FDA Approves Imbruvica for Frontline Treatment of CLL


In the phase 3 RESONATE-2 study, Imbruvica improved progression-free survival (PFS) by 84 percent in previously untreated patients with CLL or SLL.

The FDA has approved Imbruvica (ibrutinib) for the frontline treatment of chronic lymphocytic leukemia (CLL), based on data from the RESONATE-2 trial.1,2

In the phase 3 study, Imbruvica improved progression-free survival (PFS) by 84 percent versus chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma (SLL).

"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 lead investigator Jan Burger, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

"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."

RESONATE-2 included 269 treatment-naïve patients aged 65 years or older with CLL or SLL. The median age was 73 years. Patients were randomized one-to-one to receive either 420 mg of Imbruvica 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 Imbruvica if such treatment was indicated, and 43 patients did so.

The median duration of treatment was 17.4 months with Imbruvica and 7.1 months with chlorambucil. At the time of study completion, 87 percent of patients in the Imbruvica 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, compared with chlorambucil, Imbruvica led to an 84 percent reduction in the risk of progression or death; investigators calculated that risk reduction as 91 percent. At a median follow-up of 18.4 months, the median PFS was not yet reached with Imbruvica versus 19 months with chlorambucil .The median 18-month PFS rates were 94 percent and 45 percent, respectively, and the results were consistent across subgroups.

The hazard ratio for OS was 0.16 with Imbruvica versus chlorambucil. The 24-month OS rates were 98 percent versus 85 percent, respectively.

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

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

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

Rates of sustained hematologic improvements were 84 percent with Imbruvica versus 45 percent with chlorambucil in patients with baseline anemia, and were, respectively, 77 percent versus 43 percent in patients with thrombocytopenia.

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 Imbruvica, 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 percent with Imbruvica and in 2 percent with chlorambucil. There were three deaths in the Imbruvica arm and 17 in the chlorambucil arm.

Imbruvica was previously approved by the FDA for pretreated treated CLL, pretreated mantle cell lymphoma and Waldenström's macroglobulinemia.

"The [Imbruvica] story gets better and better. The results of RESONATE-2 demonstrate how [Imbruvica] can change the treatment strategies for many patients with CLL in the treatment-naïve setting. We anticipate this approval will give clinicians and more of their patients the opportunity to explore the efficacy and safety of treatment with [Imbruvica] for this disease," said Peter F. Lebowitz, Global Oncology Head, Janssen, which codevelops Imbruvica with AbbVie.


  1. Tedeschi A, Barr PM, Robak T, et al. Results from the international, randomized phase 3 study of ibrutinib versus chlorambucil in patients 65 years and older with treatment-naïve CLL/SLL (RESONATE-2). Presented at: the 57th Annual Meeting of the American Society of Hematology; Orlando, Florida; December 5-8, 2015. Abstract 495.
  2. 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. doi: 10.1056/NEJMoa1509388.
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