Adding ibrutinib to standard bendamustine and rituximab (BR) reduced the risk of disease progression by 80% compared with BR plus placebo in patients with pretreated CLL or SLL.
Asher Chanan-Khan, MD
Adding ibrutinib (Imbruvica) to standard bendamustine and rituximab (BR) reduced the risk of disease progression by 80% compared with BR plus placebo in patients with pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to results from the phase III HELIOS study.
The significant progression-free survival (PFS) benefit was determined during an interim analysis in March 2015, at which point the study was unblinded and patients receiving placebo were allowed to cross over to the ibrutinib arm.
“This becomes one of the most important changing points in the history of CLL, where the treatment of CLL patients will no longer be BR, but BR with ibrutinib,” lead study author Asher Chanan-Khan, MD, a professor of Medicine at Mayo Clinic, said when presenting the HELIOS data during a press briefing at the 2015 ASCO Annual Meeting.
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 (HR = 0.203; 95% CI, 0.150-0.276; P <.0001). The PFS benefit held up across subgroups of high-risk patients.
Commenting on the PFS data, Chanan-Khan said, “You cannot get a better hazard ratio than this. It brings a lot of joy to see such an impactful therapy altering the course of the disease so early…The [PFS] curves started to differentiate 4 months into analysis and that is a great testament of how soon the impact of this regimen was.”
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). Chanan-Khan said the crossover to the ibrutinib arm that was allowed when the trial was unblinded confounded the OS data.
The toxicity profile was similar between the two study arms, and the adverse events (AEs) in the triplet arm were consistent with previously reported safety outcomes for ibrutinib and BR. “The side effect profile was very tolerable and expected for each of the individual drugs that was in this regimen,” said Chanan-Khan.
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.
Ibrutinib is an irreversible small-molecule inhibitor of BTK and works by blocking B-cell activation and signaling, preventing the growth of malignant B cells that overexpress BTK.
The FDA initially approved Ibrutinib in November 2013 for patients with MCL following at least one prior therapy. In February 2014, the FDA approved ibrutinib for patients with previously treated CLL, which was then followed by a full FDA approval and a new indication for high-risk patients with 17p deletions in July 2014.
The full approval and expanded indication were based on data from the phase III RESONATE study, in which ibrutinib lowered the risk of progression by 75% in patients with CLL who harbored a 17p deletion and by 78% in the full population of the study when compared with ofatumumab (Arzerra). At 12 months, the OS rate was 90% for patients treated with ibrutinib compared with 81% in the ofatumumab group. The median OS was not reached for patients treated with ibrutinib (HR = 0.43; 95% CI, 0.24-0.79; P = .005).
Ibrutinib was also granted an indication for ibrutinib Waldenström’s macroglobulinemia in January 2015.
Janssen Research & Development, a subsidiary of Johnson & Johnson, funded the HELIOS trial. Janssen developed ibrutinib in collaboration with Pharmacyclics, which recently became a wholly-owned subsidiary of AbbVie in a multibillion-dollar acquisition.
Pharmacyclics announced in a press release that the full HELIOS data would be submitted to regulatory authorities for future ibrutinib labeling considerations.
“We knew ibrutinib was an effective single-agent treatment option with an established safety profile and we now have additional evidence suggesting that ibrutinib improves outcomes when combined with existing treatment regimens," HELIOS investigator Simon Rule, MD, consultant hematologist, Department of Hematology, and Head of the Lymphoma Service, Derriford Hospital in the United Kingdom, said in the press release. “The results from the HELIOS trial are very encouraging for previously-treated patients with CLL or SLL and suggest that the ibrutinib combination may be an option for these patients moving forward.”
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).