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CHMP Recommends Frontline Approval for Ibrutinib in CLL

Silas Inman @silasinman
Published: Friday, Apr 29, 2016

Jan Burger, MD, PhD

Jan Burger, MD, PhD

The Committee for Medicinal Products for Human Use (CHMP) has recommended the frontline approval for ibrutinib (Imbruvica) as a single-agent for patients with chronic lymphocytic leukemia (CLL), based on finding from the phase III RESONATE-2 study.

In the open-label international study, treatment with ibrutinib reduced the risk of progression or death by 84% compared with chlorambucil for elderly patients with CLL. After a median follow-up of 18.4 months, median progression-free survival (PFS) was not yet reached with ibrutinib versus 18.9 months with chlorambucil (HR, 0.16; 95% CI, 0.09-0.28; P <.0001). The estimated 24-month overall survival (OS) rate was 98% with ibrutinib versus 85% with chlorambucil.

“Ibrutinib continues to demonstrate impressive clinical results, and the data on which this recommendation is based once again highlight its potential to deliver improved patient outcomes for suitable patients,” Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa, said in a statement.

In the trial, 269 patients with CLL/SLL were randomized in a 1:1 ratio to receive ibrutinib (n = 136) or chlorambucil (n = 133). Ibrutinib was administered once daily at 420 mg. Chlorambucil was administered 0.5-0.8 mg/kg on days 1 and 15 of a 28-day cycle. The primary endpoint of the study was PFS by iwCLL criteria. Secondary outcome measures included OS, objective response rate (ORR), and safety.

The median age of patients enrolled in the trial was ≥72 years, and 69% had at least 1 baseline comorbidity at the time of enrollment. Overall, 8% and 9% of patients had an ECOG PS of 2 and 31% and 33% had a CIRS score >6, in the ibrutinib and chlorambucil arms, respectively. Creatinine clearance was <60 mL/min for 44% of patients in the ibrutinib arm versus 50% in the chlorambucil group.

The 18-month PFS rate was 90% with ibrutinib versus 52% with chlorambucil. The risk of death was reduced by 84% with ibrutinib versus chlorambucil (HR, 0.16; 95% CI, 0.05-0.56; P = .001). PFS remained consistent across patient subgroups, including age, Rai stage, ECOG status, bulky disease, del11q, and unmutated IGHV.

The ORR with ibrutinib was 90% versus 35% with chlorambucil. In the ibrutinib arm, 3% of responding patients experienced a partial response with lymphocytosis and 11% had a complete response. At 8 months, the ORR was 82% and 30% in the ibrutinib and chlorambucil arms, respectively.

By investigator assessment, ibrutinib reduced the risk of progression or death by 91% versus chlorambucil. Median PFS in the ibrutinib arm was not yet reached versus 15.0 months with chlorambucil (HR, 0.09; 95% CI, 0.04-0.17; P <.0001). The 18-month PFS rates were 94% and 45% in the ibrutinib and chlorambucil arms, respectively.

Overall, there were 3 deaths in the ibrutinib arm and 17 in the chlorambucil group. None of the deaths in the ibrutinib arm were attributed to disease progression. Of the deaths reported in the chlorambucil arm, 5 were from disease progression and 3 were related to infections. At the time of study completion, 87% of patients continued to receive ibrutinib.

Overall, dose reductions were required for 10% of those in the ibrutinib arm versus 19% with chlorambucil. Twelve patients discontinued ibrutinib due to adverse events (AEs), with one patient dying from pneumonia one month after discontinuation.

The majority of AEs were grade 1 in severity. Grade 3 events in the ibrutinib arm consisted of diarrhea, neutropenia, fatigue, nausea, peripheral edema, arthralgia, and neutropenia. However, fatigue, nausea, vomiting, and cytopenias were more common in the chlorambucil arm compared with ibrutinib.

Other all-grade AEs of note in the ibrutinib arm versus chlorambucil included hypertension (14% vs 0%), atrial fibrillation (6% vs 0%), and major hemorrhage (4% vs 2%). Grade 3 incidences of these events in the ibrutinib arm were 4%, 1%, and 3%, respectively. Overall, 19% of patients in the ibrutinib arm used anticoagulants and 47% received antiplatelet agents.

“The data may signal a paradigm shift and demonstrate the value of ibrutinib in the treatment-naive setting,” lead investigator Jan Burger, MD, PhD, associate professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, said in a statement when the findings were presented at the 2015 ASH Annual Meeting. “These powerful clinical results show superiority over a traditional, standard-of-care chemotherapy and have the potential to alter how we treat patients with CLL.”

The positive CHMP opinion will be sent to the European Commission (EC) for a final regulatory decision. Following the EC decision, further reimbursement discussions will take place within each member state in the European Union.

The Europe, ibrutinib is approved as a treatment for patients with relapsed or refractory mantle cell lymphoma and for patients with Waldenström’s macroglobulinemia, both as a single-agent for pretreated patients and in combination with chemoimmunotherapy in the frontline setting. Additionally, the therapy is indicated for adult patients with CLL following one prior therapy or for the frontline setting for patients with the 17p deletion or TP53 mutation

Clinical trials continue to assess ibrutinib across a number of settings, including in combination with monoclonal antibodies, such as obinutuzumab (Gazyva) and nivolumab (Opdivo). Additionally, the agent is being explored in combination with the Bcl-2 inhibitor venetoclax (ABT-199).


Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373:2425-2437.




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