FDA Expands Ibrutinib for Use in Previously Untreated Patients With CLL

March 9, 2016
Jason M. Broderick

An impressive improvement in progression-free survival (PFS) in the RESONATE-2 trial led to the FDA’s approval of ibrutinib (Imbruvica) March 4 for the frontline treatment of chronic lymphocytic leukemia, based on data from the RESONATE-2 trial.

An impressive improvement in progression-free survival (PFS) in the RESONATE-2 trial led to the FDA’s approval of ibrutinib (Imbruvica) March 4 for the frontline treatment of chronic lymphocytic leukemia (CLL), based on data from the RESONATE-2 trial.

In the phase III study, ibrutinib improved PFS by 84% versus chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma (SLL). Ibrutinib was previously approved by the FDA for pretreated treated CLL, pretreated mantle cell lymphoma, and Waldenström's macroglobulinemia.

"The results seen in the RESONATE-2 clinical trial are truly compelling and make this medicine an attractive first-line treatment option for clinicians in the hematology space," said lead investigator Jan Burger, MD, PhD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

RESONATE-2 included 269 treatment-naïve patients aged ≥65 years with CLL or SLL. The median age was 73 years. Patients were randomized 1:1 to receive either 420 mg of ibrutinib daily until progression or 0.5 to 0.8 mg/kg of chlorambucil on days 1 and 15 of each 28-day cycle, for a total of 12 cycles.

Patients with the 17p deletion were excluded from the study. Patients in the chlorambucil arm were allowed to switch over to an extension study that offered ibrutinib if such treatment was indicated, and 43 patients did so.

The median duration of treatment was 17.4 months with ibrutinib and 7.1 months with chlorambucil. At the time of study completion, 87% of patients in the ibrutinib arm remained on therapy.

The study’s primary endpoint was PFS as evaluated by an independent review committee (IRC). Overall survival (OS) and overall response rate (ORR) were secondary outcome measures.

The IRC found that, in addition to the 84% decrease in the risk of progression or death, 24-month OS rates were 98% versus 85%, respectively.

As per IRC review, ORR was 86% with ibrutinib, with 4.4% of those being complete responses, versus 35.3% with chlorambucil, 1.5% of them complete responses. Investigator-assessed ORR was 90.4%, with 9.6% of those being complete responses, versus 35.3%, with 4.5% of those being complete responses, respectively.

Ibrutinib significantly improved bone marrow function, as reflected by a sustained increase in hemoglobin and platelets.

A reduction of 50% or more in lymph node burden was observed in 91.2% versus 36.8% of patients who took ibrutinib and chlorambucil, respectively, and a reduction in spleen enlargement was seen in 75.7% versus 39.1% of patients.

Rates of sustained hematologic improvements were 84% with ibrutinib versus 45% with chlorambucil in patients with baseline anemia, and were, respectively, 77% versus 43% in patients with thrombocytopenia.v Adverse events, most of which were grade 1 and did not result in treatment discontinuation, included diarrhea, fatigue, cough, nausea, peripheral edema, dry eye, arthralgia and vomiting. Neutropenia also occurred in both arms, and was typically more severe than grade 1.

Fatigue, nausea, vomiting and cytopenias were more frequent with chlorambucil, as were side effects that led to treatment discontinuation. Hypertension was noted more frequently on ibrutinib, but was limited to grades 1 through 3 and managed without dose modification or discontinuation.

Over a median follow-up of approximately 1.5 years, major hemorrhage occurred in 4% with ibrutinib and in 2% with chlorambucil. There were 3 deaths in the ibrutinib arm and 17 in the chlorambucil arm.

"People living with CLL who have not been previously treated now have an option that significantly improved progression-free survival when compared to the oral chemotherapy used in the RESONATE-2 trial," said Burger.

Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia [published online December 6, 2015]. N Engl J Med.