Today, Pharmacyclics LLC announced the results of the Phase III HELIOS trial (CLL3001), which found that patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who received ibrutinib (IMBRUVICA®) in combination with bendamustine and rituximab (BR) experienced an 80% reduction in the risk of progression or death compared to patients receiving placebo in combination with BR. Patients also experienced a higher overall response rate (ORR, a key secondary endpoint), including achieving a higher rate of complete responses (CR), after a median follow-up of 17 months.
These data will be presented in an oral, late-breaking abstract session by lead investigator Asher Chanan-Khan, M.D., Mayo Clinic, Jacksonville, FL during the Leukemia, Myelodysplasia, and Transplantation track at 2:27 p.m. CT today at the 51st American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL.* IMBRUVICA is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.
On March 16th, an independent data monitoring committee (IDMC) unanimously recommended that the HELIOS trial be unblinded based on clinically meaningful and statistically significant treatment benefit observed in the ibrutinib arm compared to placebo+BR.
"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," said Simon Rule, M.D., Consultant Haematologist, Department of Haematology and Head of the Lymphoma Service, Derriford Hospital, Plymouth, UK and HELIOS study investigator.* "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."
HELIOS is a Janssen-sponsored, randomized, double-blind, placebo-controlled, international, multicenter Phase III study conducted in 21 countries, which evaluated the safety and efficacy of ibrutinib+BR in 578 patients with relapsed/refractory CLL/SLL who had received at least one prior therapy. Patients were randomized to receive either the combination of oral, once-daily ibrutinib 420 mg and six cycles of BR, or a matching regimen of oral, once-daily placebo and six cycles of BR. Treatment with ibrutinib or placebo continued until disease progression or unacceptable toxicity.
PFS was the primary endpoint of the study, as assessed by an independent review committee (IRC). At 18 months, IRC-assessed PFS rates were 79% for patients in the ibrutinib+BR arm compared with 24% for patients in the placebo+BR arm. Key secondary endpoints included IRC-assessed ORR and overall survival (OS). At a median follow-up of 17 months, PFS was significantly longer with ibrutinib+BR versus placebo+BR (median not reached vs. 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P<0.0001). Patients with the genetic mutation del 17p CLL were excluded from the study, but PFS rates were consistent across all other high-risk subgroups. Patients in the ibrutinib+BR arm experienced higher rates of ORR and CR/CRi (CR with incomplete hematopoietic recovery), 82.7% and 10.4%, respectively, compared to patients in the placebo+BR arm, 67.8% and 2.8%, respectively. The median OS has not yet been reached after a median follow up of 17 months.
Six cycles of BR were completed in the majority of patients in the ibrutinib and placebo arms (83% and 78%, respectively). The safety profile of ibrutinib+BR was consistent with the known individual safety profiles for the therapies. The addition of ibrutinib had no impact on the ability of BR to be administered in patients, with a similar number of BR cycles administered in both arms of the study.
"HELIOS demonstrated that when added, ibrutinib enhanced the treatment effect of standard bendamustine and rituximab treatment, resulting in a significant improvement in the outcomes for CLL and SLL patients, reducing the risk of progression or death by 80% compared to BR alone," said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. "These findings support our belief that ibrutinib can become the backbone of CLL therapy."
The most common adverse events (AEs ≥20%) of all Grades in the HELIOS trial were neutropenia (58.2% in the ibrutinib+BR arm vs. 54.7% in the placebo+BR arm); 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%). The most common Grade 3/4 AEs ( ≥15%) were neutropenia (53.7% vs. 50.5%) and thrombocytopenia (15% in both arms). Higher rates of Grade 1/2 bleeding such as 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%) were observed in patients taking ibrutinib+BR, compared with those in the placebo+BR arm. Rates of Grade 3 or greater hemorrhage were 3.8% versus 1.7%, respectively. Rates of treatment-emergent Grade 3/4 atrial fibrillation and hemorrhage were 2.8% vs. 0.7% and 2.1% vs. 1.7%, respectively. The incidence of most AEs was similar between both arms.
Ninety patients (31%) in the placebo+BR arm with confirmed progressive disease crossed over to receive ibrutinib, as permitted in the protocol. AEs were the primary reason for discontinuation in patients taking ibrutinib+BR (14.2% vs. 11.8% in patients taking placebo+BR).
A full study report will be submitted to health authorities for future labeling considerations and will also be submitted to a peer-reviewed journal for potential publication.