The FDA ( Food and Drug Administration ) has approved Imbruvica ( Ibrutinib ) as a first-line treatment for patients with chronic lymphocytic leukemia ( CLL ).
The approval is based on data from the randomized, multi-center, open-label phase 3 RESONATE-2 ( PCYC-1115 ) trial, which evaluated the use of Ibrutinib versus Chlorambucil in 269 treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma ( SLL ) aged 65 years or older.
The RESONATE-2 data were previously presented at the American Society of Hematology ( ASH ) Annual Meeting in December 2015 and also simultaneously published in The New England Journal of Medicine.
The prevalence of chronic lymphocytic leukemia is approximately 115,000 patients in the U.S. with approximately 15,000 newly diagnosed patients every year.
Chronic lymphocytic leukemia is a disease of elderly patients, with an average diagnosis age of 71.3
Imbruvica is now approved to treat CLL patients regardless of their treatment history ( treatment-naïve and previously-treated patients ).
In addition, Imbruvica is approved to treat high-risk CLL patients with del 17p, a genetic aberration that occurs when part of chromosome 17, the location of the tumor suppressor gene p53, has been lost or deleted.
Ibrutinib significantly prolonged progression-free survival ( PFS; primary endpoint ) as determined by an Independent Review Committee ( IRC ), reducing the risk of progression or death by 84% versus Chlorambucil ( hazard ratio, HR=0.161 [ 95% confidence interval: 0.091, 0.283 ]; median PFS: not reached for Ibrutinib versus 18.9 months [ 95% confidence interval: 14.1, 22.0 ] for Chlorambucil ).
Imbruvica was also associated with a significantly higher IRC-assessed overall response rate ( ORR: a composite of complete and partial responses; 82.4% vs 35.3%; P less than 0.0001 ) versus Chlorambucil.
Five patients ( 3.7% ) in the Imbruvica arm achieved a complete response, compared to two patients ( 1.5% ) in the Chlorambucil arm.
The safety of Ibrutinib in this patient population was consistent with previously reported studies. The adverse reactions reported in the U.S. Prescribing Information reflect exposure to Ibrutinib with a median duration of 17.4 months versus a median exposure to Chlorambucil of 7.1 months: nearly 2.5 times longer exposure for Ibrutinib.
Warnings and Precautions include hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, second primary malignancies, embryo-fetal toxicity and tumor lysis syndrome.
The most commonly occurring adverse reactions of all grades in CLL patients treated with Ibrutinib in the RESONATE-2 trial ( more than 20% ) were diarrhea, musculoskeletal pain, cough and rash.
RESONATE-2 is a study which enrolled 269 treatment-naïve patients with CLL or SLL aged 65 years or older in the U.S., EU and other regions.
Patients were randomized to receive either Ibrutinib 420 mg orally, once daily until progression or unacceptable toxicity, or Chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for Chlorambucil in cycle 1 was 0.5 mg/kg and was increased based on tolerability in cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.
The primary endpoint of the study was progression-free survival as assessed by an IRC according to the International Workshop on Chronic Lymphocytic Leukemia ( iWCLL ) 2008 criteria, with modification for treatment-related lymphocytosis. Key secondary endpoints included ORR ( based on the same iWCLL criteria ), overall survival ( OS ) and safety.
Ibrutinib is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase ( BTK ). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells. Ibrutinib blocks signals that tell malignant B cells to multiply and spread uncontrollably. ( Xagena )
Source: Abbvie, 2016