (ORR). An improvement in survival or disease-related symptoms was not established. In accord with the accelerated approval process, confirmation of clinical benefit in a subsequent Phase 3 study was required, which has resulted in this updated indication for the use of IMBRUVICA in patients with CLL who have received at least one prior therapy and in CLL patients with del 17p.

“The RESONATE data expands our understanding of the efficacy and safety of IMBRUVICA to an even greater degree,” said John C. Byrd, M.D., director, Division of Hematology, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital & Richard J. Solove Research Institute, and lead investigator for RESONATE.^† “This approval is particularly exciting for people with del 17p CLL, considering IMBRUVICA is the first treatment to be approved specifically for this difficult-to-treat patient population.”

CLL is a slow-growing blood cancer of white blood cells called lymphocytes, most commonly B cells.⁴ CLL is predominantly a disease of the elderly, with a median age of diagnosis of 72.⁴ In CLL, the genetic mutation del 17p occurs when part of chromosome 17 has been lost. CLL patients with del 17p have poor treatment outcomes.² Del 17p is reported in seven percent of treatment-naïve CLL cases,⁵ with approximately 20 to 40 percent of relapsed/refractory patients harboring the mutation.⁶

“We’re very pleased this approval came swiftly,” said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development, LLC. “These Phase 3 results reinforce the data on which the original approval was granted; they also offer greater clinical understanding of the impact of efficacy related to progression-free and overall survival and, more importantly, the safety of IMBRUVICA in this patient population.”

Data from this study were recently presented during an oral session at the 50^th annual meeting of the American Society of Clinical Oncology (ASCO), featured in the official ASCO press program and simultaneously published online in the New England Journal of Medicine. In January 2014, the RESONATE trial was halted early because results showed a statistically significant difference in PFS, the primary endpoint of the study, as well as in OS, a key secondary endpoint at the time of this interim analysis.

Janssen and Pharmacyclics are continuing an extensive clinical development program for IMBRUVICA, including Phase 3 study commitments in multiple patient populations.

IMBRUVICA in CLL¹

The safety and efficacy of IMBRUVICA in CLL were evaluated in the randomized, international, multi-center, open-label Phase 3 PCYC-1112 (RESONATE) trial in 391 patients with CLL or SLL, who had received at least one prior therapy. Thirty-two percent of patients in the trial had del 17p. Patients were administered either 420 mg oral ibrutinib (n=195) once-daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300 mg followed by 11 doses at 2,000 mg per dose and schedule consistent with local labeling). Data showed single-agent, once-daily IMBRUVICA significantly prolonged PFS (median not reached vs. 8.1 months; HR 0.22, 95% CI, 0.15 to 0.32; P<0.0001) and OS (HR 0.43; 95% CI, 0.24 to 0.79; P=0.05) versus intravenous ofatumumab in previously treated patients with CLL or SLL. The OS results represent a 57 percent statistically significant reduction in the risk of death in patients receiving IMBRUVICA versus those in the ofatumumab arm.

PFS was the primary endpoint of the RESONATE study, with OS, ORR and safety as key secondary endpoints. PFS, as assessed by an independent review committee according to modified International Workshop on Chronic Lymphocytic Leukemia criteria, indicated IMBRUVICA was associated with a 78 percent statistically significant reduction in the risk of death or progression versus ofatumumab. ORR was shown to be 42.6 percent in the IMBRUVICA arm, versus 4.1 percent in the ofatumumab arm.   

The Warnings and Precautions for IMBRUVICA include hemorrhage, infections, cytopenias, atrial fibrillation, second primary malignancies and embryo-fetal toxicity.¹ For more information about Warnings and Precautions, please see below in this release.

After an 8.6 month median duration of therapy, the most common Grade 3 or 4 adverse event (AE) was pneumonia* (10%). The most commonly occurring non-hematologic side effects during the RESONATE trial (AEs in 20 percent or more of patients) were diarrhea (48%), fatigue (28%), musculoskeletal pain* (28%), nausea (26%), pyrexia (fever; 24%) and rash* (24%). Hematologic adverse events included (all grades) platelet decrease (52%), neutrophil decrease (51%) and hemoglobin decrease (36%).¹ *Includes multiple ADR terms.

Approximately five percent of patients receiving IMBRUVICA in the Phase 3 RESONATE (PCYC-1112-CA) and Phase 1b/2 PCYC-1102-CA studies discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately six percent of patients.¹

The recommended dose of IMBRUVICA for CLL is 420 mg (three 140 mg capsules) orally once daily.¹

References

1. IMBRUVICA Prescribing Information, July 2014
2. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkins Lymphomas. Version 1.2014. http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf.  Accessed June 2014.
3. The New England Journal of Medicine. “Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia.” Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1400376. Accessed June 2014.
4. American Cancer Society. Detailed guide: what is chronic lymphocytic leukemia. Available from: http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf Accessed June 2014.
5. Schnaiter A, Stilgenbauer S. 17p deletion in chronic lymphocytic leukemia: risk stratification and therapeutic approach. Hematol Oncol Clin North Am. 2013;27:289-301.
6. Stilgenbauer S, Zenz T. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010: 481-8.
7. Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed June 2014.