FDA Updates Ibrutinib CLL Label With New OS, Combo Data

The FDA has expanded the label of ibrutinib (Imbruvica) to include overall survival results in treatment-naive patients with chronic lymphocytic leukemia, as well as outcomes with the BTK inhibitor when combined with bendamustine and rituximab in relapsed/refractory patients with CLL.

Jan Burger, MD, PhD

The FDA has expanded the label of ibrutinib (Imbruvica) to include overall survival (OS) results in treatment-naive patients with chronic lymphocytic leukemia (CLL), as well as outcomes with the BTK inhibitor when combined with bendamustine and rituximab (BR) in relapsed/refractory patients with CLL.

Ibrutinib 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 codevelops ibrutinib with Janssen Biotech.

The survival benefit with frontline ibrutinib was demonstrated in the phase III RESONATE-2 trial, in which the agent reduced the risk of death by 56% versus chlorambucil (HR, 0.44; 95% CI, 0.21-0.92).1 The ibrutinib plus BR data were from the phase III HELIOS trial, in which the triplet reduced the risk of disease progression or death by 80% versus BR alone (HR, 0.20; 95% CI, 0.15-0.28; P <.0001).2


“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, MD, PhD, 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 ibrutinib for the treatment of patients with CLL in the first-line setting.

The trial 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 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 chlorambucil, ibrutinib led to an 84% reduction in the risk of progression or death (HR, 0.16; 95% CI, 0.09-0.28); investigators calculated that risk reduction as 91%. At a median follow-up of 18.4 months, the median PFS was not yet reached with ibrutinib versus 19 months with chlorambucil (P <.0001) .The median 18-month PFS rates were 94% and 45%, respectively, and the results were consistent across subgroups.

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

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.

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 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.The double-blind phase III HELIOS trial randomized 578 previously treated patients with measurable relapsed/refractory CLL/SLL to BR for a maximum of six cycles plus either placebo (n = 289) or 420 mg/day of ibrutinib (n = 289). The full six cycles of BR were completed by 83% and 78% of patients in the ibrutinib 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 (>20% 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% of events. At the time of the review, 31% (n = 90) of patients had progressed on placebo and crossed over to the ibrutinib arm, as allowed by the study design.

At a median follow-up of 17.2 months, PFS with ibrutinib 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% in the ibrutinib arm versus 67.8% in the control group (P <.0001). Complete response (CR) rates (including CR with incomplete blood count recovery) were 10.4% versus 2.8% with ibrutinib versus placebo, respectively.

The OS analysis showed a nonsignificant 37% reduction in the risk of death (P = .0598).

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 ibrutinib and BR. The most frequently reported all-grade AEs in the ibrutinib versus the placebo arm were neutropenia (58.2% vs 54.7%), nausea (36.9% vs 35.2%), diarrhea (35.5% vs 23.7%), thrombocytopenia (30.7% vs. 24.4%), pyrexia (24.7% vs. 22%), anemia (22.6% vs 28.9%), and fatigue (21.6% vs 22.6%). Neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% 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% vs 1%), contusion (7.7% vs 3.1%), epistaxis (5.9% vs 3.1%), ecchymosis (3.1% vs 0.7%), and petechiae (2.8% vs 0.3%).

Grade ≥3 hemorrhage occurred in 3.8% of patients receiving the triplet, compared with 1.7% for those receiving BR alone. Grade 3/4 major hemorrhage and atrial fibrillation rates were 2.1% versus 1.7% and 2.8% versus 0.7% in the ibrutinib versus placebo arms, respectively. AEs led to treatment discontinuation in 14.2% and 11.8% 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, MD, head of Oncology at Pharmacyclics, a division of AbbVie, 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."


  1. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37.
  2. Chanan-Khan AAA, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): first results from a randomized, double-blind, placebo-controlled, phase III study. J Clin Oncol. 2015;33 (suppl; abstr LBA7005).

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