New Drug Application Submitted for Leukemia Treatment

Approval sought for Imbruvica combination for patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

Patients fighting leukemia may soon have a treatment option available to them.

The FDA last week accepted a supplemental new drug application (NDA) for ibrutinib (Imbruvica) in combination with bendamustine and rituximab for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The BTK inhibitor is co-developed by to AbbVie and Janssen Biotech.

The NDA application follows the phase 3 HELIOS study, which evaluated the addition of ibrutinib to standard rituximab therapy. The combination was found to decrease disease progression risk by 80% compared with rituximab plus placebo in patients with pretreated CLL or SLL.

"The [HELIOS] data confirm the therapy's ability to enhance the effectiveness of a commonly used treatment option in these patients when it is added to the bendamustine and rituximab combination,” said HELIOS investigator Simon Rule, MD, consultant haematologist at the Department of Haematology, and head of the Lymphoma Service, Derriford Hospital, United Kingdom.

The double-blind trial randomized 578 previously treated patients with measurable relapsed/refractory CLL/SLL to rituximab for a maximum of 6 cycles plus either placebo (n = 289) or ibrutinib at 420 mg/day of (n = 289).

The median age of patients in the trial was 64 years. Those enrolled in the trial were previously treated with an average of 2 prior therapies, while those with 17p deletions (>20% of cells) were not included in. The primary outcome measure was progression free survival (PFS), with secondary endpoints for overall survival (OS) and objective response rate (ORR).

The 6 rituximab cycles were completed by 83% of patients in the ibrutinib group and 78% of patients in the placebo group. At the time of review following 50% of events, 31% (n = 90) of patients progressed on placebo and were switched to the ibrutinib therapy group.

At 17.2 months, PFS with ibrutinib was not reached, compared with 13.3 months among patients administered rituximab alone (HR, 0.203; 95% CI, 0.150-0.276; P <.0001). PFS was consistent across the different subgroups of high-risk patients.

ORR was 82.7% in the ibrutinib group compared with 67.8% in the control group (P <.0001). Meanwhile, the complete response rates, which includes complete response with incomplete blood count recovery, were 10.4% in the ibrutinib group compared with 2.8% on placebo.

The results showed a nonsignificant 37% reduction in the risk of death. However, patients moved from the placebo treatment group to the ibrutinib arm when the trial was unblinded may have affected OS data.

The toxicity profile was similar between both treatment groups, while adverse events in the triplet arm were consistent with safety outcomes previously reported for ibrutinib and rituximab.

The most common all-grade adverse events in the ibrutinib versus placebo arms 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%), respectively.

Adverse events led to the discontinuation of treatment in 14.2% and 11.8% of patients in the triplet and control arms, respectively.

Ibrutinib was approved in November 2013 for patients with mantle cell lymphoma following at least 1 prior therapy. The drug received another approval in February 2014 for patients with previously treated CLL, which was preceded a full approval and a new indication of ibrutinib for high-risk patients with 17p deletions in July 2014.

A supplemental new drug application was also submitted for ibrutinib for treatment-naive patients with CLL who are over 65 years of age.

"We are dedicated to fully understanding the utility of Imbruvica and have several studies underway designed to evaluate the impact of the therapy as a single agent and in combination in a number of blood cancers,” said Erik von Borcke, president of Pharmacyclics, an AbbVie Company. Ultimately, our goal for Imbruvica is to be a treatment option that extends the lives of patients across a variety of types of cancers.”