The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for ibrutinib in combination with rituximab for use in treatment-naïve patients with chronic lymphocytic leukemia.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for ibrutinib (Imbruvica) in combination with rituximab (Rituxan) for use in treatment-naïve patients with chronic lymphocytic leukemia (CLL), according to an announcement from The Janssen Pharmaceutical Companies of Johnson & Johnson.1
“Ibrutinib in combination with rituximab represents an important new targeted and non-chemotherapy option for patients with CLL,” John Gribben, MD, DSc, professor of medical oncology at St. Bartholomew’s Hospital, Barts Cancer Institute, Queen Mary University of London, stated in a press release. “For people living with CLL, relapse is often inevitable. Using this combination in the frontline setting has the potential to not only extend life, but also offer a tolerability profile with less of the known chemotherapy-related events.”
The opinion is based on data from the phase 3 E1912 trial which demonstrated that the combination led to a statistically significant improvement in progression-free survival versus patients who received the standard fludarabine, cyclophosphamide, and rituximab (FCR; HR, 0.34; 95% CI, 0.22-0.52; P <.0001).2 The median PFS has not been reached in either treatment arm at a median follow-up of 37 months. The safety with the combination proved to be consistent with the known tolerability of ibrutinib.
Follow-up findings presented during the 2019 ASH Annual Meeting indicated that the PFS benefit continued to favor the combination over FCR at a median follow-up of 48 months (HR, 0.39; 95% CI, 0.26-0.57; P <.0001).3 At this time, the combination resulted in a 65% reduction in the risk of disease progression or death (HR, 0.35; 95% CI, 0.22-0.56; P <.001). Moreover, the 3-year PFS rates were 89.4% and 72.9% in the ibrutinib/rituximab arm and the FCM arm, respectively.4
Overall survival (OS) was also more favorable with the combination compared with FCR (HR, 0.34; 95% CI, 0.15-0.79; P = .009). Specifically, the OS rates with ibrutinib/rituximab and FCR were 99% and 93%, respectively.
The phase 3 study was conducted in the United States by the ECOG-ACRIN Cancer Research Group and it was sponsored by the National Institutes of Health. In the study, investigators evaluated a total of 529 patients with treatment-naïve CLL who were 70 years old or younger. Participants were randomized 2:1 to receive either the ibrutinib/rituximab combination (n = 354) or FCR (n = 175).
Ibrutinib was given at 420 mg orally on days 1 through 28 until progressive disease. In cycle 1, patients received ibrutinib alone. In cycle 2, participants were given ibrutinib plus intravenous (IV) rituximab at 50 mg/m2 on day 1 and at 325 mg/m2 on day 2. For cycles 3 to 7, IV rituximab was administered at 500 mg/m2 on day 1 with baseline ibrutinib. FCR was administered at the standard dose for 6 treatment cycles.
The median age of the participants included in the trial was 58 years and just under half, or 40.6%, of them were ≥60 years of age. Furthermore, 32.7% of participants were female and 63.3% had an ECOG performance status of 0. In 71.1% of patients, IGHV was unmutated; 22.2% of patients had an 11q deletion, 18.3% had trisomy 12, and 33.8% had deletion 13q. The primary end point of the trial was PFS and OS served as a secondary end point.
Additional results demonstrated that the improvement in PFS observed with ibrutinib/rituximab was upheld across all patient subgroups. Specifically, those with IGHV unmutated status who received ibrutinib/rituximab experienced a 74% reduction in the risk of progression or death compared with FCR (HR, 0.26; 95% CI, 0.14-0.50); the 3-year PFS rates were 90.7% and 62.5%, respectively. In those with IGHV mutations, the 3-year PFS rates were 87.7% and 88.0% with ibrutinib/rituximab and FCR, respectively (HR, 0.44; 95% CI, 0.14-1.36).
With regard to safety, rates of grade ≥3 adverse effects (AEs) were comparable between the arms; however, grade ≥3 infectious complications proved to be lower in the investigational arm compared with the control arm, at 10.5% versus 20.3%, respectively (P <.001). The rate of grade 3/4 hypertension was higher in the ibrutinib/rituximab arm versus FCR, at 18.8% versus 8.2%, respectively (P = .002). Four patients on the ibrutinib/rituximab arm experienced grade ≥3 hemorrhagic events compared with no patients on the FCR arm (P =.32). Moreover, 23 patients on the investigational arm versus 3 patients on the control arm had grade ≥3 cardiac toxic events. Four deaths were reported on the ibrutinib/rituximab arm versus 10 deaths on the FCR arm.
“The landmark head-to-head study, conducted by the ECOG-ACRIN Cancer Research Group and the National Cancer Institute has generated important, practice-changing results which challenge FCR, the gold standard of chemotherapy-based treatment regimens for younger, fit patient with previously untreated CLL fir over a decade,” Craig Tendler, MD, vice president of Clinical Development and Global Medical Affairs, Oncology, at Janssen Research & Development, stated in the press release. “We are pleased to build upon the robust body of data supporting the most widely studied BTK inhibitor as we continue to study further ibrutinib-based regimens in our mission to improve the lives of patients with complex blood cancers, like CLL.”
In April 2020, the FDA approved the expanded indication of ibrutinib for use in combination with rituximab as a frontline treatment option for adult patients with CLL or small lymphocytic lymphoma based on results from this study.