FDA Approves Ibrutinib as Initial CLL Treatment

Nick Mulcahy

Disclosures

March 04, 2016

UPDATED March 7, 2016 // The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica, Janssen/Pharmacyclics) for first-line use in patients with chronic lymphocytic leukemia (CLL).

The approval means that there is, for the first time, a chemotherapy-free option for initial treatment.

Ibrutinib is a first-in-class oral, covalent inhibitor of Bruton's tyrosine kinase. The drug has already been approved for use in patients with pretreated CLL, and in CLL patients with the del17p mutation (including as initial treatment).

The new approval was made on the basis of results from the RESONATE-2 trial, which showed that ibrutinib was superior to chlorambucil in 269 older treatment-naive patients with CLL or small lymphocytic lymphoma.

Patients were randomly assigned, in a 1:1 ratio, to receive either ibrutinib 420 mg daily until progression, or chlorambucil 0.5 mg/kg (to maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles.

Progression-free survival was the end point of the study.

At a median follow-up of 18.4 months, investigator-assessed median progression-free survival was significantly longer in the ibrutinib group than in the chlorambucil group (not reached vs 15 months; hazard ratio [HR], 0.09; < .0001).

The 18-month progression-free survival rate was better with ibrutinib than with chlorambucil (93.9% vs 44.8%). Patients receiving ibrutinib also had significantly prolonged median overall survival (not reached in either group; HR, 0.16; P = .0010). And the overall survival rate was still better with ibrutinib at 24 months (97.8% vs 85.3).

These results were first presented at the 2015 annual meeting of the American Society of Hematology (ASH), and were published simultaneously in the New England Journal of Medicine (N Engl J Med. 2015;373:2425-2437).

"There was a 91% reduction in risk of progression [by investigator] and an 84% reduction in risk of death with ibrutinib, compared with chlorambucil," lead author Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Cà Granda, Milano, Italy, summarized at the ASH meeting, as reported by Medscape Medical News.

There were fewer deaths in the ibrutinib group than in the chlorambucil group (16 vs 3).

The overall response rate was 86.0% with ibrutinib (4.4% complete response [CR] or complete remission with incomplete blood count recovery [Cri]) and 35.3% with chlorambucil (1.5% CR/CRi), and it was higher with ibrutinib at all time points.

Median event-free survival was also prolonged with ibrutinib (not reached vs 12 months; HR, 0.17, P < .0001). A reduction in lymph node burden of at least 50% was observed in more patients in the ibrutinib group than in the chlorambucil group (91.2% vs 36.8%; (< .0001).

Finally, rates of sustained hematologic improvements were significantly higher in the ibrutinib group, including patients with baseline anemia (84% vs 45%; < .0001) and thrombocytopenia (77% vs 43%; = .0054).

The most common adverse events in the ibrutinib group were grade 1, and did not result in treatment discontinuation. They included diarrhea, fatigue, cough, and nausea. The most common events in the chlorambucil group were nausea, fatigue, neutropenia, anemia, and vomiting.

Grade 3 maculopapular rash occurred in 3% of patients in the ibrutinib group and in 2% in the chlorambucil group. There were no cases of grade 4 maculopapular rashes in the ibrutinib group. Adverse events leading to treatment discontinuation were less frequent with ibrutinib than with chlorambucil (9% vs 23%).

The median age of the trial participants was 73 years, and 70% of the patients were older than 70 years.

At the ASH meeing, an expert explained why most of the study participants were in their 70s.

The researchers recruited primarily elderly patients who were felt to be unsuited to receive more aggressive and toxic treatments, which would be the standard regimen for most CLL patients, said Tait D. Shanafelt, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, who was not involved with the study.

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