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The European Commission has approved an expanded indication of ibrutinib for use in combination with rituximab in treatment-naïve adult patients with chronic lymphocytic leukemia.
The European Commission has approved an expanded indication of ibrutinib (Imbruvica) for use in combination with rituximab (Rituxan) in treatment-naïve adult patients with chronic lymphocytic leukemia (CLL), according to an announcement from The Janssen Pharmaceutical Companies of Johnson & Johnson.1
The decision was based on findings from the phase 3 E1912 study, which demonstrated that the combination of ibrutinib and rituximab led to a significant improvement in progression-free survival (PFS) compared with standard fludarabine, cyclophosphamide, and rituximab (FCR; hazard ratio [HR], 0.34; 95% CI, 0.22-0.52; P <.0001).2 The median PFS had not yet been reached in either arm at a median follow-up of 37 months.
“We are delighted with the European Commission’s decision [to approve] the use of ibrutinib in combination with rituximab for these patients,” Patrick Laroche, MD, Haematology Therapy Area Lead in Europe, Middle East, and Africa, at Janssen-Cilag, stated in a press release. “This new non-chemotherapy combination regimen can offer extended remission, as well as fewer chemotherapy-related [adverse] effects (AEs) for patients living with CLL.”
At a median follow-up of 48 months, the combination continued to demonstrate improved PFS versus FCR (HR, 0.39; 95% CI, 0.26-0.57; P <.001).3 Ibrutinib plus rituximab led to a 65% reduction in the risk of disease progression or death at 3 years (HR, 0.35; 95% CI, 0.22-0.56; P <.001). Additionally, the 3-year PFS rates for ibrutinib/rituximab and FCR were 89.4% and 72.9%, respectively.4
The HR for overall survival (OS) was also found to favor ibrutinib plus rituximab (HR, 0.34; 95% CI, 0.15-0.79; P = .009). The OS rates at 3 years with ibrutinib/rituximab versus FCR were 99% and 93%, respectively.
The study was designed by the ECOG-ACRIN Cancer Research Group and sponsored by the National Cancer Institute; it was conducted in the United States. A total of 529 patients aged 70 years or younger with previously untreated CLL were enrolled and randomized in a 2:1 fashion to receive ibrutinib/rituximab (n = 354) or FCR (n = 175).
In the trial, oral ibrutinib was given at a dose of 420 mg on days 1 to 28 until progressive disease. In cycle 1, participants were administered ibrutinib monotherapy. In cycle 2, they received ibrutinib with intravenous (IV) rituximab given at a dose of 50 mg/m2 on day 1 and a dose of 325 mg/m2 on day 2. For cycles 3 through 7, IV rituximab was administered at a dose of 500 mg/m2 on day 1 in combination with baseline ibrutinib. FCR was administered at the standard dose for 6 treatment cycles.
The median age of participants enrolled on the study was 58 years, but just under half, or 40.6% were 60 years of age or older. Additionally, 32.7% of patients were female and 63.3% had an ECOG performance status of 0. The majority of patients, or 71.1%, had unmutated IGHV, 22% had an 11q deletion, 18.3% had trisomy 12, and 33.8% had deletion 13q. Participants were split between Rai stages and 43.1% had stage III/IV disease.
The primary end point of the trial was PFS, while OS served as a secondary end point.
Additional results demonstrated that the PFS rate of ibrutinib/rituximab at 3 years was 89.4% versus 72.9% with FCR. The 3-year OS rates in the investigational and control arms were 98.8% versus 91.%, respectively.
Notably, the PFS benefit observed with ibrutinib plus rituximab was noted across all subgroups analyzed in the trial. Specifically, patients with unmutated IGHV experienced a 74% reduction in the risk of disease progression or death with ibrutinib plus rituximab versus FCR (HR, 0.26; 95% CI, 0.14-0.50).
In this subgroup, the PFS rate at 3 years was 90.7% in the investigational arm versus 62.5% in the control arm. In patients whose tumors harbored IGHV mutations experienced more favorable PFS benefit with FCR compared with ibrutinib/rituximab, at 88.0% versus 87.7%, respectively (HR, 0.44; 95% CI, 0.14-1.36).
With regard to safety, rates of grade 3 or higher AEs were comparable between the 2 treatment arms; however, grade 3 or higher infectious complications were noted to be lower in the investigational arm compared with the control arm, at 10.5% versus 20.3%, respectively (P <.001). Grade 3 or 4 neutropenia was also lower with ibrutinib/rituximab versus FCR, at 25.6% versus 44.9%, respectively (P <.001).
Moreover, grade 3 or 4 hypertension was higher in the investigational arm versus the control arm, at 18.8% versus 8.2%, respectively (P = .002). Four patients who received ibrutinib/rituximab experienced grade 3 or higher hemorrhagic events compared with no patients who were given FCR (P = .32). Twenty-three patients on the experimental arm reported grade 3 or higher cardiac toxic events compared with 3 patients on the control arm. Four deaths were reported on the ibrutinib/rituximab arm versus 10 on the FCR arm.
“Ibrutinib is the most comprehensively studied BTK inhibitor with the longest follow-up across 8 positive phase 3 trials in CLL to date, and is recognized as an important advancement in treatment for patients with CLL,” Craig Tendler, MD, vice president of Clinical Development and Global Medical Affairs, Oncology at Janssen Research & Development, LLC, added in the release. “This latest milestone highlights our commitment to studying the full potential of ibrutinib and in developing regimens which can transform what a CLL diagnosis means for patients going forward.”
In April 2020, the FDA approved the expanded indication of ibrutinib for use in combination with rituximab for the first-line treatment of adult patients with CLL or small lymphocytic leukemia based on data from E1912. Previously, in August 2018, the regulatory agency approved ibrutinib plus rituximab for patients with Waldenström macroglobulinemia across all lines of treatment.