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Frontline Ibrutinib Approved in Europe for CLL

Jason M. Broderick @jasoncology
Published: Tuesday, May 31, 2016

Paolo Ghia, MD, PhD

The European Commission has approved ibrutinib (Imbruvica) as a first-line treatment 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 <.001). The estimated 24-month overall survival (OS) rate was 98% with ibrutinib versus 85% with chlorambucil.

“Ibrutinib has shown remarkable improvements in overall survival, progression-free survival and response rates compared with chlorambucil,” Paolo Ghia, MD, PhD, associate professor of Internal Medicine at Università Vita-Salute San Raffaele in Milan, Italy, said in a statement. “The RESONATE-2 data indicate that ibrutinib can provide a much-needed first-line treatment alternative for many patients.”

In the RESONATE-2 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 body of clinical and real-world evidence in support of ibrutinib’s patient benefits continues to grow, and with this first line approval we are so pleased to be able to alter the treatment landscape and options for CLL patients,” Jane Griffiths, company group chairman, Janssen Europe, Middle East and Africa, said in a statement. “We now look forward to working with health authorities across the region to make ibrutinib available to patients in this indication as soon as possible.”

Janssen codevelops ibrutinib with Pharmacyclics, an AbbVie company.

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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