Ibrutinib Regimen Extends PFS in Phase III CLL Study

The phase III HELIOS study examining ibrutinib in combination with bendamustine and rituximab (BR) has been unblinded following the demonstration of a significant extension in progression-free survival (PFS) with the triplet compared with BR alone in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Following the unblinding, patients in the BR arm will be allowed to crossover to receive ibrutinib. Full data from the HELIOS trial were submitted for presentation at the 2015 ASCO Annual Meeting and are being prepared for regulatory submission, according to Pharmacyclics, the company developing ibrutinib.

"We are delighted by the superior efficacy observed in CLL and SLL patients treated with Imbruvica in combination with BR compared to patients in the placebo-controlled BR arm and look forward to sharing these results with the scientific community and US regulators," Danelle James, MD, MS, Head of Oncology at Pharmacyclics, said in a statement.

The phase III HELIOS study enrolled 578 previously treated patients with measurable relapsed/refractory CLL/SLL. Patients with 17p deletions were excluded from the study. All patients received BR for a maximum of 6 cycles with placebo or ibrutinib at 420 mg/day.

The study began enrolling patients in October 2012 and completed in February 2014. It was powered to detect a hazard ratio of 0.70 with a P value of .025 for significance. The interim analysis was conducted following 50% of events. The primary endpoint of the study was PFS, with secondary measures focused on overall survival (OS) and objective response rate (ORR).

In a preceding phase Ib study, the combination of ibrutinib with BR resulted in an estimated 12-month PFS of 90% in 30 patients with relapsed/refractory CLL/SLL. The ORR with the combination was 93%. The median treatment duration was 16 months. There were 5 complete responses.

"These results build upon early results in the phase I/II program and are very encouraging as we continue to explore the benefits Imbruvica provides to patients when it is combined with other treatments," James said, regarding the findings from HELIOS.

Pharmacyclics noted that unexpected side effects were not demonstrated with the ibrutinib combination in the phase III study. The most common all-grade adverse events with the combination in the phase Ib study were diarrhea (70%), nausea (66.7%), fatigue (46.7%), neutropenia (40%) and upper respiratory tract infection (36.7%). The most common grade 3/4 adverse events were neutropenia (40.0%), maculopapular rash and fatigue (10.0% each), and thrombocytopenia, febrile neutropenia, and cellulitis (6.7% each).

The FDA initially approved ibrutinib for patients with MCL who received at least one prior therapy in November 2013. Ibrutinib was approved for patients with previously treated CLL in February 2014, which was followed by a full FDA approval and a new indication for high-risk patients with 17p deletions in July 2014. In late January 2015, the FDA expanded this indication to include the treatment of patients with Waldenström’s macroglobulinemia.

The full approval for ibrutinib in CLL was based on data from the phase III RESONATE study. In this analysis, treatment with 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. 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).

"The phase III RESONATE study demonstrated significant progression-free and overall survival benefits in relapsed or refractory CLL patients against the current standard of care," lead investigator John C. Byrd, MD, from The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital & Richard J. Solove Research Institute, said when the data were presented in June 2014. "The survival improvements seen with use of ibrutinib in this study are particularly encouraging as we look toward its potential for use in patients with difficult-to-treat disease."

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.

On March 5, 2015, AbbVie announced plans to acquire Pharmacyclics for up to $21 billion. Through the acquisition, AbbVie will take control of several clinical trials, including 13 phase III clinical trials. The transaction was approved by both companies and is expected to complete in mid-2015, pending regulatory approvals.