FDA Updates Label of Imbruvica to Affirm Efficacy in Chronic Lymphocytic Leukemia


The FDA expanded the label for Imbruvica for some patients with CLL, as the drug continues to show improved survival benefits.

The label of Imbruvica (ibrutinib) was recently expanded by the FDA to include overall survival (OS) results in treatment-naïve patients with chronic lymphocytic leukemia (CLL) and outcomes with the BTK inhibitor when combined with Treanda (bendamustine) and rituximab (BR) in relapsed/refractory patients with CLL.

Imbruvica is now also approved for the treatment of patients with small lymphocytic lymphoma (SLL), regardless of whether or not they harbor a 17p deletion, according to AbbVie, which co-develops Imbruvica with Janssen Biotech.

The survival benefit with frontline Imbruvica was demonstrated in the phase 3 RESONATE-2 trial, in which the agent reduced the risk of death by 56 percent versus Leukeran (chlorambucil). The Imbruvica plus BR data were from the phase 3 HELIOS trial, in which the triplet reduced the risk of disease progression or death by 80 percent versus BR alone.

“This update helps to affirm the established efficacy, safety and tolerability of this therapy for treatment of patients with CLL/SLL, both as a monotherapy or in combination with other agents,” RESONATE-2 lead investigator Jan Burger, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, said in a statement. “It reflects the growing body of clinical evidence supporting this therapy as a potential treatment option for people living with CLL/SLL."


The RESONATE-2 trial was the basis for the FDA’s March 2016 approval of Imbruvica for the treatment of patients with CLL in the first-line setting.

The trial included 269 treatment-naïve patients aged 65 years and older with CLL or SLL. The median age was 73 years. Patients were randomized 1-1 to receive either 420 mg of Imbruvica daily until progression or 0.5 to 0.8 mg/kg of Leukeran on days one 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 Leukeran 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 Leukeran. At the time of study completion, 87 percent of patients in the Imbruvica arm remained on therapy.

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

The IRC found that, compared with Leukeran, 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 Leukeran. The median 18-month PFS rates were 94 percent and 45 percent, respectively, and the results were consistent across subgroups.

The now reported 56 percent reduction in the risk of death with Imbruvica came at a median follow-up of 28.1 months and included 41 percent of patients in the Leukeran arm who crossed over at progression to receive Imbruvica.

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

Adverse events (AEs), 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 Leukeran, 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.


The double-blind phase 3 HELIOS trial randomized 578 previously treated patients with measurable relapsed/refractory CLL/SLL to BR for a maximum of six cycles plus either placebo (289 patients) or 420 mg/day of Imbruvica (289 patients). The full six cycles of BR were completed by 83 percent and 78 percent of patients in the Imbruvica and placebo arms, respectively.

The median patient age was 64 years and patients had received an average of two prior therapies. Patients with 17p deletions (more than 20 percent of cells) were not included in the study.

The study was powered to detect a hazard ratio of 0.70 with a P value of .025 for significance. PFS was the primary outcome measure, with secondary endpoints focused on overall survival (OS) and objective response rate (ORR).

The interim analysis was conducted following 50 percent of events. At the time of the review, 31 percent (90 patients) of patients had progressed on placebo and crossed over to the Imbruvica arm, as allowed by the study design.

At a median follow-up of 17.2 months, PFS with Imbruvica was not yet reached, as compared with 13.3 months for patients receiving BR alone. The PFS benefit held up across subgroups of high-risk patients.

ORR was 82.7 percent in the Imbruvica arm versus 67.8 percent in the control group. Complete response (CR) rates (including CR with incomplete blood count recovery) were 10.4 percent versus 2.8 percent with Imbruvica versus placebo, respectively.

The OS analysis showed a nonsignificant 37 percent reduction in the risk of death.

The toxicity profile was similar between the two study arms, and the AEs in the triplet arm were consistent with previously reported safety outcomes for Imbruvica and BR. The most frequently reported all-grade AEs in the Imbruvica versus the placebo arm were neutropenia (58.2 percent vs 54.7 percent), nausea (36.9 percent vs 35.2 percent), diarrhea (35.5 percent vs 23.7 percent), thrombocytopenia (30.7 percent vs. 24.4 percent), pyrexia (24.7 percent vs. 22 percent), anemia (22.6 percent vs 28.9 percent), and fatigue (21.6 percent vs 22.6 percent). Neutropenia (53.7 percent vs 50.5 percent) and thrombocytopenia (15.0 percent in each arm) were the most commonly reported grade 3/4 AEs.

Rates of grade 1/2 bleeding were higher in the triplet versus the BR-alone arm, including hematoma (8 percent vs 1 percent), contusion (7.7 percent vs 3.1 percent), epistaxis (5.9 percent vs 3.1 percent), ecchymosis (3.1 percent vs 0.7 percent), and petechiae (2.8 percent vs 0.3 percent).

Grade 3 or higher hemorrhage occurred in 3.8 percent of patients receiving the triplet, compared with 1.7 percent for those receiving BR alone. Grade 3/4 major hemorrhage and atrial fibrillation rates were 2.1 percent versus 1.7 percent and 2.8 percent versus 0.7 percent in the Imbruvica versus placebo arms, respectively. AEs led to treatment discontinuation in 14.2 percent and 11.8 percent of patients in the triplet and control arms, respectively.

“We are pleased the FDA has added the survival data observed with Imbruvica as a first-line therapy for CLL to its prescribing information and that the indication has been expanded to include patients with SLL. Moreover, the positive results seen in the HELIOS study provide additional evidence supporting the compelling safety and efficacy seen with Imbruvica in CLL and SLL patients,” Danelle James, head of Oncology at Pharmacyclics, a division of Abbie, said in statement. "We believe the Imbruvica label is very strong for the treatment of certain hematologic malignancies and is now reinforced not only by data evaluating its use as a single agent, but also in combination with other commonly used chemotherapy regimens."

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