FDA Approval Sought for Frontline Ibrutinib in CLL

A supplemental new drug application has been submitted for the BTK inhibitor ibrutinib (Imbruvica) as a therapy for treatment-naive patients with chronic lymphocytic leukemia (CLL) who are over the age of 65, according to a statement from the company developing the BTK inhibitor, AbbVie.

The application was based on findings from the phase III RESONATE-2 trial, which demonstrated superior outcomes with ibrutinib compared with chlorambucil in untreated patients with CLL. Although exact data were not yet released, AbbVie announced that ibrutinib had improved progression-free survival (PFS), overall survival (OS), and overall response rates (ORR) compared with chlorambucil in the study.

The endpoints and design of the RESONATE-2 trial were established under a special protocol assessment with the FDA, which suggests that findings from the study will be sufficient for approval. Under the Prescription Drug User Fee Act, the FDA is scheduled to review the application within 60 days, at which point the agency will assign a review deadline. Data have been submitted for publication and presentation at an upcoming medical conference.

"This submission highlights the expanded potential and strong value of Imbruvica as a treatment for CLL," Erik von Borcke, president of Pharmacyclics, which is owned by AbbVie, said in a statement. "We are pleased treatment-naïve patients may soon have an alternative to traditional cytotoxic chemotherapy."

The phase III RESONATE-2 trial enrolled 269 treatment-naïve patients with CLL and small lymphocytic lymphoma who were aged 65 or older. Those with high-risk characteristics, such as the 17p deletion, were excluded from the study, given a lack of benefit for chlorambucil in this setting. The primary endpoint of the study was PFS, with OS and ORR as secondary outcome measures.

Patients were randomized in a 1:1 ratio to ibrutinib at 420 mg once daily or chlorambucil, which was administered on days 1 and 15 at a starting dose of 0.5 mg/kg in cycle 1 and increased by increments of 0.1 mg/kg based on tolerability until a maximum dose of 0.8 mg/kg was reached.

"We are very excited by the findings from RESONATE-2 and look forward to sharing the results from what we see as a potentially transformative study for CLL patients," Danelle James, MD, MS, Head of Oncology at Pharmacyclics, said in a statement when the results were announced. "These results from the first Imbruvica study for front-line CLL patients may support future treatment paradigms where some CLL patients requiring therapy may not need to be exposed to traditional cytotoxic chemotherapy."

In a subpopulation of the phase Ib/II PCYC-1102-CA study, single-agent ibrutinib demonstrated impressive activity in 31 untreated patients aged ≥65 years with CLL. When including lymphocytosis, which is common with BTK inhibition, the ORR was 84%, with a 10% stable disease rate. This included a 23% complete response rate.

After a median time on study of 35.2 months, the median PFS and OS were not yet reached. At 30 months, the estimated PFS rate was 96% (95% CI, 76.5-99.5) and the estimated OS rate was 97% (95% CI, 78-99.5).

Findings from this study were the basis for establishing the phase III RESONATE-2 study. Additionally, data from a group of patients with CLL in the PCYC-1102-CA trial who received at least one prior therapy (n = 48) were the basis for an accelerated approval for the drug in February 2014, which was followed by a full approval and a new indication for high-risk patients with 17p deletions in July 2014, based on the phase III RESONATE trial.

Prior to the CLL indications, the FDA initially grated an accelerated approval to ibrutinib as a treatment for patients with mantle cell lymphoma (MCL) who had received at least one prior therapy in November 2013. In late January 2015, the FDA expanded this indication to include the treatment of patients with Waldenström’s macroglobulinemia.

In March 2015, Abbvie announced the acquisition of Pharmacyclics, the developer of ibrutinib. Under the terms of the agreement, AbbVie paid $261.25 per share for Pharmacyclics, which totaled $20.2 billion. When the deal closed in late May 2015, von Borcke, the former head of Global Marketing at AbbVie, was made the president for Pharmacyclics.

Prior to the acquisition, AbbVie's lead cancer agent was the Bcl-2 inhibitor venetoclax (ABT-199), which is in late-stage development in collaboration with Genentech. Additionally, the company is developing the PI3 kinase inhibitor duvelisib. Both investigational agents are being explored in similar settings as ibrutinib.

"Over the past several years we've made tremendous progress in treating CLL, thanks in part to therapies such as Imbruvica," Richard A. Gonzalez, chairman of the Board and chief executive officer at AbbVie, said in a statement. "Based on the results from RESONATE-2, Imbruvica continues to demonstrate its strong value and we are very optimistic that it will eventually move into the frontline treatment setting, becoming an alternative option to chemotherapy for previously untreated CLL patients."

In a preclinical study presented at the 2014 ASH Annual Meeting, the combination of ABT-199 and ibrutinib had activity in circulating tumor cells from patients with CLL and MCL. In this analysis, the combination induced cellular apoptosis in 23% of samples compared with 3.8% for single-agent ibrutinib and 3.0% with ABT-199. Clinical trials assessing the combination are planned.

Ibrutinib, as a single agent or in combinations, is the topic of extensive clinical trials across a number of settings, including 13 phase III clinical trials. Within the next year, AbbVie anticipates new indications for ibrutinib in the first-line setting for patients with MCL and CLL. Additionally, within the next 3-5 years, indications are anticipated in diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.